45 results on '"Yao Wei Lu"'
Search Results
2. Set7 Deletion Prevents Glucose Intolerance and Improves the Recovery of Cardiac Function After Ischemia and Reperfusion in Obese Female Mice
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Juliane B. Miranda, Guilherme Lunardon, Vanessa M. Lima, Tábatha de Oliveira Silva, Caroline A. Lino, Leonardo Jensen, Maria Cláudia Irigoyen, Ivson Bezerra da Silva, Yao Wei Lu, Jianming Liu, Jose Donato Júnior, Maria Luiza M. Barreto-Chaves, Da-Zhi Wang, and Gabriela P. Diniz
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Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Published
- 2022
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3. Deletion of miRNA-22 Induces Cardiac Hypertrophy in Females but Attenuates Obesogenic Diet-Mediated Metabolic Disorders
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Tábatha de Oliveira Silva, Caroline A. Lino, Vanessa C. Buzatto, Paula Fontes Asprino, Yao Wei Lu, Vanessa M. Lima, Renata I. B. Fonseca, Leonardo Jensen, Gilson M. Murata, Sidney V. Filho, Márcio A. C. Ribeiro, Jose Donato Jr., Julio C. B. Ferreira, Alice C. Rodrigues, Maria Cláudia Irigoyen, Maria Luiza M. Barreto-Chaves, Zhan-Peng Huang, Pedro A. Favoretto Galante, Da-Zhi Wang, and Gabriela P. Diniz
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Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Published
- 2020
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4. Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses
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Hao Wu, Vikram Norton, Kui Cui, Bo Zhu, Sudarshan Bhattacharjee, Yao Wei Lu, Beibei Wang, Dan Shan, Scott Wong, Yunzhou Dong, Siu-Lung Chan, Douglas Cowan, Jian Xu, Diane R. Bielenberg, Changcheng Zhou, and Hong Chen
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diabetes ,comprehensive network ,system analysis ,cardiovascular disease complications ,peripheral artery disease ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Diabetes mellitus is a worldwide health problem that usually comes with severe complications. There is no cure for diabetes yet and the threat of these complications is what keeps researchers investigating mechanisms and treatments for diabetes mellitus. Due to advancements in genomics, epigenomics, proteomics, and single-cell multiomics research, considerable progress has been made toward understanding the mechanisms of diabetes mellitus. In addition, investigation of the association between diabetes and other physiological systems revealed potentially novel pathways and targets involved in the initiation and progress of diabetes. This review focuses on current advancements in studying the mechanisms of diabetes by using genomic, epigenomic, proteomic, and single-cell multiomic analysis methods. It will also focus on recent findings pertaining to the relationship between diabetes and other biological processes, and new findings on the contribution of diabetes to several pathological conditions.
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- 2022
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5. Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart
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Haipeng Guo, Yao Wei Lu, Zhiqiang Lin, Zhan-Peng Huang, Jianming Liu, Yi Wang, Hee Young Seok, Xiaoyun Hu, Qing Ma, Kathryn Li, Jan Kyselovic, Qingchuan Wang, Jenny L.-C. Lin, Jim J.-C. Lin, Douglas B. Cowan, Francisco Naya, Yuguo Chen, William T. Pu, and Da-Zhi Wang
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Science - Abstract
Intercalated discs ensure mechanical and electrochemical coupling during contraction of the heart. Here, the authors show that loss of Xinβ results in cardiomyocyte proliferation defects and cardiomyopathy by influencing the Hippo-YAP signalling pathway, thus affecting cardiac development and function.
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- 2020
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6. The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease
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Qianman Peng, Dan Shan, Kui Cui, Kathryn Li, Bo Zhu, Hao Wu, Beibei Wang, Scott Wong, Vikram Norton, Yunzhou Dong, Yao Wei Lu, Changcheng Zhou, and Hong Chen
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endothelial-to-mesenchymal transition ,cell signaling ,multidisciplinary and novel approaches ,cardiovascular disease ,Cytology ,QH573-671 - Abstract
Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, valve diseases, fibrosis, and pulmonary arterial hypertension (PAH). Therefore, a deeper understanding of the cellular and molecular mechanisms underlying EndoMT in CVD should provide urgently needed insights into reversing this condition. This review summarizes a 30-year span of relevant literature, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD.
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- 2022
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7. Therapeutic Inhibition of LincRNA-p21 Protects Against Cardiac Hypertrophy.
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Yi Wang, Mingming Zhang, Rong Wang, Jing Lin, Qing Ma, Haipeng Guo, Huihui Huang, Zhuomin Liang, Yangpo Cao, Xiaoran Zhang, Yao Wei Lu, Jianming Liu, Feng Xiao, Hualin Yan, Dimitrova, Nadya, Zhan-Peng Huang, Mably, John D., Pu, William T., and Da-Zhi Wang
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- 2024
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8. PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy
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Yao Wei Lu, Zhuomin Liang, Haipeng Guo, Tiago Fernandes, Ramon A Espinoza-Lewis, Tingting Wang, Kathryn Li, Xue Li, Gurinder Bir Singh, Yi Wang, Douglas Cowan, John D Mably, Caroline C. Philpott, Hong Chen, and Da-Zhi Wang
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Article - Abstract
SUMMARYAlanyl-transfer RNA synthetase 2 (AARS2) is a nuclear encoded mitochondrial tRNA synthetase that is responsible for charging of tRNA-Ala with alanine during mitochondrial translation. Homozygous or compound heterozygous mutations in the Aars2 gene, including those affecting its splicing, are linked to infantile cardiomyopathy in humans. However, how Aars2 regulates heart development, and the underlying molecular mechanism of heart disease remains unknown. Here, we found that poly(rC) binding protein 1 (PCBP1) interacts with the Aars2 transcript to mediate its alternative splicing and is critical for the expression and function of Aars2. Cardiomyocyte-specific deletion of Pcbp1 in mice resulted in defects in heart development that are reminiscent of human congenital cardiac defects, including noncompaction cardiomyopathy and a disruption of the cardiomyocyte maturation trajectory. Loss of Pcbp1 led to an aberrant alternative splicing and a premature termination of Aars2 in cardiomyocytes. Additionally, Aars2 mutant mice with exon-16 skipping recapitulated heart developmental defects observed in Pcbp1 mutant mice. Mechanistically, we found dysregulated gene and protein expression of the oxidative phosphorylation pathway in both Pcbp1 and Aars2 mutant hearts; these date provide further evidence that the infantile hypertrophic cardiomyopathy associated with the disorder oxidative phosphorylation defect type 8 (COXPD8) is mediated by Aars2. Our study therefore identifies Pcbp1 and Aars2 as critical regulators of heart development and provides important molecular insights into the role of disruptions in metabolism on congenital heart defects.
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- 2023
9. Ryanodine receptor 2 (RYR2) dysfunction activates the unfolded protein response and perturbs cardiomyocyte maturation
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Yuxuan Guo, Yangpo Cao, Blake D Jardin, Xiaoran Zhang, Pingzhu Zhou, Silvia Guatimosim, Junsen Lin, Zhan Chen, Yueyang Zhang, Neil Mazumdar, Fujian Lu, Qing Ma, Yao-Wei Lu, Mingming Zhao, Da-Zhi Wang, Erdan Dong, and William T Pu
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Physiology ,Physiology (medical) ,Original Article ,Cardiology and Cardiovascular Medicine - Abstract
Calcium handling capacity is a major gauge of cardiomyocyte maturity. Ryanodine receptor 2 (RYR2) is the predominant calcium channel that releases calcium from the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) to activate cardiomyocyte contraction. Although RYR2 was previously implied as a key regulator of cardiomyocyte maturation, the mechanisms remain unclear. The aim of this study is to solve this problem.We performed Cas9/AAV9-mediated somatic mutagenesis (CASAAV) to knockout RYR2 specifically in cardiomyocytes in mice. We conducted a genetic mosaic analysis to dissect the cell-autonomous function of RYR2 during cardiomyocyte maturation. We found that RYR2 depletion triggered ultrastructural and transcriptomic defects relevant to cardiomyocyte maturation. These phenotypes were associated with the drastic activation of ER stress pathways. The ER stress alleviator tauroursodeoxycholic acid (TUDCA) partially rescued the defects in RYR2-depleted cardiomyocytes. Overexpression of ATF4, a key ER stress transcription factor, recapitulated defects in RYR2-depleted cells. Integrative analysis of RNA-Seq and bioChIP-Seq data revealed that protein biosynthesis-related genes are the major direct downstream targets of ATF4.RYR2-regulated ER homeostasis is essential for cardiomyocyte maturation. Severe ER stress perturbs cardiomyocyte maturation primarily through ATF4 activation. The major downstream effector genes of ATF4 are related to protein biosynthesis.Dysfunctional calcium handling is a major factor contributing to cardiac pathogenesis, but the molecular mechanisms remain unclear. This study uncovered RYR2 as a new regulator of ER stress and cardiomyocyte maturation, providing significant insights to guide the development of therapeutic approaches to control cardiac pathogenesis. Because cardiomyocyte maturation is a major bottleneck in translational medicine using stem cell-derived cardiomyocytes, this study also pointed out RYR2 and ER homeostasis as potential targets to manipulate the maturity of stem cell-derived cardiomyocytes.
