Heart disease is a leading cause of death worldwide. Increasing evidence indicates that apoptosis, associated with detrimental structural and functional alterations, is a major contributor in the progression of cardiac remodeling and heart failure. Thus, preventing the loss of cardiomyocytes becomes critical for the maintenance of normal cardiac function. However, inhibition of cardiac cell death would hold little clinical promise, if it simply resulted in increased survival of dysfunctional cardiomyocytes. Our recent studies suggest that the small heat-shock protein Hsp20 may improve cardiac function and provide protection against cardiomyocyte death. Hsp20 is different from the other members of sHsps in the following respects: 1) It regulates both vasorelaxation and cardiac contractility;2) Overexpression of Hsp20 provides cardioprotection against p-agonist-induced apoptosis and ischemia/reperfusion-induced injury;and 3) Hsp20 contains a unique PKA/PKG phosphorylation site, RRAS, and phosphorylation of this site, significantly increases contractility and cardioprotection in cardiomyocytes. In this project, we propose further studies to elucidate the in vivo role of Hsp20 and its phosphorylation in cardiac contractility, using genetically altered mouse models. Furthermore, since alterations in the levels of Hsp20 and its phosphorylation regulate the heart's responses to stress, we propose to further investigate the efficacy of Hsp20 and specifically phosphorylated Hsp20 in the heart's remodeling process in response to pressure-overload and myocardial infarction. We also propose to determine the therapeutic significance of Hsp20 in the setting of pre-existing heart failure, using in vivo cardiac gene delivery. These studies will provide important information on the functional role of cardiac Hsp20 in vivo under physiological and pathophysiological conditions. Overall, our proposed studies will: a) advance our knowledge on the mechanisms underlying regulation of cardiac contractility and apoptotic cell death by Hsp20;and b) provide valuable insights into the potential benefits of Hsp20 in heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087861-04
Application #
7796555
Study Section
Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
Schwartz, Lisa
Project Start
2007-04-18
Project End
2012-01-31
Budget Start
2010-04-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$390,000
Indirect Cost
Name
University of Cincinnati
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Chen, Yanfang; Tang, Yaoliang; Fan, Guo-Chang et al. (2018) Extracellular vesicles as novel biomarkers and pharmaceutic targets of diseases. Acta Pharmacol Sin 39:499-500
Liu, Guan-Sheng; Zhu, Hongyan; Cai, Wen-Feng et al. (2018) Regulation of BECN1-mediated autophagy by HSPB6: Insights from a human HSPB6S10F mutant. Autophagy 14:80-97
Peng, Jiangtong; Li, Yutian; Wang, Xiaohong et al. (2018) An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPAR? Ubiquitination. Cell Rep 23:3607-3620
Mu, Xingjiang; Wang, Xiaohong; Huang, Wei et al. (2018) Circulating Exosomes Isolated from Septic Mice Induce Cardiovascular Hyperpermeability Through Promoting Podosome Cluster Formation. Shock 49:429-441
Hong, Guangliang; Zheng, Dong; Zhang, Lulu et al. (2018) Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis. Free Radic Biol Med 123:125-137
Yu, You-Jiang; Wang, Xiao-Hong; Fan, Guo-Chang (2018) Versatile effects of bacterium-released membrane vesicles on mammalian cells and infectious/inflammatory diseases. Acta Pharmacol Sin 39:514-533
Salem, Esam S B; Fan, Guo-Chang (2017) Pathological Effects of Exosomes in Mediating Diabetic Cardiomyopathy. Adv Exp Med Biol 998:113-138
Zheng, Dong; Yu, Yong; Li, Minghui et al. (2016) Inhibition of MicroRNA 195 Prevents Apoptosis and Multiple-Organ Injury in Mouse Models of Sepsis. J Infect Dis 213:1661-70
Hu, Jing; Al-Waili, Daniah; Hassan, Aishlin et al. (2016) Inhibition of cerebral vascular inflammation by brain endothelium-targeted oligodeoxynucleotide complex. Neuroscience 329:30-42
Ni, Rui; Cao, Ting; Xiong, Sidong et al. (2016) Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy. Free Radic Biol Med 90:12-23

Showing the most recent 10 out of 56 publications