1,666 results on '"Peterson, Kirk A."'
Search Results
2. Plakophilin 2 gene therapy prevents and rescues arrhythmogenic right ventricular cardiomyopathy in a mouse model harboring patient genetics
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Bradford, William H., Zhang, Jing, Gutierrez-Lara, Erika J., Liang, Yan, Do, Aryanne, Wang, Tsui-Min, Nguyen, Lena, Mataraarachchi, Nirosh, Wang, Jie, Gu, Yusu, McCulloch, Andrew, Peterson, Kirk L., and Sheikh, Farah
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- 2023
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3. Modern Basis Sets Across the Periodic Table
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Hill, J. Grant, primary and Peterson, Kirk A., additional
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- 2024
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4. A molecular ground electronic state with an occupied 5g spinor—The superheavy (E125)F molecule.
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Peterson, Kirk A. and Malli, Gulzari L.
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IONIZATION energy , *SPINORS , *ELECTRONS , *ATOMS , *MOLECULES - Abstract
Fully relativistic calculations, primarily at the 4-component coupled-cluster singles and doubles with perturbative triples [CCSD(T)] level of theory with the Dirac–Coulomb (DC) Hamiltonian, have been carried out for the superheavy (E125)F molecule using large Gaussian basis sets. The electronic ground state is determined to have an [Og]8s25g16f3 configuration on E125 with an Ω = 6 ground state and an 8p electron largely donated to F. A Mulliken population analysis indicates that the ground state is mainly ionic with a partial charge of +0.79 on E125 and a single sigma bond involving the F 2p and E125 8p spinors. The occupied g spinor is not involved in the bonding. With the largest basis set used in this work, the (0 K) dissociation energy was calculated at the DC-CCSD(T) level of theory to be 7.02 eV. Analogous calculations were also carried out for the E125 atom, both the neutral and its cation. The lowest energy electron configuration of E125+, [Og] 8 s 1 / 2 2 5 g 7 / 2 1 6 f 5 / 2 3 with a J = 6 ground state, was found to be similar to that in (E125)F, while the neutral E125 atom has an [Og] 8 s 1 / 2 2 5 g 7 / 2 1 6 f 5 / 2 2 7 d 3 / 2 1 8 p 1 / 2 1 ground state electron configuration with a J = 17/2 ground state. The ionization energy (IE) of E125 is reported for the first time and is calculated to be 4.70 eV at the DC-CCSD(T) level of theory. Non-relativistic calculations were also carried out on the E125 atom and the (E125)F molecule. The non-relativistic ground state of the E125 atom was calculated to have a 5g5 ground state with an IE of just 3.4 eV. The net effect of relativity on (E125)F is to stabilize its bonding. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Constitutive protein kinase G activation exacerbates stress-induced cardiomyopathy.
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Schwaerzer, Gerburg, Casteel, Darren, Cividini, Federico, Kalyanaraman, Hema, Zhuang, Shunhui, Gu, Yusu, Dalton, Nancy, Peterson, Kirk, Dillmann, Wolfgang, Boss, Gerry, and Pilz, Renate
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cGMP-dependent protein kinase ,cardiac hypertrophy ,fibrosis ,phosphorylation of sarcomeric proteins ,stress-induced dilated cardiomyopathy ,Angiotensin II ,Animals ,Cardiomyopathies ,Cyclic GMP-Dependent Protein Kinase Type I ,Cyclic GMP-Dependent Protein Kinases ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myocytes ,Cardiac ,Ventricular Remodeling - Abstract
BACKGROUND AND PURPOSE: Heart failure is associated with high morbidity and mortality, and new therapeutic targets are needed. Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventricular remodelling and cardiac dysfunction in the stressed heart. However, clinical trial results have been mixed and the effects of long-term PKG activation in the heart are unknown. EXPERIMENTAL APPROACH: We characterized the cardiac phenotype of mice carrying a heterozygous knock-in mutation of PKG1 (Prkg1R177Q/+ ), which causes constitutive, cGMP-independent activation of the kinase. We examined isolated cardiac myocytes and intact mice, the latter after stress induced by surgical transaortic constriction or angiotensin II (Ang II) infusion. KEY RESULTS: Cardiac myocytes from Prkg1R177Q/+ mice showed altered phosphorylation of sarcomeric proteins and reduced contractility in response to electrical stimulation, compared to cells from wild type mice. Under basal conditions, young PKG1R177Q/+ mice exhibited no obvious cardiac abnormalities, but aging animals developed mild increases in cardiac fibrosis. In response to angiotensin II infusion or fixed pressure overload induced by transaortic constriction, young PKGR177Q/+ mice exhibited excessive hypertrophic remodelling with increased fibrosis and myocyte apoptosis, leading to increased left ventricular dilation and dysfunction compared to wild type litter mates. CONCLUSION AND IMPLICATIONS: Long-term PKG1 activation in mice may be harmful to the heart, especially in the presence of pressure overload and neurohumoral stress. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
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- 2022
6. PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle
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Wu, Tongbin, Liang, Zhengyu, Zhang, Zengming, Liu, Canzhao, Zhang, Lunfeng, Gu, Yusu, Peterson, Kirk L, Evans, Sylvia M, Fu, Xiang-Dong, and Chen, Ju
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Heart Disease ,Genetics ,Cardiovascular ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,DNA-Binding Proteins ,Heart Ventricles ,Mice ,Mice ,Knockout ,Myocardium ,Myocytes ,Cardiac ,Transcription Factors ,cardiomyopathies ,chromatin immunoprecipitation sequencing ,gene expression regulation ,RNA-Seq ,transcriptome ,Cardiorespiratory Medicine and Haematology ,Public Health and Health Services ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences ,Sports science and exercise - Abstract
BackgroundLeft ventricular noncompaction cardiomyopathy (LVNC) was discovered half a century ago as a cardiomyopathy with excessive trabeculation and a thin ventricular wall. In the decades since, numerous studies have demonstrated that LVNC primarily has an effect on left ventricles (LVs) and is often associated with LV dilation and dysfunction. However, in part because of the lack of suitable mouse models that faithfully mirror the selective LV vulnerability in patients, mechanisms underlying the susceptibility of LVs to dilation and dysfunction in LVNC remain unknown. Genetic studies have revealed that deletions and mutations in PRDM16 (PR domain-containing 16) cause LVNC, but previous conditional Prdm16 knockout mouse models do not mirror the LVNC phenotype in patients, and the underlying molecular mechanisms by which PRDM16 deficiency causes LVNC are still unclear.MethodsPrdm16 cardiomyocyte-specific knockout (Prdm16cKO) mice were generated and analyzed for cardiac phenotypes. RNA sequencing and chromatin immunoprecipitation deep sequencing were performed to identify direct transcriptional targets of PRDM16 in cardiomyocytes. Single-cell RNA sequencing in combination with spatial transcriptomics was used to determine cardiomyocyte identity at the single-cell level.ResultsCardiomyocyte-specific ablation of Prdm16 in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients. PRDM16 functioned mechanistically as a compact myocardium-enriched transcription factor that activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium. Consequently, Prdm16cKO LV compact myocardial cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes or neurons. Chamber-specific transcriptional regulation by PRDM16 was attributable in part to its cooperation with LV-enriched transcription factors Tbx5 and Hand1.ConclusionsThese results demonstrate that disruption of proper specification of compact cardiomyocytes may play a key role in the pathogenesis of LVNC. They also shed light on underlying mechanisms of the LV-restricted transcriptional program governing LV chamber growth and maturation, providing a tangible explanation for the susceptibility of LV in a subset of LVNC cardiomyopathies.
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- 2022
7. Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy
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Liang, Yan, Lyon, Robert C, Pellman, Jason, Bradford, William H, Lange, Stephan, Bogomolovas, Julius, Dalton, Nancy D, Gu, Yusu, Bobar, Marcus, Lee, Mong-Hong, Iwakuma, Tomoo, Nigam, Vishal, Asimaki, Angeliki, Scheinman, Melvin, Peterson, Kirk L, and Sheikh, Farah
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Cardiovascular ,Heart Disease ,Rare Diseases ,Biotechnology ,Genetics ,2.1 Biological and endogenous factors ,Adaptor Proteins ,Signal Transducing ,Animals ,Arrhythmogenic Right Ventricular Dysplasia ,COP9 Signalosome Complex ,Desmosomes ,Disease Models ,Animal ,Female ,Humans ,Male ,Mice ,Mice ,Knockout ,Proteolysis ,Proteome ,Cardiology ,Muscle Biology ,Ubiquitin-proteosome system ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Dysregulated protein degradative pathways are increasingly recognized as mediators of human disease. This mechanism may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication, as destabilization/breakdown of the desmosomal proteome is a hallmark of genetic-based desmosomal-targeted diseases, such as the cardiac disease arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here, we uncovered a cardiac constitutive photomorphogenesis 9 (COP9) desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricted neddylation and targeted desmosomal proteome degradation. CSN6 binding, localization, levels, and function were affected in hearts of classic mouse and human models of ARVD/C affected by desmosomal loss and mutations, respectively. Loss of desmosomal proteome degradation control due to junctional reduction/loss of CSN6 and human desmosomal mutations destabilizing junctional CSN6 were also sufficient to trigger ARVD/C in mice. We identified a desmosomal resident regulatory complex that restricted desmosomal proteome degradation and disease.