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- 2022
10. <scp>mt‐Ty</scp> 5´ <scp>tiRNA</scp> regulates skeletal muscle cell proliferation and differentiation
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Jun Cao, Xin Wang, Vivek Advani, Yao Wei Lu, Andrea P. Malizia, Gurinder Bir Singh, Zhan‐Peng Huang, Jianming Liu, Chunbo Wang, Edilamar M. Oliveira, John D. Mably, Kaifu Chen, and Da‐Zhi Wang
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Cell Biology ,General Medicine - Published
- 2023
11. INKILNis a novel long noncoding RNA promoting vascular smooth muscle inflammation via scaffolding MKL1 and USP10
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Wei Zhang, Jinjing Zhao, Lin Deng, Nestor Ishimwe, Jessica Pauli, Wen Wu, Shengshuai Shan, Wolfgang Kempf, Margaret D. Ballantyne, David Kim, Qing Lyu, Matthew Bennett, Julie Rodor, Adam W. Turner, Yao Wei Lu, Ping Gao, Mihyun Choi, Ganesh Warthi, Ha Won Kim, Margarida M. Barroso, William B. Bryant, Clint L. Miller, Neal L. Weintraub, Lars Maegdefessel, Joseph M. Miano, Andrew H Baker, and Xiaochun Long
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Physiology (medical) ,Cardiology and Cardiovascular Medicine ,Article - Abstract
BACKGROUND: Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood. METHODS: Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA ( INKILN ). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of INKILN was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA–protein and protein–protein interaction assays were used to uncover a mechanistic role of INKILN in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study INKIL N expression and function in ligation injury–induced neointimal formation. RESULTS: INKILN expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. INKILN activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks interleukin-1β–induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1 and the luciferase activity of an NF-κB reporter. Furthermore, INKILN knockdown enhances MKL1 ubiquitination through reduced physical interaction with the deubiquitinating enzyme USP10 (ubiquitin-specific peptidase 10). INKILN is induced in injured carotid arteries and exacerbates ligation injury–induced neointimal formation in bacterial artificial chromosome transgenic mice. CONCLUSIONS: These findings elucidate an important pathway of VSMC inflammation involving an INKILN /MKL1/USP10 regulatory axis. Human bacterial artificial chromosome transgenic mice offer a novel and physiologically relevant approach for investigating human-specific long noncoding RNAs under vascular disease conditions.
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- 2023
12. Cardiac CIP protein regulates dystrophic cardiomyopathy
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Haipeng Guo, Jian Ding, Zhiqiang Lin, Xinxue Liao, Zhongliang Deng, Yao Wei Lu, Fei Gu, Xiaoyun Hu, William T. Pu, Wang Min, Masaharu Kataoka, Mao Nie, Huaqun Chen, Xin He, Yugang Dong, Jinghai Chen, Zhan-Peng Huang, Jianming Liu, and Da-Zhi Wang
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Cardiomyopathy, Dilated ,Duchenne muscular dystrophy ,Transgene ,Dystrophin ,Mice ,Fibrosis ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Pharmacology ,biology ,business.industry ,Nuclear Proteins ,Heart ,NFAT ,Dilated cardiomyopathy ,medicine.disease ,Muscular Dystrophy, Duchenne ,Calcineurin ,Heart failure ,Mice, Inbred mdx ,Cancer research ,biology.protein ,Molecular Medicine ,Original Article ,Cardiomyopathies ,business ,Co-Repressor Proteins - Abstract
Heart failure is a leading cause of fatality in Duchenne muscular dystrophy (DMD) patients. Previously, we discovered that cardiac and skeletal-muscle-enriched CIP proteins play important roles in cardiac function. Here, we report that CIP, a striated muscle-specific protein, participates in the regulation of dystrophic cardiomyopathy. Using a mouse model of human DMD, we found that deletion of CIP leads to dilated cardiomyopathy and heart failure in young, non-syndromic mdx mice. Conversely, transgenic overexpression of CIP reduces pathological dystrophic cardiomyopathy in old, syndromic mdx mice. Genome-wide transcriptome analyses reveal that molecular pathways involving fibrogenesis and oxidative stress are affected in CIP-mediated dystrophic cardiomyopathy. Mechanistically, we found that CIP interacts with dystrophin and calcineurin (CnA) to suppress the CnA-Nuclear Factor of Activated T cells (NFAT) pathway, which results in decreased expression of Nox4, a key component of the oxidative stress pathway. Overexpression of Nox4 accelerates the development of dystrophic cardiomyopathy in mdx mice. Our study indicates CIP is a modifier of dystrophic cardiomyopathy and a potential therapeutic target for this devastating disease.
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- 2022
13. Corrigendum: MEF2 transcription factors are key regulators of sprouting angiogenesis
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Natalia Sacilotto, Kira M. Chouliaras, Leonid L. Nikitenko, Yao Wei Lu, Martin Fritzsche, Marsha D. Wallace, Svanhild Nornes, Fernando García-Moreno, Sophie Payne, Esther Bridges, Ke Liu, Daniel Biggs, Indrika Ratnayaka, Shane P. Herbert, Zoltán Molnár, Adrian L. Harris, Benjamin Davies, Gareth L. Bond, George Bou-Gharios, John J. Schwarz, and Sarah De Val
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Genetics ,cardiovascular system ,Developmental Biology ,Research Paper - Abstract
In this study, Saccilotto et al. investigated the molecular connection between proangiogenic signals and downstream gene expression during angiogenesis. By characterizing a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, the authors identified MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA.
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- 2022
14. Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression
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Kui Cui, Xinlei Gao, Beibei Wang, Hao Wu, Kulandaisamy Arulsamy, Yunzhou Dong, Yuling Xiao, Xingya Jiang, Marina V. Malovichko, Kathryn Li, Qianman Peng, Yao Wei Lu, Bo Zhu, Rongbin Zheng, Scott Wong, Douglas B. Cowan, MacRae Linton, Sanjay Srivastava, Jinjun Shi, Kaifu Chen, and Hong Chen
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Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Background: Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically target macrophage Epsins with specially designed S2P-conjugated lipid nanoparticles, which encapsulate small-interfering RNAs to suppress Epsins. Methods: We used single-cell RNA sequencing with our newly developed algorithm MEBOCOST (Metabolite-mediated Cell Communication Modeling by Single Cell Transcriptome) to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells. Biomedical, cellular, and molecular approaches were utilized to investigate the role of macrophage Epsins in regulating lipid metabolism and transport. We performed this study using myeloid-specific Epsin double knockout (LysM-DKO) mice and mice with a genetic reduction of ABCG1 (ATP-binding cassette subfamily G member 1; LysM-DKO-ABCG1 fl/+ ). The nanoparticles targeting lesional macrophages were developed to encapsulate interfering RNAs to treat atherosclerosis. Results: We revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages. Inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing lesional macrophage-specific nanoparticle delivery of Epsin small-interfering RNAs, we showed that silencing of macrophage Epsins diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, we demonstrated that Epsins bound to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promoted ABCG1 degradation via lysosomes and hampered ABCG1-mediated cholesterol efflux and reverse cholesterol transport. In a LysM-DKO-ABCG1 fl/+ mouse model, enhanced cholesterol efflux and reverse transport due to Epsin deficiency was suppressed by the reduction of ABCG1. Conclusions: Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux.
