9 results on '"Small, Eric M."'
Search Results
2. A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction.
- Author
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Chen S, Zhang Y, Lighthouse JK, Mickelsen DM, Wu J, Yao P, Small EM, and Yan C
- Subjects
- Animals, Cardiomegaly genetics, Cardiomegaly pathology, Disease Models, Animal, Fibroblasts pathology, Mice, Mice, Knockout, Myocytes, Cardiac pathology, Phosphoric Diester Hydrolases genetics, Transcriptome, Cardiomegaly enzymology, Fibroblasts enzymology, Myocytes, Cardiac enzymology, Phosphoric Diester Hydrolases metabolism, Ventricular Remodeling
- Abstract
Background: Heart failure is a leading cause of death worldwide. Cyclic nucleotide phosphodiesterases (PDEs), through degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. Our preliminary screening studies have revealed PDE10A upregulation in the diseased heart. However, the roles of PDE10A in cardiovascular biology and disease are largely uncharacterized. The current study is aimed to investigate the regulation and function of PDE10A in cardiac cells and in the progression of cardiac remodeling and dysfunction., Methods: We used isolated adult mouse cardiac myocytes and fibroblasts, as well as preclinical mouse models of hypertrophy and heart failure. The PDE10A selective inhibitor TP-10, and global PDE10A knock out mice were used., Results: We found that PDE10A expression remains relatively low in normal and exercised heart tissues. However, PDE10A is significantly upregulated in mouse and human failing hearts. In vitro, PDE10A deficiency or inhibiting PDE10A with selective inhibitor TP-10, attenuated cardiac myocyte pathological hypertrophy induced by Angiotensin II, phenylephrine, and isoproterenol, but did not affect cardiac myocyte physiological hypertrophy induced by IGF-1 (insulin-like growth factor 1). TP-10 also reduced TGF-β (transforming growth factor-β)-stimulated cardiac fibroblast activation, proliferation, migration and extracellular matrix synthesis. TP-10 treatment elevated both cAMP and cGMP levels in cardiac myocytes and cardiac fibroblasts, consistent with PDE10A as a cAMP/cGMP dual-specific PDE. In vivo, global PDE10A deficiency significantly attenuated myocardial hypertrophy, cardiac fibrosis, and dysfunction induced by chronic pressure overload via transverse aorta constriction or chronic neurohormonal stimulation via Angiotensin II infusion. Importantly, we demonstrated that the pharmacological effect of TP-10 is specifically through PDE10A inhibition. In addition, TP-10 is able to reverse pre-established cardiac hypertrophy and dysfunction. RNA-Sequencing and bioinformatics analysis further identified a PDE10A-regualted transcriptome involved in cardiac hypertrophy, fibrosis, and cardiomyopathy., Conclusions: Taken together, our study elucidates a novel role for PDE10A in the regulation of pathological cardiac remodeling and development of heart failure. Given that PDE10A has been proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy for preventing and treating cardiac diseases associated with cardiac remodeling.
- Published
- 2020
- Full Text
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3. Pre-existing fibroblasts of epicardial origin are the primary source of pathological fibrosis in cardiac ischemia and aging.
- Author
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Quijada P, Misra A, Velasquez LS, Burke RM, Lighthouse JK, Mickelsen DM, Dirkx RA Jr, and Small EM
- Subjects
- Animals, Cell Lineage, Diastole, Fibrosis, Heart physiopathology, Mice, Knockout, Myocardial Ischemia physiopathology, Serum Response Factor metabolism, Stem Cells metabolism, Trans-Activators metabolism, Ventricular Remodeling, WT1 Proteins metabolism, Aging pathology, Fibroblasts pathology, Myocardial Ischemia pathology, Pericardium pathology
- Abstract
Serum response factor (SRF) and the SRF co-activators myocardin-related transcription factors (MRTFs) are essential for epicardium-derived progenitor cell (EPDC)-mobilization during heart development; however, the impact of developmental EPDC deficiencies on adult cardiac physiology has not been evaluated. Here, we utilize the Wilms Tumor-1 (Wt1)-Cre to delete Mrtfs or Srf in the epicardium, which reduced the number of EPDCs in the adult cardiac interstitium. Deficiencies in Wt1-lineage EPDCs prevented the development of cardiac fibrosis and diastolic dysfunction in aged mice. Mice lacking MRTF or SRF in EPDCs also displayed preservation of cardiac function following myocardial infarction partially due to the depletion of Wt1 lineage-derived cells in the infarct. Interestingly, depletion of Wt1-lineage EPDCs allows for the population of the infarct with a Wt1-negative cell lineage with a reduced fibrotic profile. Taken together, our study conclusively demonstrates the contribution of EPDCs to both ischemic cardiac remodeling and the development of diastolic dysfunction in old age, and reveals the existence of an alternative Wt1-negative source of resident fibroblasts that can populate the infarct., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
4. Sacubitril/Valsartan Decreases Cardiac Fibrosis in Left Ventricle Pressure Overload by Restoring PKG Signaling in Cardiac Fibroblasts.