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- 2021
8. Joint survey of the experimental high-resolution spectra of H16O37Cl and H16O35Cl with a reanalysis of the [formula omitted] band
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Ecseri, Gábor, Simkó, Irén, Furtenbacher, Tibor, Rácsai, Balázs, Fusina, Luciano, Di Lonardo, Gianfranco, Peterson, Kirk A., and Császár, Attila G.
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- 2023
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9. Cardiomyocyte Expression of ZO-1 Is Essential for Normal Atrioventricular Conduction but Does Not Alter Ventricular Function
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Zhang, Jianlin, Vincent, Kevin P, Peter, Angela K, Klos, Matthew, Cheng, Hongqiang, Huang, Selina M, Towne, Jordan K, Ferng, Debbie, Gu, Yusu, Dalton, Nancy D, Chan, Yunghang, Li, Ruixia, Peterson, Kirk L, Chen, Ju, McCulloch, Andrew D, Knowlton, Kirk U, and Ross, Robert S
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Heart Disease ,Cardiovascular ,1.1 Normal biological development and functioning ,Underpinning research ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Atrioventricular Block ,Atrioventricular Node ,Cadherins ,Connexins ,Male ,Mice ,Myocytes ,Cardiac ,NAV1.5 Voltage-Gated Sodium Channel ,Ventricular Function ,Vinculin ,Zonula Occludens-1 Protein ,alpha Catenin ,atrioventricular block ,conduction system ,coxsackie adenovirus receptor ,myocytes ,cardiac ,vinculin ,zonula occludens ,myocytes ,cardiac ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology - Abstract
RationaleZO-1 (Zonula occludens-1), a plasma membrane-associated scaffolding protein regulates signal transduction, transcription, and cellular communication. Global deletion of ZO-1 in the mouse is lethal by embryonic day 11.5. The function of ZO-1 in cardiac myocytes (CM) is largely unknown.ObjectiveTo determine the function of CM ZO-1 in the intact heart, given its binding to other CM proteins that have been shown instrumental in normal cardiac conduction and function.Methods and resultsWe generated ZO-1 CM-specific knockout (KO) mice using α-Myosin Heavy Chain-nuclear Cre (ZO-1cKO) and investigated physiological and electrophysiological function by echocardiography, surface ECG and conscious telemetry, intracardiac electrograms and pacing, and optical mapping studies. ZO-1cKO mice were viable, had normal Mendelian ratios, and had a normal lifespan. Ventricular morphometry and function were not significantly different between the ZO-1cKO versus control (CTL) mice, basally in young or aged mice, or even when hearts were subjected to hemodynamic loading. Atrial mass was increased in ZO-1cKO. Electrophysiological and optical mapping studies indicated high-grade atrioventricular (A-V) block in ZO-1cKO comparing to CTL hearts. While ZO-1-associated proteins such as vinculin, connexin 43, N-cadherin, and α-catenin showed no significant change with the loss of ZO-1, Connexin-45 and Coxsackie-adenovirus (CAR) proteins were reduced in atria of ZO-1cKO. Further, with loss of ZO-1, ZO-2 protein was increased significantly in ventricular CM in a presumed compensatory manner but was still not detected in the AV nodal myocytes. Importantly, the expression of the sodium channel protein NaV1.5 was altered in AV nodal cells of the ZO-1cKO versus CTL.ConclusionsZO-1 protein has a unique physiological role in cardiac nodal tissue. This is in alignment with its known interaction with CAR and Cx45, and a new function in regulating the expression of NaV1.5 in AV node. Uniquely, ZO-1 is dispensable for function of the working myocardium.
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- 2020
10. A Computational Assessment of Actinide Dioxide Cations AnO2 2+ for An = U to Lr: The Limited Stability Range of the Hexavalent Actinyl Moiety, [OAnO]2+
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Vasiliu, Monica, Jian, Tian, Gibson, John K, Peterson, Kirk A, and Dixon, David A
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Chemical Sciences ,Physical Chemistry ,Inorganic Chemistry ,Physical Chemistry (incl. Structural) ,Other Chemical Sciences ,Inorganic & Nuclear Chemistry ,Inorganic chemistry ,Macromolecular and materials chemistry - Abstract
The isolated gas-phase actinide dioxide dications, AnO22+, were evaluated by DFT and coupled cluster CCSD(T) calculations for 12 actinides, An = U-Lr. CASSCF calculations were used to define the orbitals for the CCSD(T) calculations. The characteristic linear [O═An═O]2+ hexavalent actinyl(VI) was found to be the lowest energy structure for An = U, Np, and Pu, which also form stable actinyl(VI) species in solution and possibly for Am when spin-orbit effects are included. For Am, there is a divalent [AnII(O2)]2+ structure where the dioxygen is an end-on physisorbed η1-3O2 2 kcal/mol above the actinyl when spin-orbit effects are included which lower the energy of the actinyl structure. For An = Cm, Bk, and Lr, the lowest energy structure is trivalent [AnIII(O2-)]2+ where the dioxygen is a side-on superoxide, η2-O2-. For Cm, the actinyl is close in energy to the ground state when spin-orbit effects are included. For An = Cf, Es, Fm, Md, and No, the lowest energy structure is divalent [AnII(O2)]2+ where the dioxygen is an end-on physisorbed η1-3O2. The relative energies suggest that curyl(VI) and berkelyl(VI), like well-known americyl(VI), might be stabilized by coordinating ligands in condensed phases. The results further indicate that for californyl and beyond, the actinyl(VI) moieties will probably be elusive even using strong donor ligands. The prevalence of low oxidation states (OSs) An(II) and An(III) for transplutonium actinides reflects stabilization of the 5f orbitals and validates established trends, including the remarkably high stability of divalent No. Bond distances and other parameters suggest maximum bond covalency around plutonyl(VI), with a particularly substantial decrease in bond strength between americyl(VI) and curyl(VI).
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- 2020
11. A Computational Assessment of Actinide Dioxide Cations AnO22+ for An = U to Lr: The Limited Stability Range of the Hexavalent Actinyl Moiety, [O═An═O]2.
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Vasiliu, Monica, Jian, Tian, Gibson, John K, Peterson, Kirk A, and Dixon, David A
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Inorganic Chemistry ,Physical Chemistry ,Other Chemical Sciences ,Inorganic & Nuclear Chemistry ,Physical Chemistry (incl. Structural) - Abstract
The isolated gas-phase actinide dioxide dications, AnO22+, were evaluated by DFT and coupled cluster CCSD(T) calculations for 12 actinides, An = U-Lr. CASSCF calculations were used to define the orbitals for the CCSD(T) calculations. The characteristic linear [O═An═O]2+ hexavalent actinyl(VI) was found to be the lowest energy structure for An = U, Np, and Pu, which also form stable actinyl(VI) species in solution and possibly for Am when spin-orbit effects are included. For Am, there is a divalent [AnII(O2)]2+ structure where the dioxygen is an end-on physisorbed η1-3O2 2 kcal/mol above the actinyl when spin-orbit effects are included which lower the energy of the actinyl structure. For An = Cm, Bk, and Lr, the lowest energy structure is trivalent [AnIII(O2-)]2+ where the dioxygen is a side-on superoxide, η2-O2-. For Cm, the actinyl is close in energy to the ground state when spin-orbit effects are included. For An = Cf, Es, Fm, Md, and No, the lowest energy structure is divalent [AnII(O2)]2+ where the dioxygen is an end-on physisorbed η1-3O2. The relative energies suggest that curyl(VI) and berkelyl(VI), like well-known americyl(VI), might be stabilized by coordinating ligands in condensed phases. The results further indicate that for californyl and beyond, the actinyl(VI) moieties will probably be elusive even using strong donor ligands. The prevalence of low oxidation states (OSs) An(II) and An(III) for transplutonium actinides reflects stabilization of the 5f orbitals and validates established trends, including the remarkably high stability of divalent No. Bond distances and other parameters suggest maximum bond covalency around plutonyl(VI), with a particularly substantial decrease in bond strength between americyl(VI) and curyl(VI).