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- 2022
15. Abstract P314: Loss Of Set7 Prevents Isoproterenol-induced Heart Dysfunction
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Guilherme Lunardon, Tábatha de Oliveira Silva, Caroline Lino, Yao Wei Lu, Juliane Miranda, Paula Asprino, Maria Claudia Irigoyen, Ana Paula Takano, Maria Luiza Barreto-Chaves, Da-Zhi Wang, Amanda De Almeida Silva, and Gabriela P Diniz
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Internal Medicine - Abstract
Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and dysfunction. The Set7 methyltransferase regulates the expression of several genes through methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in heart dysfunction remains unknown. To answer this question, wild type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol (iso) or saline (s) subcutaneously for 14 days. The WTiso mice displayed decreased Set7 activity in the heart compared to WTs mice (Table 1). Both WTiso and KOiso mice exhibited increased heart weight to tibia length ratio (HW/TL) and cardiomyocyte area. However, KOiso mice had higher HW/TL and cardiomyocyte area compared to WTiso mice. Sirius Red staining revealed that both WT and KO mice injected with iso had increased myocardial fibrosis compared to their controls. Nonetheless, loss of Set7 attenuated iso-induced myocardial fibrosis. Echocardiogram showed that WTiso mice had lower ejection fraction (EF) and fractional shortening (FS), and higher E/A ratio compared to WTs mice. Conversely, KOiso mice did not show alteration on these parameters compared to their controls. RNA sequencing analysis revealed that biological processes related to oxidant detoxication, cellular respiration, and anti-inflammatory response were enriched in the heart of KOiso mice compared to WTiso mice. On the other hand, biological processes related to cell aging, interferon production, and immune response were downregulated in the heart of KOiso mice compared to WTiso mice. Collectively, our data suggest that Set7 deletion prevents iso-induced heart dysfunction.
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- 2022
16. Abstract P2059: Poly(rC)-binding Protein-1 (Pcbp1) Is Essential For Heart Development
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Yao Wei Lu, Zhuomin Liang, Haipeng Guo, Tiago Fernandes, Xiaoyun Hu, Ramon Espinoza-Lewis, Douglas B Cowan, Hong Chen, and Da-Zhi Wang
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Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Rationale: Proper development of the heart relies on a tightly regulated, yet diverse, pattern of gene expression that is governed by transcriptional, post-transcriptional, and translational processes. Congenital heart disease (CHD) is the most common birth defect and a leading cause of morbidity and mortality in children. While the genetic cause of some types of CHD has been identified, the molecular basis for the rest remains elusive. Poly(rC)-binding protein 1 (Pcbp1) is a RNA-binding protein that regulates RNA processing as well as post-transcriptional and translational processes in a variety of biological systems. Hypothesis: Pcbp1 play a critical role in regulating heart development by governing Notch and UPR pathways and mediating proper Aars2 gene splicing. Methods and Results: Germline deletion of Pcbp1 results in lethality before embryonic day (E) 8.5. We generated a cardiac-specific deletion of Pcbp1 by crossing Pcbp1-Flox with cTNT-Cre mice (Pcbp1-cKO cTNT ) and found that Pcbp1-cKO cTNT mice is 50% lethal perinatally. Embryonic hearts of Pcbp1-cKO cTNT mice displayed ventricular non-compaction and abnormal ventricular apex formation. Deep RNA sequencing of Pcbp1-cKO cTNT hearts revealed alteration of gene expression profiles reflective on ventricular maturation delay and dysregulation of Notch and UPR pathways. Interestingly, loss of Pcbp1 in cardiomyocytes disrupts alternative splicing of many important genes including Aars2, a gene associated with congenital mitochondrial cardiomyopathy. Pcbp1 deficiency resulted in creation of an Aars2 exon16-skipping variant, leading to its premature termination. eCLIP-seq showed that Pcbp1 primarily binds to CU-rich motifs at 3’UTR, distal intron and CDS regions of targets, and it interacts with regions of Aars2 transcript near exon 16. Using CRISPR/Cas9 technology, we knocked in loxP sites flanking the exon 16 of Aars2 (Aars2-Flox), and cross the floxed mice with cTNT-Cre mice to generate cardiac-specific exon16 deletion mutant of Aars2 (Aars2-cKO cTNT ). Intriguingly, abnormality in Aars2-cKO cTNT embryonic heart phenocopy aspects of ventricular non-compaction and malformation observed in Pcbp1-cKO cTNT heart. Accordingly, the transcriptome from hearts of Pcbp1-cKO cTNT and Aars2-cKO cTNT display high concordance and similarity and share strikingly common dysregulated pathways. Conclusions: We discover a novel function of Pcbp1 in heart development by regulating Notch and UPR pathways. Additionally, Pcbp1 is indispensable for Aars2 gene splicing, whose deficiency is associated with congenital cardiomyopathy. Our findings suggest modulating Pcbp1 in developing hearts may offer a novel therapeutic intervention for congenital heart failure.
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- 2022
17. Abstract 196: Poly (rC)-binding Protein-1 (Pcbp1) Is Essential For Vascular Development
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Yao Wei Lu, Bo Zhu, Douglas B Cowan, Da-Zhi Wang, and Hong Chen
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Cardiology and Cardiovascular Medicine - Abstract
The formation of the heart and the connecting vessels is essential for the function of the vertebrates, as vascular deficiency during embryonic development often leads to embryonic lethality. The vasculature forms as a branching network of endothelial cells (ECs) that becomes specified and assembles into vessels. the formation of new blood vessels from the existing vasculatures, or angiogenesis, is fundamental during development and pathological processes. Critical factors in governing vascular development are often required for organismal survival. Hence, gaining a complete understanding of the developmental process requires unique approaches to study tissue or cell-type specific functions. Poly(rC)-Binding Protein 1 (Pcbp1) is an evolutionarily conserved RNA binding protein that is not well understood in vivo . Pcbp1 is abundantly expressed in the angiogenic endothelium. However, little is known about the function and mechanism of Pcbp1 in the context of angiogenesis and vascular development. Germline deletion of Pcbp1 results in peri-implantation lethality, which limits its potential for studying the role of Pcbp1 in development. To address this deficit, we had generated an inducible endothelial deletion of Pcbp1 with Cdh5-Cre ERT2 (Pcbp1-ieKO) to study its role in vascular development. When the EC deletion was induced at embryonic day (E) 9.5, Pcbp1-ieKO exhibited inadequate angiogenesis in the hindbrain at E12.5. Furthermore, when the EC deletion was induced at postnatal day (P) 1, Pcbp1-ieKO displayed reduced coronary and brain vascular density, as well as blunted retinal angiogenesis at P6. Single-cell RNA sequencing of Pcbp1-ieKO retina at P6 revealed a significant reduction in EC population and expression of genes critical for angiogenesis downstream of VEGF signaling and NOTCH activation. Notably, knockdown of Pcbp1 in human colony-forming endothelial cells (hCFEC) blunts the VEGFR2 and NOTCH activation upon VEGFA treatment. Our preliminary results suggest Pcbp1 is a critical regulator for angiogenesis, future studies will be directed at identifying the mechanism of Pcbp1 in regulating VEGF and NOTCH signaling, ultimately to provide insights for novel therapeutic strategies to control angiogenesis in cardiovascular disease.
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- 2022
18. MEF2 (Myocyte Enhancer Factor 2) Is Essential for Endothelial Homeostasis and the Atheroprotective Gene Expression Program
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Yao Wei Lu, Brennan D. Gerlach, Peter A. Vincent, Nina Martino, John J. Schwarz, John M. Lamar, and Alejandro P. Adam
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Mef2 ,Endothelium ,Chemistry ,Inflammation ,Cell biology ,Stress (mechanics) ,medicine.anatomical_structure ,Gene expression ,cardiovascular system ,Shear stress ,medicine ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Lamin ,Homeostasis - Abstract
Objective: Atherosclerosis predominantly forms in regions of oscillatory shear stress while regions of laminar shear stress are protected. This protection is partly through the endothelium in laminar flow regions expressing an anti-inflammatory and antithrombotic gene expression program. Several molecular pathways transmitting these distinct flow patterns to the endothelium have been defined. Our objective is to define the role of the MEF2 (myocyte enhancer factor 2) family of transcription factors in promoting an atheroprotective endothelium. Approach and Results: Here, we show through endothelial-specific deletion of the 3 MEF2 factors in the endothelium, Mef2a, -c, and -d, that MEF2 is a critical regulator of vascular homeostasis. MEF2 deficiency results in systemic inflammation, hemorrhage, thrombocytopenia, leukocytosis, and rapid lethality. Transcriptome analysis reveals that MEF2 is required for normal regulation of 3 pathways implicated in determining the flow responsiveness of the endothelium. Specifically, MEF2 is required for expression of Klf2 and Klf4, 2 partially redundant factors essential for promoting an anti-inflammatory and antithrombotic endothelium. This critical requirement results in phenotypic similarities between endothelial-specific deletions of Mef2a/c/d and Klf2/4 . In addition, MEF2 regulates the expression of Notch family genes, Notch1, Dll1, and Jag1, which also promote an atheroprotective endothelium. In contrast to these atheroprotective pathways, MEF2 deficiency upregulates an atherosclerosis promoting pathway through increasing the amount of TAZ (transcriptional coactivator with PDZ-binding motif). Conclusions: Our results implicate MEF2 as a critical upstream regulator of several transcription factors responsible for gene expression programs that affect development of atherosclerosis and promote an anti-inflammatory and antithrombotic endothelium. Graphic Abstract: A graphic abstract is available for this article.