- Author
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Burke RM, Lighthouse JK, Mickelsen DM, and Small EM
- Subjects
- Angiotensin Receptor Antagonists therapeutic use, Animals, Biphenyl Compounds, Drug Combinations, Fibroblasts metabolism, Fibrosis drug therapy, Heart drug effects, Heart physiopathology, Heart Failure physiopathology, Heart Ventricles physiopathology, Male, Mice, Inbred C57BL, Neprilysin antagonists & inhibitors, Valsartan, Aminobutyrates pharmacology, Cyclic GMP-Dependent Protein Kinases drug effects, Fibroblasts drug effects, Heart Failure drug therapy, Heart Ventricles drug effects, Tetrazoles pharmacology
- Abstract
Background Heart failure (HF) is invariably accompanied by development of cardiac fibrosis, a form of scarring that increases muscular tissue rigidity and decreases cardiac contractility. Cardiac fibrosis arises from a pathological attempt to repair tissue damaged during maladaptive remodeling. Treatment options to block or reverse fibrosis have proven elusive. Neprilysin is an endopeptidase that degrades vasoactive peptides, including atrial natriuretic peptide. Thus, neprilysin inhibition reduces hypertension, ultimately limiting maladaptive cardiac remodeling. LCZ696, which consists of an angiotensin receptor blocker (valsartan [VAL]) and a neprilysin inhibitor (sacubitril [SAC]), was shown to be well tolerated and significantly reduced the risk of death and hospitalization in HF patients with reduced ejection fraction. We hypothesized that SAC/VAL directly inhibits fibroblast activation and development of pathological fibrosis. Methods and Results We used a mouse model of left ventricle pressure overload coupled to in vitro studies in primary mouse and human cardiac fibroblasts (CFs) to study the impact of SAC/VAL on CF activation and cardiac fibrosis. SAC/VAL significantly ameliorated pressure overload-induced cardiac fibrosis by blocking CF activation and proliferation, leading to functional improvement. Mechanistically, the beneficial impact of SAC/VAL at least partially stemmed from restoration of PKG (protein kinase G) signaling in HF patient-derived CF, which inhibited Rho activation associated with myofibroblast transition. Conclusions This study reveals that SAC/VAL acts directly on CF to prevent maladaptive cardiac fibrosis and dysfunction during pressure overload-induced hypertrophy and suggests that SAC/VAL should be evaluated as a direct antifibrotic therapeutic for conditions such as HF with preserved ejection fraction.
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- 2019
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5. Activated Human Lung Fibroblasts Produce Extracellular Vesicles with Antifibrotic Prostaglandins.
- Author
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Lacy SH, Woeller CF, Thatcher TH, Pollock SJ, Small EM, Sime PJ, and Phipps RP
- Subjects
- Cell Differentiation drug effects, Cells, Cultured, Dinoprostone metabolism, Exosomes drug effects, Exosomes metabolism, Extracellular Matrix drug effects, Extracellular Matrix metabolism, Extracellular Vesicles metabolism, Female, Fibroblasts metabolism, Humans, Interleukin-1beta metabolism, Lung drug effects, Lung metabolism, Male, Myofibroblasts drug effects, Myofibroblasts metabolism, Pulmonary Fibrosis drug therapy, Pulmonary Fibrosis metabolism, Signal Transduction drug effects, Transforming Growth Factor beta metabolism, Antifibrinolytic Agents pharmacology, Extracellular Vesicles drug effects, Fibroblasts drug effects, Prostaglandins pharmacology
- Abstract
The differentiation of interstitial lung fibroblasts into contractile myofibroblasts that proliferate and secrete excessive extracellular matrix is critical for the pathogenesis of pulmonary fibrosis. Certain lipid signaling molecules, such as prostaglandins (PGs), can inhibit myofibroblast differentiation. However, the sources and delivery mechanisms of endogenous PGs are undefined. Activated primary human lung fibroblasts (HLFs) produce PGs such as PGE
2 . We report that activation of primary HLFs with IL-1β inhibited transforming growth factor β-induced myofibroblast differentiation in both the IL-1β-treated cells themselves (autocrine signal) and adjacent naive HLFs in cocultures (paracrine signal). Additionally, we demonstrate for the first time that at least some of the antifibrotic effect of activated fibroblasts on nearby naive fibroblasts is carried by exosomes and other extracellular vesicles that contain several PGs, including high levels of the antifibrotic PGE2 . Thus, activated fibroblasts communicate with surrounding cells to limit myofibroblast differentiation and maintain homeostasis. This work opens the way for future research into extracellular vesicle-mediated intercellular signaling in the lung and may inform the development of novel therapies for fibrotic lung diseases.- Published
- 2019
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6. Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure.