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- 2020
12. Activation of Water by Pentavalent Actinide Dioxide Cations: Characteristic Curium Revealed by a Reactivity Turn after Americium
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Jian, Tian, Dau, Phuong Diem, Shuh, David K, Vasiliu, Monica, Dixon, David A, Peterson, Kirk A, and Gibson, John K
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Inorganic Chemistry ,Chemical Sciences ,CSD-46-All CSGB ,Physical Chemistry (incl. Structural) ,Other Chemical Sciences ,Inorganic & Nuclear Chemistry ,Inorganic chemistry ,Macromolecular and materials chemistry - Abstract
Swapping of an oxygen atom of water with that of a pentavalent actinide dioxide cation, AnO2+ also called an "actinyl", requires activation of an An-O bond. It was previously found that such oxo exchange in the gas phase occurs for the first two actinyls, PaO2+ and UO2+, but not the next two, NpO2+ and PuO2+. The An-O bond dissociation energies (BDEs) decrease from PaO2+ to PuO2+, such that the observation of a parallel decrease in the An-O bond reactivity is intriguing. To elucidate oxo exchange, we here extend experimental studies to AmO2+, americyl(V), and CmO2+, curyl(V), which were produced in remarkable abundance by electrospray ionization of Am3+ and Cm3+ solutions. Like other AnO2+, americyl(V) and curyl(V) adsorb up to four H2O molecules to form tetrahydrates AnO2(H2O)4+ with the actinide hexacoordinated by oxygen atoms. It was found that AmO2+ does not oxo-exchange, whereas CmO2+ does, establishing a "turn" to increasing the reactivity from americyl to curyl, which validates computational predictions. Because oxo exchange occurs via conversion of an actinyl(V) hydrate, AnO2(H2O)+, to an actinide(V) hydroxide, AnO(OH)2+, it reflects the propensity for actinyl(V) hydrolysis: PaO2+ hydrolyzes and oxo-exchanges most easily, despite the fact that it has the highest BDE of all AnO2+. A reexamination of the computational results for actinyl(V) oxo exchange reveals distinctive properties and chemistry of curyl(V) species, particularly CmO(OH)2+.
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- 2019
13. miR-486 is modulated by stretch and increases ventricular growth.
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Lange, Stephan, Banerjee, Indroneal, Carrion, Katrina, Serrano, Ricardo, Habich, Louisa, Kameny, Rebecca, Lengenfelder, Luisa, Dalton, Nancy, Meili, Rudolph, Börgeson, Emma, Peterson, Kirk, Ricci, Marco, Lincoln, Joy, Ghassemian, Majid, Fineman, Jeffery, Del Álamo, Juan, and Nigam, Vishal
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Cardiology ,Cardiovascular disease ,Cell Biology ,Noncoding RNAs ,Proteomics ,Animals ,Animals ,Newborn ,Biomechanical Phenomena ,Cell Proliferation ,Cells ,Cultured ,Heart Ventricles ,Humans ,Hypoplastic Left Heart Syndrome ,Mechanotransduction ,Cellular ,Mice ,MicroRNAs ,Myocytes ,Cardiac ,STAT1 Transcription Factor ,Sheep - Abstract
Perturbations in biomechanical stimuli during cardiac development contribute to congenital cardiac defects such as hypoplastic left heart syndrome (HLHS). This study sought to identify stretch-responsive pathways involved in cardiac development. miRNA-Seq identified miR-486 as being increased in cardiomyocytes exposed to cyclic stretch in vitro. The right ventricles (RVs) of patients with HLHS experienced increased stretch and had a trend toward higher miR-486 levels. Sheep RVs dilated from excessive pulmonary blood flow had 60% more miR-486 compared with control RVs. The left ventricles of newborn mice treated with miR-486 mimic were 16.9%-24.6% larger and displayed a 2.48-fold increase in cardiomyocyte proliferation. miR-486 treatment decreased FoxO1 and Smad signaling while increasing the protein levels of Stat1. Stat1 associated with Gata-4 and serum response factor (Srf), 2 key cardiac transcription factors with protein levels that increase in response to miR-486. This is the first report to our knowledge of a stretch-responsive miRNA that increases the growth of the ventricle in vivo.
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- 2019
14. Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B12 analog.
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Schwaerzer, Gerburg K, Kalyanaraman, Hema, Casteel, Darren E, Dalton, Nancy D, Gu, Yusu, Lee, Seunghoe, Zhuang, Shunhui, Wahwah, Nisreen, Schilling, Jan M, Patel, Hemal H, Zhang, Qian, Makino, Ayako, Milewicz, Dianna M, Peterson, Kirk L, Boss, Gerry R, and Pilz, Renate B
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Aorta ,Thoracic ,Myocytes ,Smooth Muscle ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Marfan Syndrome ,Aneurysm ,Dissecting ,Aortic Aneurysm ,Thoracic ,Disease Models ,Animal ,Cobamides ,Acetylcysteine ,Free Radical Scavengers ,Echocardiography ,Oxidative Stress ,Female ,Male ,Gene Knock-In Techniques ,HEK293 Cells ,Primary Cell Culture ,Cyclic GMP-Dependent Protein Kinase Type I ,Gain of Function Mutation ,Aorta ,Thoracic ,Myocytes ,Smooth Muscle ,Transgenic ,Aneurysm ,Dissecting ,Aortic Aneurysm ,Disease Models ,Animal - Abstract
People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1R177Q/+ aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B12-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.
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- 2019
15. Nexilin Is a New Component of Junctional Membrane Complexes Required for Cardiac T-Tubule Formation
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Liu, Canzhao, Spinozzi, Simone, Chen, Jia-Yu, Fang, Xi, Feng, Wei, Perkins, Guy, Cattaneo, Paola, Guimarães-Camboa, Nuno, Dalton, Nancy D, Peterson, Kirk L, Wu, Tongbin, Ouyang, Kunfu, Fu, Xiang-Dong, Evans, Sylvia M, and Chen, Ju
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Medical Physiology ,Biomedical and Clinical Sciences ,Rare Diseases ,Cardiovascular ,Genetics ,Heart Disease ,Aetiology ,2.1 Biological and endogenous factors ,Underpinning research ,1.1 Normal biological development and functioning ,Animals ,Calcium Channels ,L-Type ,Cardiomyopathy ,Dilated ,Cell Membrane ,Cells ,Cultured ,Intercellular Junctions ,Mice ,Mice ,Knockout ,Mice ,Transgenic ,Microfilament Proteins ,Muscle Fibers ,Skeletal ,Myocytes ,Cardiac ,cardiomyopathy ,junctional membrane complexes ,T-tubule ,membrane contact sites ,T-tubule ,membrane contact sites ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Public Health and Health Services ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences ,Sports science and exercise - Abstract
BackgroundMembrane contact sites are fundamental for transmission and translation of signals in multicellular organisms. The junctional membrane complexes in the cardiac dyads, where transverse (T) tubules are juxtaposed to the sarcoplasmic reticulum, are a prime example. T-tubule uncoupling and remodeling are well-known features of cardiac disease and heart failure. Even subtle alterations in the association between T-tubules and the junctional sarcoplasmic reticulum can cause serious cardiac disorders. NEXN (nexilin) has been identified as an actin-binding protein, and multiple mutations in the NEXN gene are associated with cardiac diseases, but the precise role of NEXN in heart function and disease is still unknown.MethodsNexn global and cardiomyocyte-specific knockout mice were generated. Comprehensive phenotypic and RNA sequencing and mass spectrometry analyses were performed. Heart tissue samples and isolated single cardiomyocytes were analyzed by electron and confocal microscopy.ResultsGlobal and cardiomyocyte-specific loss of Nexn in mice resulted in a rapidly progressive dilated cardiomyopathy. In vivo and in vitro analyses revealed that NEXN interacted with junctional sarcoplasmic reticulum proteins, was essential for optimal calcium transients, and was required for initiation of T-tubule invagination and formation.ConclusionsThese results demonstrated that NEXN is a pivotal component of the junctional membrane complex and is required for initiation and formation of T-tubules, thus providing insight into mechanisms underlying cardiomyopathy in patients with mutations in NEXN.
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- 2019
16. Gas Phase Hydrolysis and Oxo‐Exchange of Actinide Dioxide Cations: Elucidating Intrinsic Chemistry from Protactinium to Einsteinium
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Vasiliu, Monica, Gibson, John K, Peterson, Kirk A, and Dixon, David A
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Inorganic Chemistry ,Chemical Sciences ,Physical Chemistry ,actinides ,computational chemistry ,ion-molecule reactions ,reaction mechanisms ,transuranium elements ,General Chemistry ,Chemical sciences - Abstract
Gas-phase bimolecular reactions of metal cations with water provide insights into intrinsic characteristics of hydrolysis. For the actinide dioxide cations, actinyl(V) AnO2 + , melding of experiment and computation provides insights into trends for hydrolysis, as well as for oxo-exchange between actinyls and water that proceeds by a hydrolysis pathway. Here this line of inquiry is further extended into the actinide series with CCSD(T) computations of potential energy surfaces, for the reaction pathway for oxo-exchange through hydrolysis of nine actinyl(V) ions, from PaO2 + to EsO2 + . The computed surfaces are in accord with previous experimental results for oxo-exchange, and furthermore predict spontaneous exchange for CmO2 + , BkO2 + , CfO2 + and EsO2 + , but not for AmO2 + . Natural Bond Order analysis of the species involved in both hydrolysis and oxo-exchange reveals an inverse correlation between the barrier to hydrolysis and the charge on the actinide centre, q(An). Based on this correlation, it can be concluded that hydrolysis, and related phenomena such as oxo-exchange, become less favourable as the charge on the metal centre decreases. The new results provide a straightforward rationalization of trends across a wide swathe of the actinide series.