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- 2021
19. Sox17 mediates adult arterial endothelial cell adaptation to hemodynamics
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Diana Kim, Alexander Grath, Yao Wei Lu, Karl Chung, Max Winkelman, John J. Schwarz, and Guohao Dai
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Biomaterials ,Mechanics of Materials ,Biophysics ,Ceramics and Composites ,Bioengineering - Abstract
Sox17 is a critical regulator of arterial identity during early embryonic vascular development. However, its role in adult endothelial cells (ECs) are not fully understood. Sox17 is highly expressed in arterial ECs but not in venous ECs throughout embryonic development to adulthood suggesting that it may play a functional role in adult arteries. Here, we investigated Sox17 mediated phenotypical changes in adult ECs. To precisely control the temporal expression level of Sox17, we designed a tetracycline-inducible lentiviral gene expression system to express Sox17 selectively in cultured venous ECs. We confirmed that Sox17-induced ECs exhibit a gene profile favoring arterial and tip cell identity. Furthermore, in comparison to control ECs, Sox17-activated ECs under shear leads to greater expression of arterial markers and suppression of venous identity. These data suggest that Sox17 enables greater hemodynamic adaptability of ECs in response to fluid shear stress. Here, we also demonstrate key morphogenic behaviors of Sox17-mediated ECs. In both vasculogenic and angiogenic 3D fibrin gel studies, Sox17-mediated ECs prefer to form cohesive vessels with one another while interfering the vessel formation of the control ECs. Sox17-mediated ECs elicit hyper-sprouting behavior in the presence of pericytes but not fibroblasts, suggesting Sox17 mediated sprouting frequency is dependent on supporting cell type. Using a microfluidic chip, we also show that Sox17-mediated ECs maintain thinner diameter vessels that do not widen under interstitial flow like the control ECs. Taken together, these data showed that Sox17 mediated EC gene expression and phenotypical changes are highly modulated in the context of biomechanical stimuli, suggesting Sox17 plays a role in regulating the arterial ECs adaptability under arterial hemodynamics as well as tip cells behavior during angiogenesis and vasculogenesis. The results from this study may be valuable in improving vein graft adaptation to arterial hemodynamics and bioengineering microvasculature for tissue engineering applications.
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- 2023
20. Set7 deletion prevents glucose intolerance and improves the recovery of cardiac function after ischemia and reperfusion in obese female mice
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Juliane B, Miranda, Guilherme, Lunardon, Vanessa M, Lima, Tábatha, de Oliveira Silva, Caroline A, Lino, Leonardo, Jensen, Maria Cláudia, Irigoyen, Ivson Bezerra, da Silva, Yao Wei, Lu, Jianming, Liu, Jose, Donato Júnior, Maria Luiza M, Barreto-Chaves, Da-Zhi, Wang, and Gabriela P, Diniz
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Mice, Knockout ,Mice ,Ischemia ,Physiology ,Glucose Intolerance ,Reperfusion ,Animals ,Mice, Obese ,Female ,Obesity ,Diet, High-Fat ,DOENÇAS METABÓLICAS - Abstract
Background/Aims: An obesogenic diet (high fat and sugar, low fiber) is associated with an increased risk for metabolic and cardiovascular disorders. Previous studies have demonstrated that epigenetic changes can modify gene transcription and protein function, playing a key role in the development of several diseases. The methyltransferase Set7 methylates histone and non-histone proteins, influencing diverse biological and pathological processes. However, the functional role of Set7 in obesity-associated metabolic and cardiovascular complications is unknown. Methods: Wild type and Set7 knockout female mice were fed a normal diet or an obesogenic diet for 12 weeks. Body weight gain and glucose tolerance were measured. The 3T3-L1 cells were used to determine the role of Set7 in white adipogenic differentiation. Cardiac morphology and function were evaluated by histology and echocardiography. An ex vivo Langendorff perfusion system was used to model cardiac ischemia/reperfusion (I/R). Results: Here, we report that Set7 protein levels were enhanced in the heart and perigonadal adipose tissue (PAT) of female mice fed an obesogenic diet. Significantly, loss of Set7 prevented obesogenic diet-induced glucose intolerance in female mice although it did not affect the obesogenic diet-induced increase in body weight gain and adiposity in these animals, nor did Set7 inhibition change white adipogenic differentiation in vitro. In addition, loss of Set7 prevented the compromised cardiac functional recovery following ischemia and reperfusion (I/R) injury in obesogenic diet-fed female mice; however, deletion of Set7 did not influence obesogenic diet-induced cardiac hypertrophy nor the hemodynamic and echocardiographic parameters. Conclusion: These data indicate that Set7 plays a key role in obesogenic diet-induced glucose intolerance and compromised myocardial functional recovery after I/R in obese female mice.
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- 2022
21. Set7 deletion attenuates isoproterenol-induced cardiac fibrosis and delays cardiac dysfunction
- Author
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Guilherme Lunardon, Tábatha de Oliveira Silva, Caroline A. Lino, Yao Wei Lu, Juliane B. Miranda, Paula F. Asprino, Amanda de Almeida Silva, Gabrielle T. Nepomuceno, Maria Cláudia Costa Irigoyen, Marcela S. Carneiro-Ramos, Ana Paula C. Takano, Herculano da Silva Martinho, Maria Luiza M. Barreto-Chaves, Da-Zhi Wang, and Gabriela P. Diniz
- Subjects
Male ,Mice, Knockout ,Mice, Inbred C57BL ,Mice ,Ventricular Remodeling ,Isoproterenol ,Animals ,Cardiomegaly ,Myocytes, Cardiac ,General Medicine ,DNA MITOCONDRIAL ,Cardiomyopathies ,Fibrosis - Abstract
Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild-type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E′-wave deceleration time and E/A ratio compared with their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress.
- Published
- 2022
22. Set7 Deletion Prevents Glucose Intolerance and Improves the Recovery of Cardiac Function after Ischemia and Reperfusion in Obese Female Mice
- Author
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Juliane Miranda, Guilherme Lunardon, Vanessa Lima, Tábatha de Oliveira Silva, Leonardo Jensen, Maria Cláudia Irigoyen, Ivson da Silva, Jose Jr Donato, Maria Luiza Barreto-Chaves, Yao Wei Lu, Jianming Liu, Da-Zhi Wang, and Gabriela Placoná Diniz
- Published
- 2022
23. Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart
- Author
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Douglas B. Cowan, Qing Ma, Kathryn Li, Francisco J. Naya, Haipeng Guo, Yi Wang, Qingchuan Wang, Xiaoyun Hu, Zhiqiang Lin, Jianming Liu, Jan Kyselovic, Hee Young Seok, Da-Zhi Wang, Jenny Li-Chun Lin, Yao Wei Lu, William T. Pu, Zhan-Peng Huang, Yuguo Chen, and Jim J.-C. Lin
- Subjects
Male ,0301 basic medicine ,Cardiomyopathy ,General Physics and Astronomy ,Cell Cycle Proteins ,Cell Communication ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Myocyte ,Myocytes, Cardiac ,lcsh:Science ,Mice, Knockout ,Neurofibromin 2 ,Multidisciplinary ,Heart development ,Chemistry ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Signal transducing adaptor protein ,LIM Domain Proteins ,Cell biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Phosphorylation ,Female ,Signal transduction ,Intercalated disc ,Signal Transduction ,Cell signalling ,Cardiomyopathy, Dilated ,Cell signaling ,Science ,Heart Ventricles ,Protein Serine-Threonine Kinases ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,Animals ,Hippo Signaling Pathway ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,YAP-Signaling Proteins ,General Chemistry ,medicine.disease ,Cardiovascular biology ,Mice, Inbred C57BL ,Cytoskeletal Proteins ,030104 developmental biology ,Mutation ,lcsh:Q - Abstract
Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice—indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases., Intercalated discs ensure mechanical and electrochemical coupling during contraction of the heart. Here, the authors show that loss of Xinβ results in cardiomyocyte proliferation defects and cardiomyopathy by influencing the Hippo-YAP signalling pathway, thus affecting cardiac development and function.