- Author
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Burke RM, Lighthouse JK, Quijada P, Dirkx RA Jr, Rosenberg A, Moravec CS, Alexis JD, and Small EM
- Subjects
- Adult, Aged, Animals, Cornified Envelope Proline-Rich Proteins genetics, Heart Failure genetics, Heart Failure physiopathology, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Myocardium metabolism, Proteolysis, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Tumor Suppressor Protein p53 genetics, Cell Proliferation, Cornified Envelope Proline-Rich Proteins metabolism, Fibroblasts metabolism, Heart Failure metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small proline-rich protein 2b ( Sprr2b ) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-β1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis., Competing Interests: Conflict of interest statement: E.M.S. is the recipient of a research grant from Novartis Pharmaceuticals.
- Published
- 2018
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7. Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction.
- Author
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Small EM, Thatcher JE, Sutherland LB, Kinoshita H, Gerard RD, Richardson JA, Dimaio JM, Sadek H, Kuwahara K, and Olson EN
- Subjects
- Amides pharmacology, Angiotensin II administration & dosage, Animals, Base Sequence, COS Cells, Chlorocebus aethiops, Collagen genetics, Collagen Type I, Disease Models, Animal, Extracellular Matrix Proteins genetics, Fibroblasts drug effects, Fibroblasts pathology, Fibrosis, Male, Mice, Mice, Knockout, Molecular Sequence Data, Myocardial Infarction genetics, Myocardial Infarction pathology, Myocardium pathology, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle pathology, Phenotype, Promoter Regions, Genetic, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology, Time Factors, Trans-Activators deficiency, Trans-Activators genetics, Transcription, Genetic, Transfection, Transforming Growth Factor beta1 metabolism, rho-Associated Kinases metabolism, Cell Transdifferentiation drug effects, Cell Transdifferentiation genetics, Extracellular Matrix Proteins metabolism, Fibroblasts metabolism, Myocardial Infarction metabolism, Myocardium metabolism, Myocytes, Smooth Muscle metabolism, Trans-Activators metabolism, Ventricular Remodeling drug effects, Ventricular Remodeling genetics
- Abstract
Rationale: Myocardial infarction (MI) results in loss of cardiac myocytes in the ischemic zone of the heart, followed by fibrosis and scar formation, which diminish cardiac contractility and impede angiogenesis and repair. Myofibroblasts, a specialized cell type that switches from a fibroblast-like state to a contractile, smooth muscle-like state, are believed to be primarily responsible for fibrosis of the injured heart and other tissues, although the transcriptional mediators of fibrosis and myofibroblast activation remain poorly defined. Myocardin-related transcription factors (MRTFs) are serum response factor (SRF) cofactors that promote a smooth muscle phenotype and are emerging as components of stress-responsive signaling., Objective: We aimed to examine the effect of MRTF-A on cardiac remodeling and fibrosis., Methods and Results: Here, we show that MRTF-A controls the expression of a fibrotic gene program that includes genes involved in extracellular matrix production and smooth muscle cell differentiation in the heart. In MRTF-A-null mice, fibrosis and scar formation following MI or angiotensin II treatment are dramatically diminished compared with wild-type littermates. This protective effect of MRTF-A deletion is associated with a reduction in expression of fibrosis-associated genes, including collagen 1a2, a direct transcriptional target of SRF/MRTF-A., Conclusions: We conclude that MRTF-A regulates myofibroblast activation and fibrosis in response to the renin-angiotensin system and post-MI remodeling.
- Published
- 2010
- Full Text
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8. Activation of MRTF-A–dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing
- Author
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Velasquez, Lissette S., Sutherland, Lillian B., Liuc, Zhenan, Grinnell, Frederick, Kamm, Kristine E., Schneider, Jay W., Olson, Eric N., and Small, Eric M.
- Published
- 2013
9. β-Adrenergic Blockade in Ischemia-Reperfusion Injury: βARKing Up a New Tree.
- Author
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Small, Eric M. and Burke, Ryan M.
- Subjects
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SYMPATHOLYTIC agents , *REPERFUSION injury , *HEART cells , *G protein-coupled receptor kinases , *TRANSFORMING growth factors , *GALLEIN , *CORONARY disease , *FIBROBLASTS , *HEART failure , *PLANTS , *SYMPATHOMIMETIC agents - Published
- 2017
- Full Text
- View/download PDF
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