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- 2019
17. Combinatorial interactions of genetic variants in human cardiomyopathy.
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Deacon, Dekker C, Happe, Cassandra L, Chen, Chao, Tedeschi, Neil, Manso, Ana Maria, Li, Ting, Dalton, Nancy D, Peng, Qian, Farah, Elie N, Gu, Yusu, Tenerelli, Kevin P, Tran, Vivien D, Chen, Ju, Peterson, Kirk L, Schork, Nicholas J, Adler, Eric D, Engler, Adam J, Ross, Robert S, and Chi, Neil C
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Extracellular Matrix ,Myocytes ,Cardiac ,Pluripotent Stem Cells ,Animals ,Humans ,Mice ,Cardiomyopathy ,Dilated ,Genetic Predisposition to Disease ,Pedigree ,Gene Expression Regulation ,Up-Regulation ,Muscle Contraction ,Inheritance Patterns ,Models ,Biological ,Female ,Male ,Genetic Variation ,Cardiovascular ,Stem Cell Research ,Rare Diseases ,Heart Disease ,Biotechnology ,Human Genome ,Genetics ,2.1 Biological and endogenous factors - Abstract
Dilated cardiomyopathy (DCM) is a leading cause of morbidity and mortality worldwide; yet how genetic variation and environmental factors impact DCM heritability remains unclear. Here, we report that compound genetic interactions between DNA sequence variants contribute to the complex heritability of DCM. By using genetic data from a large family with a history of DCM, we discovered that heterozygous sequence variants in the TROPOMYOSIN 1 (TPM1) and VINCULIN (VCL) genes cose-gregate in individuals affected by DCM. In vitro studies of patient-derived and isogenic human-pluripotent-stem-cell-derived cardio-myocytes that were genome-edited via CRISPR to create an allelic series of TPM1 and VCL variants revealed that cardiomyocytes with both TPM1 and VCL variants display reduced contractility and sarcomeres that are less organized. Analyses of mice genetically engineered to harbour these human TPM1 and VCL variants show that stress on the heart may also influence the variable penetrance and expressivity of DCM-associated genetic variants in vivo. We conclude that compound genetic variants can interact combinatorially to induce DCM, particularly when influenced by other disease-provoking stressors.
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- 2019
18. Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids.
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Yeang, Calvin, Hasanally, Devin, Que, Xuchu, Hung, Ming-Yow, Stamenkovic, Aleksandra, Chan, David, Chaudhary, Rakesh, Margulets, Victoria, Edel, Andrea L, Hoshijima, Masahiko, Gu, Yusu, Bradford, William, Dalton, Nancy, Miu, Phuong, Cheung, David Yc, Jassal, Davinder S, Pierce, Grant N, Peterson, Kirk L, Kirshenbaum, Lorrie A, Witztum, Joseph L, Tsimikas, Sotirios, and Ravandi, Amir
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Heart Disease - Coronary Heart Disease ,Heart Disease ,Cardiovascular ,Animals ,Cell Death ,Cells ,Cultured ,Disease Models ,Animal ,Male ,Membrane Proteins ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mitochondria ,Heart ,Mitochondrial Proteins ,Myocardial Infarction ,Myocardial Reperfusion Injury ,Myocytes ,Cardiac ,Oxidation-Reduction ,Oxidative Stress ,Phospholipids ,Rats ,Sprague-Dawley ,Receptors ,LDL ,Signal Transduction ,Single-Chain Antibodies ,Oxidized phospholipids center dot Coronary artery disease center dot Myocardial infarction center dot Ischaemic heart disease center dot Ischaemia-reperfusion injury center dot Mass spectrometry - Abstract
Aims:Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results:OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P
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- 2019
19. A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure.
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Pollak, Adam J, Liu, Canzhao, Gudlur, Aparna, Mayfield, Joshua E, Dalton, Nancy D, Gu, Yusu, Chen, Ju, Heller Brown, Joan, Hogan, Patrick G, Wiley, Sandra E, Peterson, Kirk L, and Dixon, Jack E
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Sarcoplasmic Reticulum ,Endoplasmic Reticulum ,Myocytes ,Cardiac ,Animals ,Humans ,Mice ,Calcium ,Phosphotransferases ,Calcium-Binding Proteins ,Calsequestrin ,Extracellular Matrix Proteins ,Calcium Signaling ,Phosphorylation ,Homeostasis ,Heart Failure ,Secretory Pathway ,Stromal Interaction Molecule 1 ,Stim 1 ,biochemistry ,calcium ,calsequestrin 2 ,chemical biology ,heart disease ,mouse ,protein kinase ,Biochemistry and Cell Biology - Abstract
Ca2+ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmic reticulum (SR) proteins involved in Ca2+ signaling have been shown to be phosphorylated, the biochemical and physiological roles of protein phosphorylation within the lumen of the SR remain essentially uncharacterized. Our laboratory recently identified an atypical protein kinase, Fam20C, which is uniquely localized to the secretory pathway lumen. Here, we show that Fam20C phosphorylates several SR proteins involved in Ca2+ signaling, including calsequestrin2 and Stim1, whose biochemical activities are dramatically regulated by Fam20C mediated phosphorylation. Notably, phosphorylation of Stim1 by Fam20C enhances Stim1 activation and store-operated Ca2+ entry. Physiologically, mice with Fam20c ablated in cardiomyocytes develop heart failure following either aging or induced pressure overload. We extended these observations to show that non-muscle cells lacking Fam20C display altered ER Ca2+ signaling. Overall, we show that Fam20C plays an overarching role in ER/SR Ca2+ homeostasis and cardiac pathophysiology.
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- 2018
20. Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.
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Que, Xuchu, Hung, Ming-Yow, Yeang, Calvin, Gonen, Ayelet, Prohaska, Thomas A, Sun, Xiaoli, Diehl, Cody, Määttä, Antti, Gaddis, Dalia E, Bowden, Karen, Pattison, Jennifer, MacDonald, Jeffrey G, Ylä-Herttuala, Seppo, Mellon, Pamela L, Hedrick, Catherine C, Ley, Klaus, Miller, Yury I, Glass, Christopher K, Peterson, Kirk L, Binder, Christoph J, Tsimikas, Sotirios, and Witztum, Joseph L
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Macrophages ,Peritoneal ,Animals ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Mice ,Fatty Liver ,Aortic Valve Stenosis ,Hypercholesterolemia ,Disease Progression ,Inflammation ,Phosphorylcholine ,Cholesterol ,Lipoproteins ,LDL ,Phospholipids ,Immunoglobulin M ,Receptors ,LDL ,Apoptosis ,Oxidation-Reduction ,Female ,Atherosclerosis ,Single-Chain Antibodies ,Macrophages ,Peritoneal ,Inbred C57BL ,Transgenic ,Lipoproteins ,LDL ,Receptors ,General Science & Technology - Abstract
Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis.
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- 2018
21. Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages
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Moore-Morris, Thomas, Cattaneo, Paola, Guimarães-Camboa, Nuno, Bogomolovas, Julius, Cedenilla, Marta, Banerjee, Indroneal, Ricote, Mercedes, Kisseleva, Tatiana, Zhang, Lunfeng, Gu, Yusu, Dalton, Nancy D, Peterson, Kirk L, Chen, Ju, Pucéat, Michel, and Evans, Sylvia M
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Cardiovascular ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Animals ,Bone Marrow Cells ,Bone Marrow Transplantation ,Cell Lineage ,Cells ,Cultured ,Collagen Type I ,Mice ,Mice ,Inbred C57BL ,Myocardial Infarction ,Myofibroblasts ,Pericardium ,bone marrow ,fibroblasts ,fibrosis ,heart diseases ,myocardial infarction ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology - Abstract
RATIONALE:Myocardial infarction is a major cause of adult mortality worldwide. The origin(s) of cardiac fibroblasts that constitute the postinfarct scar remain controversial, in particular the potential contribution of bone marrow lineages to activated fibroblasts within the scar. OBJECTIVE:The aim of this study was to establish the origin(s) of infarct fibroblasts using lineage tracing and bone marrow transplants and a robust marker for cardiac fibroblasts, the Collagen1a1-green fluorescent protein reporter. METHODS AND RESULTS:Using genetic lineage tracing or bone marrow transplant, we found no evidence for collagen-producing fibroblasts derived from hematopoietic or bone marrow lineages in hearts subjected to permanent left anterior descending coronary artery ligation. In fact, fibroblasts within the infarcted area were largely of epicardial origin. Intriguingly, collagen-producing fibrocytes from hematopoietic lineages were observed attached to the epicardial surface of infarcted and sham-operated hearts in which a suture was placed around the left anterior descending coronary artery. CONCLUSIONS:In this controversial field, our study demonstrated that the vast majority of infarct fibroblasts were of epicardial origin and not derived from bone marrow lineages, endothelial-to-mesenchymal transition, or blood. We also noted the presence of collagen-producing fibrocytes on the epicardial surface that resulted at least in part from the surgical procedure.