- Published
- 2020
24. Transcriptional control of a novel long noncoding RNA Mymsl in smooth muscle cells by a single Cis-element and its initial functional characterization in vessels
- Author
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Jinjing Zhao, Mihyun Choi, Wei Zhang, Mingfu Wu, Yao Wei Lu, and Xiaochun Long
- Subjects
0301 basic medicine ,Serum Response Factor ,Vascular smooth muscle ,Transcription, Genetic ,Myocytes, Smooth Muscle ,Down-Regulation ,Regulatory Sequences, Nucleic Acid ,030204 cardiovascular system & hematology ,Biology ,Article ,Transcriptome ,Open Reading Frames ,03 medical and health sciences ,0302 clinical medicine ,Serum response factor ,Transcriptional regulation ,medicine ,Animals ,Myocytes, Cardiac ,Molecular Biology ,Transcription factor ,Aorta ,Gene Editing ,Mice, Knockout ,Genome ,Cardiac muscle ,Nuclear Proteins ,Cell Differentiation ,Extracellular Matrix ,Cell biology ,Mice, Inbred C57BL ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Myocardin ,Mutation ,Trans-Activators ,cardiovascular system ,Blood Vessels ,RNA, Long Noncoding ,Cardiology and Cardiovascular Medicine ,Chromatin immunoprecipitation - Abstract
Differentiated vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular homeostasis. While the coding transcriptome of the differentiated VSMC phenotype has been defined, we know little about its noncoding signature. Herein, we identified a Myocardin-induced muscle specific long noncoding RNA (lncRNA) (Mymsl) downregulated upon VSMC phenotypic modulation. We demonstrated an essential role of a proximal consensus CArG element in response to MYOCD/SRF in vitro. To validate the in vivo role of this CArG element, we generated CArG mutant mice via CRISPR-Cas9 genome editing. While the CArG mutation had no impact on the expression of surrounding genes, it abolished Mymsl expression in SMCs, but not skeletal and cardiac muscle. Chromatin immunoprecipitation assays (ChIPs) showed decreased SRF binding to CArG region in mutants whereas the enrichment of H3K79Me2 remained the same. RNA-seq analysis showed a downregulation of matrix genes in aortas from Mymsl knockout mice, which was further validated in injured carotid arteries. Our study defined the transcriptional control of a novel lncRNA in SMCs via a single transcription factor binding site, which may offer a new strategy for generating SMC-specific knockout mouse models. We also provided in vivo evidence supporting the potential importance of Mymsl in vascular pathophysiology.
- Published
- 2020
25. Set7 deletion attenuates isoproterenol-induced cardiac fibrosis and delays cardiac dysfunction.
- Author
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Lunardon, Guilherme, de Oliveira Silva, Tábatha, Lino, Caroline A., Yao Wei Lu, Miranda, Juliane B., Asprino, Paula F., de Almeida Silva, Amanda, Nepomuceno, Gabrielle T., Costa Irigoyen, Maria Cláudia, Carneiro-Ramos, Marcela S., C. Takano, Ana Paula, da Silva Martinho, Herculano, Barreto-Chaves, Maria Luiza M., Da-Zhi Wang, and Diniz, Gabriela P.
- Subjects
HEART diseases ,HEART fibrosis ,CARDIAC hypertrophy ,ISOPROTERENOL ,MITOCHONDRIAL DNA ,DNA methyltransferases ,PENILE erection ,METHYLTRANSFERASES ,DIASTOLE (Cardiac cycle) - Abstract
Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild-type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E′-wave deceleration time and E/A ratio compared with their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
26. Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction
- Author
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Xuyang Fu, Yingchao Wang, Jianqiu Pei, Xiaoxuan Dong, Feng Gao, Jinghai Chen, Jun Jiang, Jian-an Wang, Tian Liang, Douglas B. Cowan, Ning Liu, Xinyang Hu, Feng Zhang, Da-Zhi Wang, and Yao Wei Lu
- Subjects
Mice, Knockout ,biology ,business.industry ,Regeneration (biology) ,Gene Expression Profiling ,Phosphatase ,Myocardial Infarction ,PTEN Phosphohydrolase ,medicine.disease ,Article ,Mice ,Physiology (medical) ,Cardiac repair ,medicine ,biology.protein ,Cancer research ,PTEN ,Tensin ,Animals ,Myocytes, Cardiac ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Cardiomyocyte proliferation ,Cell Proliferation - Published
- 2020
27. Set7 Deletion Prevents Glucose Intolerance and Improves the Recovery of Cardiac Function After Ischemia and Reperfusion in Obese Female Mice.
- Author
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Miranda, Juliane B., Lunardon, Guilherme, Lima, Vanessa M., de Oliveira Silva, Tábatha, Lino, Caroline A., Jensen, Leonardo, Cláudia Irigoyen, Maria, Bezerra da Silva, Ivson, Yao Wei Lu, Jianming Liu, Júnior, Jose Donato, Barreto-Chaves, Maria Luiza M., Da-Zhi Wang, and Diniz, Gabriela P.
- Subjects
GLUCOSE intolerance ,MYOCARDIAL reperfusion ,WEIGHT gain ,REPERFUSION ,CARDIOVASCULAR diseases ,OBESITY ,TRANSCRIPTION factors ,CATECHOL-O-methyltransferase - Abstract
Background/Aims: An obesogenic diet (high fat and sugar, low fiber) is associated with an increased risk for metabolic and cardiovascular disorders. Previous studies have demonstrated that epigenetic changes can modify gene transcription and protein function, playing a key role in the development of several diseases. The methyltransferase Set7 methylates histone and non-histone proteins, influencing diverse biological and pathological processes. However, the functional role of Set7 in obesity-associated metabolic and cardiovascular complications is unknown. Methods: Wild type and Set7 knockout female mice were fed a normal diet or an obesogenic diet for 12 weeks. Body weight gain and glucose tolerance were measured. The 3T3-L1 cells were used to determine the role of Set7 in white adipogenic differentiation. Cardiac morphology and function were evaluated by histology and echocardiography. An ex vivo Langendorff perfusion system was used to model cardiac ischemia/reperfusion (I/R). Results: Here, we report that Set7 protein levels were enhanced in the heart and perigonadal adipose tissue (PAT) of female mice fed an obesogenic diet. Significantly, loss of Set7 prevented obesogenic diet-induced glucose intolerance in female mice although it did not affect the obesogenic diet-induced increase in body weight gain and adiposity in these animals, nor did Set7 inhibition change white adipogenic differentiation in vitro. In addition, loss of Set7 prevented the compromised cardiac functional recovery following ischemia and reperfusion (I/R) injury in obesogenic diet-fed female mice; however, deletion of Set7 did not influence obesogenic diet-induced cardiac hypertrophy nor the hemodynamic and echocardiographic parameters. Conclusion: These data indicate that Set7 plays a key role in obesogenic dietinduced glucose intolerance and compromised myocardial functional recovery after I/R in obese female mice. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
28. Deletion of miRNA-22 induces cardiac hypertrophy in females but attenuates obesogenic diet-mediated metabolic disorders
- Author
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Alice Cristina Rodrigues, Leonardo Jensen, Renata Inzinna Fonseca, Vanessa Buzatto, Maria Claudia Irigoyen, Tábatha de Oliveira Silva, Pedro A. F. Galante, Caroline Antunes Lino, Gabriela Placoná Diniz, Sidney V. Filho, Maria Luiza Morais Barreto-Chaves, Yao Wei Lu, Gilson Masahiro Murata, Jose Jr Donato, Paula Fontes Asprino, Vanessa Morais Lima, Julio C.B. Ferreira, Zhan-Peng Huang, Da-Zhi Wang, and Márcio A. C. Ribeiro
- Subjects
0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,Physiology ,Heart growth ,Cardiomegaly ,White adipose tissue ,Diet, High-Fat ,lcsh:Physiology ,lcsh:Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Metabolic Diseases ,Internal medicine ,Animals ,Medicine ,lcsh:QD415-436 ,Obesity ,Beta oxidation ,HORMÔNIOS TIREOIDIANOS ,Mice, Knockout ,lcsh:QP1-981 ,business.industry ,Myocardium ,medicine.disease ,MicroRNAs ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,Female ,business ,Gene Deletion ,Dyslipidemia ,Hormone - Abstract
Background/Aims: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. Methods: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. Results: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. Conclusion: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females.
