There is growing awareness that the heart has receptors for a wide range of cytokines and growth factors, activation of which can enhance myocyte survival and growth. While there has been interest in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis in the regulation of cardiac development and performance, only recently is it appreciated that the hypothalamic hormone, GH releasing hormone also exerts cardiac signaling activity, and that the GHRH receptor is present on myocytes. Recently, we demonstrated that a potent growth hormone releasing hormone agonist (GHRH-A: JI-38) stimulated substantial cardiac repair following acute ischemic injury without stimulating unwanted side effects associated with the GH axis. In addition, Granata et al. demonstrated that GHRH(1-44) promotes survival of cardiomyocytes following ischemia reperfusion. The availability of potent GHRH agonists offers a major new therapeutic opportunity. The overall goal of this project is to use well-validated animal models of ischemic injury and LV dysfunction (rodent and porcine, in use in our laboratory) to test the hypothesis that activation of cardiac GHRH receptors by potent agonists can reverse remodeling and improve recovery of functional performance following myocardial infarction (MI). We propose a program of work to determine the mechanism of action and manifestations of this effect. We will in three aims test the following hypothesis: To test the hypothesis that the effects of GHRH-A are mediated by direct receptor activation of the GHRH-R within the heart;To test the hypothesis that GHRH-A directly activates endogenous cardiac stem cells;Investigate the protective effects of GHRH agonist in a pig model of MI. This proposal has major implications for developing a promising new treatment strategy for the prevention and reversal of remodeling following MI.
We have recently discovered that growth hormone releasing hormone exerts cardioprotective effects following acute myocardial infarction. The goal of this proposal is to advance this novel observation by performing in-depth studies of the mechanism of action of this response in the situation of chronic myocardial infarction that has led to remodeling of the ventricle. In addition, we will test the very novel idea that growth hormone releasing hormone activates cardiac stem cells. Finally, we will perform translational studies in a large animal model of myocardial infarction to gain additional insights into the mechanism of action of this new signaling pathway and to advance the potential therapeutic implications of this new discovery.
|Mayourian, Joshua; Ceholski, Delaine K; Gorski, Przemek A et al. (2018) Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility. Circ Res 122:933-944|
|Starke, Robert M; Thompson, John W; Ali, Muhammad S et al. (2018) Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis. Arterioscler Thromb Vasc Biol 38:610-621|
|Bagno, Luiza; Hatzistergos, Konstantinos E; Balkan, Wayne et al. (2018) Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges. Mol Ther 26:1610-1623|
|Schulman, Ivonne Hernandez; Khan, Aisha; Hare, Joshua M (2018) Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine. Circ Res 123:1030-1032|
|Bolli, Roberto; Hare, Joshua (2018) Introduction to a Compendium on Regenerative Cardiology. Circ Res 123:129-131|
|Arora, Himanshu; Panara, Kush; Kuchakulla, Manish et al. (2018) Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth. Proc Natl Acad Sci U S A 115:11298-11303|
|Kanelidis, Anthony J; Premer, Courtney; Lopez, Juan et al. (2017) Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Preclinical Studies and Clinical Trials. Circ Res 120:1139-1150|
|Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686|
|Tompkins, Bryon A; Rieger, Angela C; Florea, Victoria et al. (2017) New insights into cell-based therapy for heart failure from the CHART-1 study. Eur J Heart Fail 19:1530-1533|
|Fernández-Avilés, Francisco; Sanz-Ruiz, Ricardo; Climent, Andreu M et al. (2017) Global position paper on cardiovascular regenerative medicine. Eur Heart J 38:2532-2546|
Showing the most recent 10 out of 72 publications