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- 2018
22. Remarkably High Stability of Late Actinide Dioxide Cations: Extending Chemistry to Pentavalent Berkelium and Californium
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Dau, Phuong D, Vasiliu, Monica, Peterson, Kirk A, Dixon, David A, and Gibson, John K
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Inorganic Chemistry ,Chemical Sciences ,Physical Chemistry ,actinides ,density functional calculations ,gas-phase reactions ,redox chemistry ,transuranium elements ,General Chemistry ,Chemical sciences - Abstract
Actinyl chemistry is extended beyond Cm to BkO2+ and CfO2+ through transfer of an O atom from NO2 to BkO+ or CfO+ , establishing a surprisingly high lower limit of 73 kcal mol-1 for the dissociation energies, D[O-(BkO+ )] and D[O-(CfO+ )]. CCSD(T) computations are in accord with the observed reactions, and characterize the newly observed dioxide ions as linear pentavalent actinyls; these being the first Bk and Cf species with oxidation states above IV. Computations of actinide dioxide cations AnO2+ for An=Pa to Lr reveal an unexpected minimum for D[O-(CmO+ )]. For CmO2+ , and AnO2+ beyond EsO2+ , the most stable structure has side-on bonded η2 -(O2 ), as AnIII peroxides for An=Cm and Lr, and as AnII superoxides for An=Fm, Md, and No. It is predicted that the most stable structure of EsO2+ is linear [O=EsV =O]+ , einsteinyl, and that FmO2+ and MdO2+ , like CmO2+ , also have actinyl(V) structures as local energy minima. The results expand actinide oxidation state chemistry, the realm of the distinctive actinyl moiety, and the non-periodic character towards the end of the periodic table.
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- 2017
23. Toward a W4-F12 approach: Can explicitly correlated and orbital-based ab initio CCSD(T) limits be reconciled?
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Sylvetsky, Nitai, Peterson, Kirk A., Karton, Amir, and Martin, Jan M. L.
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Physics - Chemical Physics ,Physics - Computational Physics - Abstract
In the context of high-accuracy computational thermochemistry, the valence CCSD correlation component of molecular atomization energies present the most severe basis set convergence problem, followed by the (T) component. In the present paper, we make a detailed comparison, for an expanded version of the W4-11 thermochemistry benchmark, between on the one hand orbital-based CCSD/AV{5,6}Z+d and CCSD/ACV{5,6}Z extrapolation, and on the other hand CCSD-F12b calculations with cc-pVQZ-F12 and cc-pV5Z-F12 basis sets. This latter basis set, now available for H--He, B--Ne, and Al--Ar, is shown to be very close to the basis set limit. Apparent differences (which can reach 0.35 kcal/mol for systems like CCl4) between orbital-based and CCSD-F12b basis set limits disappear if basis sets with additional radial flexibility, such as ACV{5,6}Z, are used for the orbital calculation. Counterpoise calculations reveal that, while TAEs with V5Z-F12 basis sets are nearly free of BSSE, orbital calculations have significant BSSE even with AV(6+d)Z basis sets, leading to non-negligible differences between raw and counterpoise-corrected extrapolated limits. This latter problem is greatly reduced by switching to ACV{5,6}Z core-valence basis sets, or simply adding an additional zeta to just the valence orbitals. Previous reports that all-electron approaches like HEAT lead to different CCSD(T) limits than valence limit+CV correction approaches like FPD and W4 theory can be rationalized in terms of the greater radial flexibility of core-valence basis sets. W4-F12 is found to agree slightly better than W4 with ATcT (active thermochemical tables) data, at a substantial saving in CPU time and especially I/O overhead. A W4-F12 calculation on benzene is presented as a proof of concept., Comment: Journal of Chemical Physics, in press
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- 2016
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24. Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
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Fang, Xi, Bogomolovas, Julius, Wu, Tongbin, Zhang, Wei, Liu, Canzhao, Veevers, Jennifer, Stroud, Matthew J, Zhang, Zhiyuan, Ma, Xiaolong, Mu, Yongxin, Lao, Dieu-Hung, Dalton, Nancy D, Gu, Yusu, Wang, Celine, Wang, Michael, Liang, Yan, Lange, Stephan, Ouyang, Kunfu, Peterson, Kirk L, Evans, Sylvia M, and Chen, Ju
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Biological Sciences ,Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease ,Rare Diseases ,Genetics ,Cardiovascular ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Adaptor Proteins ,Signal Transducing ,Animals ,Apoptosis Regulatory Proteins ,Cardiomyopathies ,Coculture Techniques ,Echocardiography ,HSP70 Heat-Shock Proteins ,Heart Failure ,Heat-Shock Proteins ,Kaplan-Meier Estimate ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Molecular Chaperones ,Mutation ,Myocytes ,Cardiac ,Phenotype ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure.
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- 2017
25. Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo
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Guimarães-Camboa, Nuno, Cattaneo, Paola, Sun, Yunfu, Moore-Morris, Thomas, Gu, Yusu, Dalton, Nancy D, Rockenstein, Edward, Masliah, Eliezer, Peterson, Kirk L, Stallcup, William B, Chen, Ju, and Evans, Sylvia M
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Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research ,Regenerative Medicine ,Transplantation ,Underpinning research ,1.1 Normal biological development and functioning ,Adipocytes ,Aging ,Cell Lineage ,Cicatrix ,Fibroblasts ,Gene Expression Regulation ,Developmental ,Green Fluorescent Proteins ,Humans ,Integrases ,Mesenchymal Stem Cells ,Muscle Development ,Muscle ,Smooth ,Vascular ,Myocytes ,Smooth Muscle ,Neurons ,Organ Specificity ,Pericytes ,Phenotype ,Receptor ,Platelet-Derived Growth Factor beta ,T-Box Domain Proteins ,lineage tracing ,mesenchymal stem cells ,mural cells ,pericytes ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Pericytes are widely believed to function as mesenchymal stem cells (MSCs), multipotent tissue-resident progenitors with great potential for regenerative medicine. Cultured pericytes isolated from distinct tissues can differentiate into multiple cell types in vitro or following transplantation in vivo. However, the cell fate plasticity of endogenous pericytes in vivo remains unclear. Here, we show that the transcription factor Tbx18 selectively marks pericytes and vascular smooth muscle cells in multiple organs of adult mouse. Fluorescence-activated cell sorting (FACS)-purified Tbx18-expressing cells behaved as MSCs in vitro. However, lineage-tracing experiments using an inducible Tbx18-CreERT2 line revealed that pericytes and vascular smooth muscle cells maintained their identity in aging and diverse pathological settings and did not significantly contribute to other cell lineages. These results challenge the current view of endogenous pericytes as multipotent tissue-resident progenitors and suggest that the plasticity observed in vitro or following transplantation in vivo arises from artificial cell manipulations ex vivo.
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- 2017
26. Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy
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Fang, Xi, Stroud, Matthew J, Ouyang, Kunfu, Fang, Li, Zhang, Jianlin, Dalton, Nancy D, Gu, Yusu, Wu, Tongbin, Peterson, Kirk L, Huang, Hsien-Da, Chen, Ju, and Wang, Nanping
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Medical Physiology ,Biomedical and Clinical Sciences ,Diabetes ,Heart Disease ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,3T3 Cells ,Adipocytes ,Animals ,Cardiomegaly ,Cells ,Cultured ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,MicroRNAs ,Myocytes ,Cardiac ,PPAR gamma ,Rosiglitazone ,TOR Serine-Threonine Kinases ,Thiazolidinediones ,Tuberous Sclerosis Complex 1 Protein ,Tumor Suppressor Proteins ,Biomedical and clinical sciences ,Health sciences - Abstract
Adipose tissue is a key endocrine organ that governs systemic homeostasis. PPARγ is a master regulator of adipose tissue signaling that plays an essential role in insulin sensitivity, making it an important therapeutic target. The selective PPARγ agonist rosiglitazone (RSG) has been used to treat diabetes. However, adverse cardiovascular effects have seriously hindered its clinical application. Experimental models have revealed that PPARγ activation increases cardiac hypertrophy. RSG stimulates cardiac hypertrophy and oxidative stress in cardiomyocyte-specific PPARγ knockout mice, implying that RSG might stimulate cardiac hypertrophy independently of cardiomyocyte PPARγ. However, candidate cell types responsible for RSG-induced cardiomyocyte hypertrophy remain unexplored. Utilizing cocultures of adipocytes and cardiomyocytes, we found that stimulation of PPARγ signaling in adipocytes increased miR-200a expression and secretion. Delivery of miR-200a in adipocyte-derived exosomes to cardiomyocytes resulted in decreased TSC1 and subsequent mTOR activation, leading to cardiomyocyte hypertrophy. Treatment with an antagomir to miR-200a blunted this hypertrophic response in cardiomyocytes. In vivo, specific ablation of PPARγ in adipocytes was sufficient to blunt hypertrophy induced by RSG treatment. By delineating mechanisms by which RSG elicits cardiac hypertrophy, we have identified pathways that mediate the crosstalk between adipocytes and cardiomyocytes to regulate cardiac remodeling.
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- 2016
27. The cc-pV5Z-F12 basis set: reaching the basis set limit in explicitly correlated calculations
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Peterson, Kirk A., Kesharwani, Manoj Kumar, and Martin, Jan M. L.