- Published
- 2020
29. Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina
- Author
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Anthony M. Lowery, Guohao Dai, Peter Vincent, Harold A. Singer, Alejandro P. Adam, Li-Yan Sun, John J. Schwarz, and Yao Wei Lu
- Subjects
0301 basic medicine ,Neointima ,Mef2 ,Endothelium ,Anatomy ,Biology ,Internal elastic lamina ,Tunica intima ,Actin cytoskeleton ,Cell biology ,Endothelial stem cell ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,cardiovascular system ,medicine ,Cardiology and Cardiovascular Medicine ,Transcription factor - Abstract
Objective— Laminar flow activates myocyte enhancer factor 2 (MEF2) transcription factors in vitro to induce expression of atheroprotective genes in the endothelium. Here we sought to establish the role of Mef2c in the vascular endothelium in vivo. Approach and Results— To study endothelial Mef2c, we generated endothelial-specific deletion of Mef2c using Tie2-Cre or Cdh5-Cre-ER T2 and examined aortas and carotid arteries by en face immunofluorescence. We observed enhanced actin stress fiber formation in the Mef2c-deleted thoracic aortic endothelium (laminar flow region), similar to those observed in normal aortic inner curvature (disturbed flow region). Furthermore, Mef2c deletion resulted in the de novo formation of subendothelial intimal cells expressing markers of differentiated smooth muscle in the thoracic aortas and carotids. Lineage tracing showed that these cells were not of endothelial origin. To define early events in intimal development, we induced endothelial deletion of Mef2c and examined aortas at 4 and 12 weeks postinduction. The number of intimal cell clusters increased from 4 to 12 weeks, but the number of cells within a cluster peaked at 2 cells in both cases, suggesting ongoing migration but minimal proliferation. Moreover, we identified cells extending from the media through fenestrations in the internal elastic lamina into the intima, indicating transfenestral smooth muscle migration. Similar transfenestral migration was observed in wild-type carotid arteries ligated to induce neointimal formation. Conclusions— These results indicate that endothelial Mef2c regulates the endothelial actin cytoskeleton and inhibits smooth muscle cell migration into the intima.
- Published
- 2017
30. Deletion of miRNA-22 Induces Cardiac Hypertrophy in Females but Attenuates Obesogenic Diet-Mediated Metabolic Disorders.
- Author
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de Oliveira Silva, Tábatha, Lino, Caroline A., Buzatto, Vanessa C., Fontes Asprino, Paula, Yao Wei Lu, Lima, Vanessa M., Fonseca, Renata I. B., Jensen, Leonardo, Murata, Gilson M., Filho, Sidney V., Ribeiro, Márcio A. C., Donato Jr., Jose, Ferreira, Julio C. B., Rodrigues, Alice C., Irigoyen, Maria Cláudia, Barreto-Chaves, Maria Luiza M., Zhan-Peng Huang, Favoretto Galante, Pedro A., Da-Zhi Wang, and Diniz, Gabriela P.
- Subjects
MICRORNA ,DELETION mutation ,CARDIAC hypertrophy ,OBESITY complications ,HEART metabolism disorders ,GENE knockout ,DYSLIPIDEMIA ,ANIMAL models in research - Abstract
Background/Aims: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. Methods: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. Results: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. Conclusion: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
31. Abstract 895: The Role of Poly(rC)-Binding Protein-1 in Heart Development
- Author
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Tiago Fernandes, Yao Wei Lu, Da-Zhi Wang, Xiaoyun Hu, Haipeng Guo, and Ramon A Espinoza-Lewis
- Subjects
endocrine system ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Heart development ,Physiology ,Binding protein ,Nucleic acid ,SUPERFAMILY ,Homology (chemistry) ,Iron transport ,Cardiology and Cardiovascular Medicine - Abstract
Poly(rC)-Binding Protein-1 (Pcbp1) belongs to the KH homology superfamily of nucleic acid-binding proteins, which has been implicated in a vast array of biological processes such as iron transport, RNA processing, post-transcriptional and translational regulations. Germline deletion of Pcbp1 results in embryonic lethality before embryonic day (E) 8.5. To investigate the role of Pcbp1 in heart development, we generated cardiac-specific conditional deletion of Pcbp1 (Pcbp1-cKO) by crossing the Pcbp1-flox with cTNT-Cre mice. The observed frequencies for Pcbp1-cKO at E12.5 and E16.5 are normal, but no surviving Pcbp1-cKO mice were observed at weaning, suggesting the Pcbp1-cKO is perinatal lethal. E12.5 Pcbp1-cKO hearts are smaller with thin myocardium. At E16.5, Pcbp1 cKO hearts displayed ventricular non-compaction and abnormal ventricular apex formation. To understand molecular mechanisms, we perform RNA sequencing follow by differential gene expression analysis in Pcbp1-cKO hearts at E16.5. We found 241 genes were significantly dysregulated and identified unfolded protein response as a key pathway dysregulated. Furthermore, through alternative splicing analysis, we identified 168 uniquely spliced junctions in 139 genes. Of these, 10 differentially spliced genes are also differentially expressed. Future studies will be performed to better understand the biological function and mechanism of Pcbp1 in the heart. Together, this study suggests Pcbp1 is an important regulator of heart development.
- Published
- 2019
32. Abstract 919: Intercalated Disk Protein Xin-beta is Required for the Hippo/YAP Signaling in the Heart
- Author
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Tiago Fernandes, Francisco J. Naya, Zhiqiang Lin, Yuxuan Guo, Xiaoyun Hu, Jenny Li-Chun Lin, Haipeng Guo, Jim J.-C. Lin, Da-Zhi Wang, Jianming Liu, William T. Pu, Zhan-Peng Huang, Yi Wang, and Yao Wei Lu
- Subjects
Physiology ,Intercalated disk ,business.industry ,Cardiomyopathy ,medicine ,Cancer research ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business ,Beta (finance) ,Cause of death - Abstract
Cardiovascular diseases continue to be a leading cause of death and disability. Despite this alarming fact, there is lack of effectual treatment and the molecular mechanisms underlying these devastating diseases remain elusive. Intercalated disk (ICD) is not only essential for the integrity of cardiomyocytes to withstand the strong mechanical forces imposed by constant heart beating; it is also critical for the dissemination of the electrical signal that initiates cardiac contraction. However, relatively less is known about how ICD transmits pathophysiological signals in cardiomyocytes to modulate gene expression and cardiac function. The Xin-α and Xin-β, belongs to a family of Xin-repeat containing proteins, are primarily located at the ICD of adult cardiomyocytes. They play an important role during heart development. Interestingly, the human homologue of the mouse Xin-β gene was mapped to a locus associated with cardiomyopathy; most importantly, mutations in Xin-α and Xin-β have been found in patients with cardiomyopathy, underscoring the importance of Xin genes to cardiac disease. Our previous studies have shown that Xin-β KO mice die postnatally with severe cardiomyopathy. Here, we report that loss of Xin-β results in defect in cardiomyocyte proliferation. Unbiased transcriptome analyses reveal that gene program related to the Hippo/Yap pathway is altered, leading to the hypothesis that Xin-β regulates cardiomyocyte proliferation and cardiac function by modulating the Hippo/Yap signaling. We identify physical and genetic interaction between Xin-β and components of the Hippo/Yap pathway. We further show that the expression of Xin-β is transcriptionally regulated by Mef2a, Yap and Tead1, suggesting the presence of a Xin-β/Yap feedback regulatory network in the heart. Strikingly, cardiac-specific overexpression of Yap markedly rescues cardiac defects in Xin-β KO mice; indicating a functional and genetic interaction between Xin-β and Yap. Together, our study reveals a novel molecular mechanism by which the ICD protein Xin-β modulates important pathophysiological Hippo/Yap signals to control heart development and cardiac function. Molecules uncovered here will become candidate targets for therapeutic treatment of cardiac disease.
- Published
- 2019
33. Non-coding RNA in Ischemic and Non-ischemic Cardiomyopathy
- Author
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Da-Zhi Wang and Yao Wei Lu
- Subjects
0301 basic medicine ,Ischemic cardiomyopathy ,Ventricular Remodeling ,business.industry ,Cardiomyopathy ,RNA ,030204 cardiovascular system & hematology ,medicine.disease ,Non-coding RNA ,Bioinformatics ,03 medical and health sciences ,MicroRNAs ,030104 developmental biology ,0302 clinical medicine ,Heart failure ,Gene expression ,microRNA ,medicine ,Animals ,Humans ,RNA, Long Noncoding ,Cardiology and Cardiovascular Medicine ,business ,Cardiomyopathies ,Gene - Abstract
This review aims to summarize and discuss the function and molecular mechanism of miRNA and lncRNA in the heart, focusing on ischemic and non-ischemic cardiomyopathy. Extensive studies in the past decades have identified numerous protein-coding genes that are highly expressed in the heart, playing essential roles in the regulation of cardiac gene expression, heart development, and function. Furthermore, mutations in many of these genes have been identified and are linked to cardiovascular disease. Intriguingly, it is now recognized that majority of our genome is “non-coding,” which produces a large amount of non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence has indicated that these classes of non-coding RNAs participate in most (if not all) aspects of cardiac gene expression, cardiomyocyte proliferation, differentiation, and cardiac remodeling in response to stress. Recent findings have demonstrated important functions for non-coding RNA in ischemic and non-ischemic cardiomyopathy. It is expected that non-coding RNAs will become promising therapeutic targets for cardiovascular diseases.
- Published
- 2018
34. Transforming growth factor β1 suppresses proinflammatory gene program independent of its regulation on vascular smooth muscle differentiation and autophagy
- Author
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Ping Gao, Yao Wei Lu, Jiemei Ye, Alejandro P. Adam, Xiaochun Long, Wen Wu, and Harold A. Singer
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,Vascular smooth muscle ,ATG5 ,Myocytes, Smooth Muscle ,Biology ,Article ,Muscle, Smooth, Vascular ,Proinflammatory cytokine ,Cell Line ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Autophagy ,Humans ,STAT3 ,Aorta ,Inflammation ,Activator (genetics) ,NF-kappa B ,Cell Differentiation ,Cell Biology ,Cell biology ,030104 developmental biology ,STAT protein ,biology.protein ,cardiovascular system ,Trans-Activators ,Transforming growth factor ,Signal Transduction - Abstract
Transforming growth factor β (TGFβ) signaling plays crucial roles in maintaining vascular integrity and homeostasis, and is established as a strong activator of vascular smooth muscle cell (VSMC) differentiation. Chronic inflammation is a hallmark of various vascular diseases. Although TGFβ signaling has been suggested to be protective against inflammatory aortic aneurysm progression, its exact effects on VSMC inflammatory process and the underlying mechanisms are not fully unraveled. Here we revealed that TGFβ1 suppressed the expression of a broad array of proinflammatory genes while potently induced the expression of contractile genes in cultured primary human coronary artery SMCs (HCASMCs). The regulation of TGFβ1 on VSMC contractile and proinflammatory gene programs appeared to occur in parallel and both processes were through a SMAD4-dependent canonical pathway. We also showed evidence that the suppression of TGFβ1 on VSMC proinflammatory genes was mediated, at least partially through the blockade of signal transducer and activator of transcription 3 (STAT3) and NF-κB pathways. Interestingly, our RNA-seq data also revealed that TGFβ1 suppressed gene expression of a battery of autophagy mediators, which was validated by western blot for the conversion of microtubule-associated protein light chain 3 (LC3) and by immunofluo-rescence staining for LC3 puncta. However, impairment of VSMC autophagy by ATG5 deletion failed to rescue TGFβ1 influence on both VSMC contractile and proinflammatory gene programs, suggesting that TGFβ1-regulated VSMC differentiation and inflammation are not attributed to TGFβ1 suppression on autophagy. In summary, our results demonstrated an important role of TGFβ signaling in suppressing proinflammatory gene program in cultured primary human VSMCs via the blockade on STAT3 and NF-κB pathway, therefore providing novel insights into the mechanisms underlying the protective role of TGFβ signaling in vascular diseases.
- Published
- 2018
35. Abstract 511: Mef2 Transcription Factors are Essential Regulators of Endothelial Morphology and Functions
- Author
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John J. Schwarz and Yao Wei Lu
- Subjects
Morphology (linguistics) ,Endothelium ,Chemistry ,Laminar flow ,Blood flow ,In vitro ,Cell biology ,medicine.anatomical_structure ,Gene expression ,cardiovascular system ,Shear stress ,MEF2 Transcription Factors ,medicine ,Cardiology and Cardiovascular Medicine - Abstract
Background: Laminar shear stress on the endothelium promotes atheroprotecive gene expression. In vitro experiments support a model of laminar shear stress activating the Mef2 transcription factors that in turn induce transcription of Klf2 and Klf4, which regulate many anti-inflammatory and anti-thrombotic genes. However, this model has not been tested in vivo. Three Mef2 transcription factors (Mef2a, -c, and -d) are expressed in the endothelium. To understand their functions and test this model, we generated mice with inducible, endothelial-specific deletions of Mef2c, Mef2a/c, and Mef2a/c/d. Methods & Results: We previously reported that endothelial Mef2c inhibits the formation of endothelial actin stress fibers and migration of smooth muscle cells across the internal elastic lamina into the intima. Combined deletion of endothelial Mef2a/c produced a similar phenotype. Neither of these deletions affected survival or altered the levels of Klf2 or Klf4. However, combined deletions of Mef2a/c/d led to death 10-14 days after induction. Pulmonary hemorrhage was consistently observed as was variable amounts in other organs. En face imaging of the aorta and vena cava revealed a substantial increase in endothelial cell density and proliferation. The aortic endothelium displayed extensive actin stress fibers but the overall organization was not substantially changed. However, the vena cava was disorganized with endothelial cell aggregation. Transcriptome analysis showed ≥ 2-fold alterations in expression of 894 genes, with many important for endothelial function. Notably, Klf2 and Klf4 were both decreased in Mef2a/c/d deficient aortic endothelium to a similar extent as the Mef2s. This is consistent with the phenotypic similarity of Klf2/4 and Mef2a/c/d deletions. Comparison of genes altered by Klf2/4 and Mef2a/c/d deletions revealed that 37% of Mef2-dependent genes are also Klf2/4-dependent. Conclusions: Together, these data support a model in which Mef2 transcription factors redundantly regulate endothelial expression of Klf2 and Klf4 in response to shear stress to promote atheroprotective gene expression. They further regulate expression of many genes important for endothelial function independently of Klf2/4.
- Published
- 2018
36. Intercellular junctions and endothelial permeability are regulated by cell chirality
- Author
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Yao Wei Lu, Leo Q. Wan, John J. Schwarz, Gurleen Kaur, Poulomi Ray, and Jie Fan
- Subjects
medicine.anatomical_structure ,Endothelial permeability ,Chemistry ,Cell ,Genetics ,medicine ,Biophysics ,Chirality (chemistry) ,Molecular Biology ,Biochemistry ,Cell junction ,Biotechnology - Published
- 2018
37. Deletion of miRNA-22 Induces Cardiac Hypertrophy in Females but Attenuates Obesogenic Diet-Mediated Metabolic Disorders.
- Author
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de Oliveira Silva, Tábatha, Lino, Caroline A., Buzatto, Vanessa C., Fontes Asprino, Paula, Yao Wei Lu, Lima, Vanessa M., Fonseca, Renata I. B., Jensen, Leonardo, Murata, Gilson M., Filho, Sidney V., Ribeiro, Márcio A. C., Donato Jr., Jose, Ferreira, Julio C. B., Rodrigues, Alice C., Cláudia Irigoyen, Maria, Barreto-Chaves, Maria Luiza M., Zhan-Peng Huang, Favoretto Galante, Pedro A., Da-Zhi Wang, and Diniz, Gabriela P.
- Subjects
OBESITY ,MICRORNA ,CARDIAC hypertrophy ,METABOLIC disorders ,DYSLIPIDEMIA ,FEMALES - Abstract
Background/Aims: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. Methods: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. Results: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. Conclusion: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
38. Selective expression of TSPAN2 in vascular smooth muscle is independently regulated by TGF-β1/SMAD and myocardin/serum response factor
- Author
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Wen Wu, Emiley Tou, Xiaochun Long, Mingfu Wu, Jinjing Zhao, Yao Wei Lu, David Jourd'heuil, Jiemei Ye, Harold A. Singer, Wei Zhang, and Ping Gao
- Subjects
0301 basic medicine ,Male ,Serum Response Factor ,Vascular smooth muscle ,Tetraspanins ,Cellular differentiation ,Myocytes, Smooth Muscle ,Nerve Tissue Proteins ,Smad Proteins ,SMAD ,Biochemistry ,Muscle, Smooth, Vascular ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Serum response factor ,Genetics ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,Regulation of gene expression ,Chemistry ,Research ,Nuclear Proteins ,Cell Differentiation ,musculoskeletal system ,TSPAN2 ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,Myocardin ,cardiovascular system ,Trans-Activators ,Transcriptome ,Chromatin immunoprecipitation ,tissues ,Biotechnology - Abstract
Tetraspanins (TSPANs) comprise a large family of 4-transmembrane domain proteins. The importance of TSPANs in vascular smooth muscle cells (VSMCs) is unexplored. Given that TGF-β1 and myocardin (MYOCD) are potent activators for VSMC differentiation, we screened for TGF-β1 and MYOCD/serum response factor (SRF)-regulated TSPANs in VSMC by using RNA-seq analyses and RNA-arrays. TSPAN2 was found to be the only TSPAN family gene induced by TGF-β1 and MYOCD, and reduced by SRF deficiency in VSMCs. We also found that TSPAN2 is highly expressed in smooth muscle-enriched tissues and down-regulated in in vitro models of VSMC phenotypic modulation. TSPAN2 expression is attenuated in mouse carotid arteries after ligation injury and in failed human arteriovenous fistula samples after occlusion by dedifferentiated neointimal VSMC. In vitro functional studies showed that TSPAN2 suppresses VSMC proliferation and migration. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that TSPAN2 is regulated by 2 parallel pathways, MYOCD/SRF and TGF-β1/SMAD, via distinct binding elements within the proximal promoter. Thus, we identified the first VSMC-enriched and MYOCD/SRF and TGF-β1/SMAD-dependent TSPAN family member, whose expression is intimately associated with VSMC differentiation and negatively correlated with vascular disease. Our results suggest that TSPAN2 may play important roles in vascular disease.-Zhao, J., Wu, W., Zhang, W., Lu, Y. W., Tou, E., Ye, J., Gao, P., Jourd'heuil, D., Singer, H. A., Wu, M., Long, X. Selective expression of TSPAN2 in vascular smooth muscle is independently regulated by TGF-β1/SMAD and myocardin/serum response factor.