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Physics - Chemical Physics ,Physics - Computational Physics - Abstract
We have developed and benchmarked a new extended basis set for explicitly correlated calculations, namely cc-pV5Z-F12. It is offered in two variants, cc-pV5Z-F12 and cc- pV5Z-F12(rev2), the latter of which has additional basis functions on hydrogen not present in the cc-pVnZ-F12 (n=D,T,Q) sequence.A large uncontracted 'reference' basis set is used for benchmarking. cc-pVnZ-F12 (n=D, T, Q, 5) is shown to be a convergent hierarchy. Especially the cc- pV5Z-F12(rev2) basis set can yield the valence CCSD component of total atomization energies (TAEs), without any extrapolation, to an accuracy normally associated with aug-cc-pV{5,6}Z extrapolations. SCF components are functionally at the basis set limit, while the MP2 limit can be approached to as little as 0.01 kcal/mol without extrapolation. The determination of (T) appears to be the most difficult of the three components and cannot presently be accomplished without extrapolation or scaling. (T) extrapolation from cc-pV{T,Q}Z-F12 basis sets, combined with CCSD-F12b/cc-pV5Z-F12 calculations appears to be an accurate combination for explicitly correlated thermochemistry. For accurate work on noncovalent interactions, basis set superposition error with the cc-pV5Z-F12 basis set is shown to be so small that counterpoise corrections can be neglected for all but the most exacting purposes., Comment: Molecular Physics, in press (Nicholas C. Handy memorial issue). DOI preassigned
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- 2014
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28. Probing Antioxidant-Related Properties for Phenolic Compounds.
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Soares, Iuri N., Peterson, Kirk A., and de Souza, Gabriel L. C.
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- 2024
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29. Desmosomal junctions are necessary for adult sinus node function
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Mezzano, Valeria, Liang, Yan, Wright, Adam T, Lyon, Robert C, Pfeiffer, Emily, Song, Michael Y, Gu, Yusu, Dalton, Nancy D, Scheinman, Melvin, Peterson, Kirk L, Evans, Sylvia M, Fowler, Steven, Cerrone, Marina, McCulloch, Andrew D, and Sheikh, Farah
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Cardiovascular ,Heart Disease ,Aetiology ,2.1 Biological and endogenous factors ,Action Potentials ,Age Factors ,Animals ,Atrial Function ,Biological Clocks ,Cells ,Cultured ,Connexins ,Desmoplakins ,Desmosomes ,Genetic Predisposition to Disease ,Heart Rate ,Humans ,Mice ,Knockout ,Mutation ,Myocytes ,Cardiac ,Phenotype ,Sick Sinus Syndrome ,Sinoatrial Node ,Time Factors ,Desmosome ,Sinus node dysfunction ,Physiology ,function ,Arrhythmia ,Heart rate variability ,Physiology/function - Abstract
AimsCurrent mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbour desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown.Methods and resultsTo determine the role of desmosomes in pacemaker function, we generated a novel mouse model harbouring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line. Hcn4-Cre targets cells of the adult mouse sinoatrial node (SAN) and can ablate DSP expression in the adult DSP csKO SAN resulting in specific loss of desmosomal proteins and structures. Dysregulation of DSP via loss-of-function (adult DSP csKO mice) and mutation (clinical case of a patient harbouring a pathogenic DSP variant) in mice and man, respectively, revealed that desmosomal dysregulation is associated with a primary phenotype of increased sinus pauses/dysfunction in the absence of cardiomyopathy. Underlying defects in beat-to-beat regulation were also observed in DSP csKO mice in vivo and intact atria ex vivo. DSP csKO SAN exhibited migrating lead pacemaker sites associated with connexin 45 loss. In vitro studies exploiting ventricular cardiomyocytes that harbour DSP loss and concurrent early connexin loss phenocopied the loss of beat-to-beat regulation observed in DSP csKO mice and atria, extending the importance of DSP-associated mechanisms in driving beat-to-beat regulation of working cardiomyocytes.ConclusionWe provide evidence of a mechanism that implicates an essential role for desmosomes in cardiac pacemaker function, which has broad implications in better understanding mechanisms underlying beat-to-beat regulation as well as sinus node disease and dysfunction.
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- 2016
30. Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure
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Zhang, Zhiyuan, Mu, Yongxin, Veevers, Jennifer, Peter, Angela K, Manso, Ana Maria, Bradford, William H, Dalton, Nancy D, Peterson, Kirk L, Knowlton, Kirk U, Ross, Robert S, Zhou, Xinmin, and Chen, Ju
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Medical Physiology ,Biomedical and Clinical Sciences ,Genetics ,Cardiovascular ,Heart Disease ,1.1 Normal biological development and functioning ,Underpinning research ,Age Factors ,Animals ,Cardiomyopathies ,Cytoskeletal Proteins ,Disease Progression ,Down-Regulation ,Fibrosis ,Gene Expression Regulation ,Developmental ,Genetic Predisposition to Disease ,Gestational Age ,Heart Failure ,Hypertrophy ,Left Ventricular ,Integrin beta1 ,Mice ,Knockout ,Muscle Proteins ,Myocytes ,Cardiac ,Phenotype ,cardiomyopathies ,integrins ,mice ,knockout ,myocytes ,cardiac ,sarcolemma ,myocytes ,cardiac ,Biochemistry and Cell Biology ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Medical physiology - Abstract
BackgroundThe striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in Caenorhabditis elegans and Danio rerio suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined.Methods and resultsThe current studies were designed to investigate the role of Kindlin-2 in the mammalian heart. We generated a series of cardiac myocyte-specific Kindlin-2 knockout mice with excision of the Kindlin-2 gene in either developing or adult cardiac myocytes. We found that mice lacking Kindlin-2 in the early developing heart are embryonic lethal. We demonstrate that deletion of Kindlin-2 at late gestation or in adult cardiac myocytes resulted in heart failure and premature death, which were associated with enlargement of the heart and extensive fibrosis. In addition, integrin β1D protein expression was significantly downregulated in the adult heart.ConclusionsKindlin-2 is required to maintain integrin β1D protein stability. Postnatal loss of Kindlin-2 from cardiac myocytes leads to progressive heart failure, showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function.
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- 2016
31. Notch-independent RBPJ controls angiogenesis in the adult heart.
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Díaz-Trelles, Ramón, Scimia, Maria Cecilia, Bushway, Paul, Tran, Danh, Monosov, Anna, Monosov, Edward, Peterson, Kirk, Rentschler, Stacey, Cabrales, Pedro, Ruiz-Lozano, Pilar, and Mercola, Mark
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Coronary Vessels ,Myocytes ,Cardiac ,Animals ,Humans ,Mice ,Paracrine Communication ,Gene Expression Regulation ,Neovascularization ,Physiologic ,Female ,Male ,Hypoxia-Inducible Factor 1 ,alpha Subunit ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,Microvessels ,HEK293 Cells ,Hypoxia ,Hypoxia-Inducible Factor 1 ,alpha Subunit ,Myocytes ,Cardiac ,Neovascularization ,Physiologic - Abstract
Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury.
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- 2016
32. MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy.
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Lange, Stephan, Gehmlich, Katja, Lun, Alexander S, Blondelle, Jordan, Hooper, Charlotte, Dalton, Nancy D, Alvarez, Erika A, Zhang, Xiaoyu, Bang, Marie-Louise, Abassi, Yama A, Dos Remedios, Cristobal G, Peterson, Kirk L, Chen, Ju, and Ehler, Elisabeth
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Cell Line ,COS Cells ,Animals ,Humans ,Mice ,Escherichia coli ,Cardiomyopathy ,Dilated ,Muscle Proteins ,Nuclear Proteins ,Repressor Proteins ,Signal Transduction ,Gene Expression Regulation ,Male ,Protein Kinase C-alpha ,Heart Failure ,LIM Domain Proteins ,Chlorocebus aethiops ,Cardiomyopathy ,Dilated - Abstract
MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKCα signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKCα. In end-stage DCM, PKCα is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLCβ1. In mice deficient for both MLP and CARP the chronic PKCα signalling chain at the intercalated disc is broken and they remain healthy. Our results suggest that the main role of MLP in heart lies in the direct inhibition of PKCα and that chronic uninhibited PKCα activity at the intercalated disc in the absence of functional MLP leads to heart failure.