- Published
- 2017
39. Venous Endothelial Marker COUP-TFII Regulates the Distinct Pathologic Potentials of Adult Arteries and Veins
- Author
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Guohao Dai, Qingjie Wang, Peter A. Vincent, John J. Schwarz, Xiaofeng Cui, Yao Wei Lu, Diana Kim, Taylor B. Dorsey, Young Lee, and Vivian K. Lee
- Subjects
Pathology ,medicine.medical_specialty ,Endothelium ,Cellular differentiation ,Hemodynamics ,Down-Regulation ,030204 cardiovascular system & hematology ,Biology ,Article ,Veins ,COUP Transcription Factor II ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Osteogenesis ,medicine ,Animals ,Humans ,COUP-TFII ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,Multidisciplinary ,Cell Differentiation ,Arteries ,Phenotype ,Up-Regulation ,medicine.anatomical_structure ,Endothelium, Vascular ,Biomarkers ,Signal Transduction ,Transcription Factors - Abstract
Arteries and veins have very different susceptibility to certain vascular diseases such as atherosclerosis and vascular calcification. The molecular mechanisms of these differences are not fully understood. In this study, we discovered that COUP-TFII, a transcription factor critical for establishing the venous identity during embryonic vascular development, also regulates the pathophysiological functions of adult blood vessels, especially those directly related to vascular diseases. Specifically, we found that suppression of COUP-TFII in venous ECs switched its phenotype toward pro-atherogenic by up-regulating the expression of inflammatory genes and down-regulating anti-thrombotic genes. ECs with COUP-TFII knockdown also readily undergo endothelial-to-mesenchymal transition (EndoMT) and subsequent osteogenic differentiation with dramatically increased osteogenic transcriptional program and calcium deposition. Consistently, over-expression of COUP-TFII led to the completely opposite effects. In vivo validation of these pro-atherogenic and osteogenic genes also demonstrates a broad consistent differential expression pattern in mouse aorta vs. vena cava ECs, which cannot be explained by the difference in hemodynamic flow. These data reveal phenotypic modulation by different levels of COUP-TFII in arterial and venous ECs and suggest COUP-TFII may play an important role in the different susceptibilities of arteries and veins to vascular diseases such as atherosclerosis and vascular calcification.
- Published
- 2015
40. Potentiation of TNF‐induced inflammatory transcriptional regulation by SFK activation (278.3)
- Author
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Peter A. Vincent, Yao Wei Lu, John J. Schwarz, Hiba Alsaffar, Anthony M. Lowery, Nina Martino, and Alejandro P. Adam
- Subjects
Chemistry ,Genetics ,Transcriptional regulation ,Long-term potentiation ,Tumor necrosis factor alpha ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2014
41. Insulin-like growth factor-1 receptor activation prevents high glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis
- Author
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Yong-Jian Geng, Yao Wei Lu, Yao-Hua Song, Hanjing Wu, Romesh Khardori, and Yangxin Li
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Biophysics ,Apoptosis ,DNA Fragmentation ,Mitochondrion ,Biology ,Biochemistry ,Umbilical vein ,Insulin-like growth factor ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Endothelial dysfunction ,Insulin-Like Growth Factor I ,RNA, Small Interfering ,Receptor ,Molecular Biology ,Cells, Cultured ,Cytochrome c ,Cytochromes c ,Cell Biology ,medicine.disease ,Mitochondria ,Endocrinology ,Glucose ,biology.protein ,Endothelium, Vascular - Abstract
Vascular disease is the leading cause of morbidity and mortality in patients with diabetes. Persistent hyperglycemia--the dominant metabolic derangement of diabetes, can cause endothelial cell apoptosis. Diabetes is often associated with low insulin like growth factor-1 (IGF-1), and the latter state has been linked to adverse risk profile and increased cardiovascular disease incidence. Since IGF-1 acts as an important survival factor for multiple cell types, this study was to investigate whether IGF-1 exert regulatory effects on high glucose-induced apoptosis of vascular endothelial cells. Exposure to high glucose dose- and time-dependently induced apoptotic changes (e.g., DNA fragmentation, altered mitochondrial membrane potential, and cytochrome-c release) in human umbilical vein endothelial cells (HUVECs). Addition of IGF-1 blocked the high glucose effect in a manner dependent on expression of IGF-1 receptor (IGF-1R) since silencing IGF-1R with small interference RNA could diminish the IGF-1' anti-apoptosis effect. Our findings show that enhanced IGF-1 signaling inhibits glucose-induced apoptosis in HUVECs by reducing mitochondrial dysfunction, and maintaining the mitochondrial retention of cytochrome-c. These results may have therapeutic implications in preventing/reducing diabetes associated endothelial dysfunction.
- Published
- 2009
42. microRNA-221 regulates high glucose-induced endothelial dysfunction
- Author
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Yong-Jian Geng, Fan Li, Yao Wei Lu, Tong Yang, Yao-Hua Song, and Yangxin Li
- Subjects
medicine.medical_specialty ,Endothelium ,Biophysics ,Stem cell factor ,Biology ,Carbohydrate metabolism ,Biochemistry ,Umbilical vein ,Article ,Cell Movement ,Internal medicine ,microRNA ,medicine ,Humans ,Endothelial dysfunction ,Receptor ,Molecular Biology ,Cells, Cultured ,Cell Biology ,medicine.disease ,Endothelial stem cell ,MicroRNAs ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Endocrinology ,Glucose ,Hyperglycemia ,Endothelium, Vascular - Abstract
Persistent hyperglycemia in diabetes causes endothelial cell dysfunction. Exposure to high levels of glucose, which mimics hyperglycemia, induced expression of microRNA 221 (miR-221) but reduced expression of c-kit, the receptor for stem cell factor in human umbilical vein endothelial cells (HUVECs). In addition, high glucose treatment impaired endothelial cell migration. Incubation with the antisense miR-221 oligonucleotide AMO-221 reduced expression of miR-221 and restored c-kit protein expression in HUVECs treated with high levels of glucose. Furthermore, AMO-221 treatment abolished the inhibitory effect of high glucose exposure on HUVECs transmigration. Thus, under hyperglycemic conditions, miR-221 is induced in HUVECs, which consequently triggers inhibition of c-kit and impairment of HUVECs migration. These findings suggest that manipulation of the miR-221-c-kit pathway may offer a novel strategy for treatment of vascular dysfunction in diabetic patients.
- Published
- 2009
43. Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina.
- Author
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Yao Wei Lu, Lowery, Anthony M., Li-Yan Sun, Singer, Harold A., Guohao Dai, Adam, Alejandro P., Vincent, Peter A., and Schwarz, John J.
- Published
- 2017
- Full Text
- View/download PDF
44. Selective expression of TSPAN2 in vascular smooth muscle is independently regulated by TGF-ß1/SMAD and myocardin/serum response factor.
- Author
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Jinjing Zhao, Wen Wu, Wei Zhang, Yao Wei Lu, Tou, Emiley, Jiemei Ye, Ping Gao, Jourd'heuil, David, Singer, Harold A., Mingfu Wu, and Xiaochun Long
- Published
- 2017
- Full Text
- View/download PDF
45. MEF2 transcription factors are key regulators of sprouting angiogenesis.
- Author
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Sacilotto, Natalia, Chouliaras, Kira M., Nikitenko, Leonid L., Yao Wei Lu, Fritzsche, Martin, Wallace, Marsha D., Nornes, Svanhild, García-Moreno, Fernando, Payne, Sophie, Bridges, Esther, Ke Liu, Biggs, Daniel, Ratnayaka, Indrika, Herbert, Shane P., Molnár, Zoltán, Harris, Adrian L., Davies, Benjamin, Bond, Gareth L., Bou-Gharios, George, and Schwarz, John J.
- Subjects
- *
TRANSCRIPTION factors , *GENE expression , *NEOVASCULARIZATION , *VASCULAR endothelial growth factors , *HISTONE acetyltransferase - Abstract
Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factorA (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
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