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- 2016
33. Selective Life‐Long Skeletal Myofiber—Targeted VEGF Gene Ablation Impairs Exercise Capacity in Adult Mice
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Tang, Kechun, Gu, Yusu, Dalton, Nancy D, Wagner, Harrieth, Peterson, Kirk L, Wagner, Peter D, and Breen, Ellen C
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Heart Disease ,Cardiovascular ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Capillaries ,Exercise Test ,Gene Expression Regulation ,Developmental ,Mice ,Mice ,Knockout ,Muscle Fatigue ,Muscle Fibers ,Skeletal ,Muscle ,Skeletal ,Physical Exertion ,Vascular Endothelial Growth Factor A ,Biochemistry and Cell Biology ,Medical Physiology ,Biochemistry & Molecular Biology - Abstract
Exercise is dependent on adequate oxygen supply for mitochondrial respiration in both cardiac and locomotor muscle. To determine whether skeletal myofiber VEGF is critical for regulating exercise capacity, independent of VEGF function in the heart, ablation of the VEGF gene was targeted to skeletal myofibers (skmVEGF-/-) during embryogenesis (∼ E9.5), leaving intact VEGF expression by all other cells in muscle. In adult mice, VEGF levels were decreased in the soleus (by 65%), plantaris (94%), gastrocnemius (74%), EDL (99%) and diaphragm (64%) (P
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- 2016
34. Coupled Cluster Study of the Heats of Formation of UF6 and the Uranium Oxyhalides, UO2X2 (X = F, Cl, Br, I, and At)
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Andriola, Devon M., primary and Peterson, Kirk A., additional
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- 2023
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35. Joint survey of the experimental high-resolution spectra of H16O37Cl and H16O35 Cl with a reanalysis of the 2ν2 band
- Author
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Ecseri, Gábor, primary, Simkó, Irén, additional, Furtenbacher, Tibor, additional, Rácsai, Balázs, additional, Fusina, Luciano, additional, Di Lonardo, Gianfranco, additional, Peterson, Kirk A., additional, and Császár, Attila G., additional
- Published
- 2023
- Full Text
- View/download PDF
36. Reliable Potential Energy Surfaces for the Reactions of H2O with ThO2, PaO2 +, UO2 2+, and UO2 +
- Author
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Vasiliu, Monica, Peterson, Kirk A, Gibson, John K, and Dixon, David A
- Subjects
Physical Sciences ,Chemical Sciences ,Atomic ,Molecular and Optical Physics ,Physical Chemistry ,Atomic ,Molecular ,Nuclear ,Particle and Plasma Physics ,Physical Chemistry (incl. Structural) ,Theoretical and Computational Chemistry ,Physical chemistry ,Theoretical and computational chemistry ,Atomic ,molecular and optical physics - Abstract
The potential energy surfaces for the reactions of H2O with ThO2, PaO2(+), UO2(2+), and UO2(+) have been calculated at the coupled cluster CCSD(T) level extrapolated to the complete basis set limit with additional corrections including scalar relativistic and spin-orbit. The reactions proceed by the formation of an initial Lewis acid-base adduct (H2O)AnO2(0/+/2+) followed by a proton transfer to generate the dihydroxide AnO(OH)2(0/+/2+). The results are in excellent agreement with mass spectrometry experiments and prior calculations of hydrolysis reactions of the group 4 transition metal dioxides MO2. The differences in the energies of the stationary points on the potential energy surface are explained in terms of the charges on the system and the populations on the metal center. The use of an improved starting point for the coupled cluster CCSD(T) calculations based on density functional theory with the PW91 exchange-correlation functional or Brueckner orbitals is described. The importance of including second-order spin-orbit corrections for closed-shell molecules is also described. These improvements in the calculations are correlated with the 5f populations on the actinide.
- Published
- 2015
37. Reliable Potential Energy Surfaces for the Reactions of H2O with ThO2, PaO2(+), UO2(2+), and UO2(.).
- Author
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Vasiliu, Monica, Peterson, Kirk A, Gibson, John K, and Dixon, David A
- Subjects
Theoretical and Computational Chemistry ,Atomic ,Molecular ,Nuclear ,Particle and Plasma Physics ,Physical Chemistry (incl. Structural) - Abstract
The potential energy surfaces for the reactions of H2O with ThO2, PaO2(+), UO2(2+), and UO2(+) have been calculated at the coupled cluster CCSD(T) level extrapolated to the complete basis set limit with additional corrections including scalar relativistic and spin-orbit. The reactions proceed by the formation of an initial Lewis acid-base adduct (H2O)AnO2(0/+/2+) followed by a proton transfer to generate the dihydroxide AnO(OH)2(0/+/2+). The results are in excellent agreement with mass spectrometry experiments and prior calculations of hydrolysis reactions of the group 4 transition metal dioxides MO2. The differences in the energies of the stationary points on the potential energy surface are explained in terms of the charges on the system and the populations on the metal center. The use of an improved starting point for the coupled cluster CCSD(T) calculations based on density functional theory with the PW91 exchange-correlation functional or Brueckner orbitals is described. The importance of including second-order spin-orbit corrections for closed-shell molecules is also described. These improvements in the calculations are correlated with the 5f populations on the actinide.
- Published
- 2015
38. Normalization of Naxos plakoglobin levels restores cardiac function in mice
- Author
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Zhang, Zhiwei, Stroud, Matthew J, Zhang, Jianlin, Fang, Xi, Ouyang, Kunfu, Kimura, Kensuke, Mu, Yongxin, Dalton, Nancy D, Gu, Yusu, Bradford, William H, Peterson, Kirk L, Cheng, Hongqiang, Zhou, Xinmin, and Chen, Ju
- Subjects
Genetics ,Heart Disease ,Cardiovascular ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Arrhythmias ,Cardiac ,Arrhythmogenic Right Ventricular Dysplasia ,Codon ,Nonsense ,Desmoplakins ,Fibrosis ,Frameshift Mutation ,Gene Knock-In Techniques ,Genes ,Lethal ,Hair Diseases ,Heart Ventricles ,Humans ,Keratoderma ,Palmoplantar ,Mice ,Myocardial Contraction ,Myocardium ,Myocytes ,Cardiac ,Nonsense Mediated mRNA Decay ,Peptide Fragments ,Phenotype ,RNA Stability ,RNA ,Messenger ,Sequence Deletion ,Wnt Signaling Pathway ,gamma Catenin ,Medical and Health Sciences ,Immunology - Abstract
Arrhythmogenic cardiomyopathy (AC) is associated with mutations in genes encoding intercalated disc proteins and ultimately results in sudden cardiac death. A subset of patients with AC have the autosomal recessive cardiocutaneous disorder Naxos disease, which is caused by a 2-base pair deletion in the plakoglobin-encoding gene JUP that results in a truncated protein with reduced expression. In mice, cardiomyocyte-specific plakoglobin deficiency recapitulates many aspects of human AC, and overexpression of the truncated Naxos-associated plakoglobin also results in an AC-like phenotype; therefore, it is unclear whether Naxos disease results from loss or gain of function consequent to the plakoglobin mutation. Here, we generated 2 knockin mouse models in which endogenous Jup was engineered to express the Naxos-associated form of plakoglobin. In one model, Naxos plakoglobin bypassed the nonsense-mediated mRNA decay pathway, resulting in normal levels of the truncated plakoglobin. Moreover, restoration of Naxos plakoglobin to WT levels resulted in normal heart function. Together, these data indicate that a gain of function in the truncated form of the protein does not underlie the clinical phenotype of patients with Naxos disease and instead suggest that insufficiency of the truncated Naxos plakoglobin accounts for disease manifestation. Moreover, these results suggest that increasing levels of truncated or WT plakoglobin has potential as a therapeutic approach to Naxos disease.
- Published
- 2015
39. Mitochondrial Reprogramming Induced by CaMKII&dgr; Mediates Hypertrophy Decompensation
- Author
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Westenbrink, B Daan, Ling, Haiyun, Divakaruni, Ajit S, Gray, Charles BB, Zambon, Alexander C, Dalton, Nancy D, Peterson, Kirk L, Gu, Yusu, Matkovich, Scot J, Murphy, Anne N, Miyamoto, Shigeki, Dorn, Gerald W, and Heller Brown, Joan
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Genetics ,Heart Disease ,Cardiovascular ,Aetiology ,2.1 Biological and endogenous factors ,Acetylcysteine ,Animals ,Apoptosis ,Benzylamines ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Cardiomegaly ,Cardiomyopathy ,Dilated ,Cells ,Cultured ,Disease Progression ,GTP-Binding Protein alpha Subunits ,Gq-G11 ,Gene Expression Profiling ,Heart Failure ,Ion Channels ,Male ,Mice ,Mice ,Knockout ,Mice ,Transgenic ,Mitochondria ,Heart ,Mitochondrial Proteins ,Myocytes ,Cardiac ,Oxidative Stress ,PPAR alpha ,Point Mutation ,Pressure ,RNA Interference ,RNA ,Messenger ,RNA ,Small Interfering ,Rats ,Reactive Oxygen Species ,Sequence Analysis ,RNA ,Sulfonamides ,Transfection ,Uncoupling Protein 3 ,calcium-calmodulin-dependent protein kinase type 2 ,G-protein ,Gq ,heart failure ,mitochondrial uncoupling protein 3 ,oxidative stress ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
RationaleSustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation.ObjectiveTo determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq.Methods and resultsCompared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion.ConclusionsMitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.
- Published
- 2015
40. Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model
- Author
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Lyon, Robert C, Mezzano, Valeria, Wright, Adam T, Pfeiffer, Emily, Chuang, Joyce, Banares, Katherine, Castaneda, Allan, Ouyang, Kunfu, Cui, Li, Contu, Riccardo, Gu, Yusu, Evans, Sylvia M, Omens, Jeffrey H, Peterson, Kirk L, McCulloch, Andrew D, and Sheikh, Farah
- Subjects
Biological Sciences ,Genetics ,Heart Disease ,Pediatric ,Cardiovascular ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Animals ,Newborn ,Arrhythmias ,Cardiac ,Arrhythmogenic Right Ventricular Dysplasia ,Brugada Syndrome ,Cardiac Conduction System Disease ,Catecholamines ,Connexin 43 ,Connexins ,Desmoplakins ,Disease Models ,Animal ,Electrocardiography ,Gene Expression ,Heart ,Heart Conduction System ,Magnetic Resonance Imaging ,Mice ,Mice ,Knockout ,Myocardium ,Myocytes ,Cardiac ,Phosphorylation ,Physical Conditioning ,Animal ,Gap Junction alpha-5 Protein ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) termed a 'disease of the desmosome' is an inherited cardiomyopathy that recently underwent reclassification owing to the identification of left-dominant and biventricular disease forms. Homozygous loss-of-function mutations in the desmosomal component, desmoplakin, are found in patients exhibiting a biventricular form of ARVC; however, no models recapitulate the postnatal hallmarks of the disease as seen in these patients. To gain insights into the homozygous loss-of-function effects of desmoplakin in the heart, we generated cardiomyocyte-specific desmoplakin-deficient mice (DSP-cKO) using ventricular myosin light chain-2-Cre mice. Homozygous DSP-cKO mice are viable but display early ultrastructural defects in desmosomal integrity leading to a cardiomyopathy reminiscent of a biventricular form of ARVC, which includes cell death and fibro-fatty replacement within the ventricle leading to biventricular dysfunction, failure and premature death. DSP-cKO mice also exhibited ventricular arrhythmias that are exacerbated with exercise and catecholamine stimulation. Furthermore, DSP-cKO hearts exhibited right ventricular conduction defects associated with loss of connexin 40 expression and electrical wavefront propagation defects associated with loss of connexin 43 expression. Dose-dependent assessment of the effects of loss of desmoplakin in neonatal ventricular cardiomyocytes revealed primary loss of connexin 43 levels, phosphorylation and function independent of the molecular dissociation of the mechanical junction complex and fibro-fatty manifestation associated with ARVC, suggesting a role for desmoplakin as a primary stabilizer of connexin integrity. In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC.
- Published
- 2014
41. The muscle ankyrin repeat proteins CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to pressure overload.
- Author
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Bang, Marie-Louise, Gu, Yusu, Dalton, Nancy D, Peterson, Kirk L, Chien, Kenneth R, and Chen, Ju
- Subjects
Myocardium ,Heart ,Animals ,Mice ,Knockout ,Mice ,Muscle Proteins ,Nuclear Proteins ,Repressor Proteins ,Gene Targeting ,Gene Order ,Phenotype ,Female ,Male ,Genetic Loci ,Genetic Association Studies ,General Science & Technology - Abstract
Ankrd1/CARP, Ankrd2/Arpp, and Ankrd23/DARP belong to a family of stress inducible ankyrin repeat proteins expressed in striated muscle (MARPs). The MARPs are homologous in structure and localized in the nucleus where they negatively regulate gene expression as well as in the sarcomeric I-band, where they are thought to be involved in mechanosensing. Together with their strong induction during cardiac disease and the identification of causative Ankrd1 gene mutations in cardiomyopathy patients, this suggests their important roles in cardiac development, function, and disease. To determine the functional role of MARPs in vivo, we studied knockout (KO) mice of each of the three family members. Single KO mice were viable and had no apparent cardiac phenotype. We therefore hypothesized that the three highly homologous MARP proteins may have redundant functions in the heart and studied double and triple MARP KO mice. Unexpectedly, MARP triple KO mice were viable and had normal cardiac function both at basal levels and in response to mechanical pressure overload induced by transverse aortic constriction as assessed by echocardiography and hemodynamic studies. Thus, CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to mechanical pressure overload.
- Published
- 2014
42. Improved accuracy benchmarks of small molecules using correlation consistent basis sets
- Author
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Feller, David, Peterson, Kirk A., Ruscic, Branko, Cramer, Christopher, Series editor, Truhlar, Donald G., Series editor, Wilson, Angela K., editor, Peterson, Kirk A., editor, and Woon, David E., editor
- Published
- 2015
- Full Text
- View/download PDF
43. Correlation consistent, Douglas–Kroll–Hess relativistic basis sets for the 5 p and 6 p elements
- Author
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Bross, David H., Peterson, Kirk A., Cramer, Christopher, Series editor, Truhlar, Donald G., Series editor, Wilson, Angela K., editor, Peterson, Kirk A., editor, and Woon, David E., editor
- Published
- 2015
- Full Text
- View/download PDF
44. Thom H. Dunning, Jr.: Contributions to chemical theory and computing
- Author
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Wilson, Angela K., Peterson, Kirk A., Woon, David E., Cramer, Christopher, Series editor, Truhlar, Donald G., Series editor, Wilson, Angela K., editor, Peterson, Kirk A., editor, and Woon, David E., editor
- Published
- 2015
- Full Text
- View/download PDF
45. Active Thermochemical Tables: dissociation energies of several homonuclear first-row diatomics and related thermochemical values
- Author
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Ruscic, Branko, Feller, David, Peterson, Kirk A., Cramer, Christopher, Series editor, Truhlar, Donald G., Series editor, Wilson, Angela K., editor, Peterson, Kirk A., editor, and Woon, David E., editor
- Published
- 2015
- Full Text
- View/download PDF
46. Prion-Induced Amyloid Heart Disease with High Blood Infectivity in Transgenic Mice
- Author
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Trifilo, Matthew J., Yajima, Toshitaka, Gu, Yusu, Dalton, Nancy, Peterson, Kirk L., Race, Richard E., Meade-White, Kimberly, Portis, John L., Masliah, Eliezer, Knowlton, Kirk U., and Chesebro, Bruce
- Published
- 2006
47. ThAu2−, ThAu2O−, and ThAuOH− anions: Photoelectron spectroscopic and theoretical characterization.
- Author
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Zhu, Zhaoguo, Marshall, Mary, Bowen, Kit H., and Peterson, Kirk A.
- Subjects
HEAT of formation ,NATURAL orbitals ,PHOTOELECTRON spectroscopy ,HYBRID securities ,PHOTOELECTRON spectra ,ANIONS - Abstract
The thorium–gold negative ions ThAu
2 − , ThAu2 O− , and ThAuOH− have been observed and experimentally characterized by anion photoelectron spectroscopy. These experiments are accompanied by extensive ab initio electronic structure calculations using a relativistic composite methodology based primarily on coupled cluster singles and doubles with perturbative triples calculations. The theoretical electron affinities (EAs) at 0 K agree with the experimental adiabatic EAs to within 0.02 eV for all species. Two separate isomers were located in the calculations for ThAuOH− , and detachment from both of these appears to be present in the photoelectron spectrum. Excited electronic states of the neutral molecules are reported at the equation of motion-coupled cluster singles and doubles level of theory. Atomization energies and heats of formation are also calculated for each neutral species and have expected uncertainties of 3 and 4 kcal/mol, respectively. The σ bonds between Th and Au are determined by natural bond orbital analysis to consist of predominately sd hybrids on Th bonding with the Au 6s orbital. In order to investigate the correspondence between the bonding in Th–Au and Th–F molecules, a limited number of calculations were also carried out on most of the F-analogs of this study. These results demonstrate that Au does behave like F in these cases, although the Th–F σ bonds are much more ionic compared to Th–Au. This results in an EA for ThF2 that is 10 kcal/mol smaller than that of ThAu2 . The EA values for the Th(IV) species, i.e., ThX2 O and ThXOH, only differed, however, by 3–4 kcal/mol. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
48. The Cardiovascular Physiologic Actions of Urocortin II: Acute Effects in Murine Heart Failure
- Author
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Bale, Tracy L., Hoshijima, Masahiko, Gu, Yusu, Dalton, Nancy, Anderson, Keith R., Lee, Kuo-Fen, Rivier, Jean, Chien, Kenneth R., Vale, Wylie W., and Peterson, Kirk L.
- Published
- 2004
49. Spontaneous recanalization of a completely occluded saphenous vein graft two months following acute myocardial infarction with persistent one year patency
- Author
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Hu, Patrick P., Peterson, Kirk L., and Tsimikas, Sotirios
- Subjects
Medicine & Public Health ,Hematology ,Cardiology ,Angioplasty ,Drug eluting stent ,Myocardial infarction ,Thrombolysis ,Fibrinolysis - Abstract
Acute myocardial infarction resulting from saphenous vein graft occlusion occurs not infrequently in patients who have undergone coronary artery bypass graft surgery. In this case report, we present a novel case of spontaneous recanalization of a thrombotic graft occlusion in a patient who presented with a subacute myocardial infarction. The patient was treated medically with aspirin as the only anti-platelet agent. Interestingly, he presented 2 months later with new onset angina. Coronary angiography demonstrated complete resolution of thrombus but a severe focal stenosis in the distal anastomoses. Following drug eluting stent placement, a favorable clinical course has ensued and patency confirmed on follow up angiography at 1 year.
- Published
- 2009
50. A Novel Functional Role for Cereblon in Cardiac Cell-Cell Junction Protein Homeostasis, Function and Arrhythmias
- Author
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Fujita, Kyohei, primary, Bradford, William, additional, Zhang, Jing, additional, Wang, Tsui-Min, additional, Gu, Yusu, additional, Peterson, Kirk, additional, and Sheikh, Farah, additional
- Published
- 2023
- Full Text
- View/download PDF
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