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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107110-04
Application #
8589378
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$595,467
Indirect Cost
$206,273
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Tompkins, Bryon A; Natsumeda, Makoto; Balkan, Wayne et al. (2017) What Is the Future of Cell-Based Therapy for Acute Myocardial Infarction. Circ Res 120:252-255
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
Gesmundo, Iacopo; Miragoli, Michele; Carullo, Pierluigi et al. (2017) Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure. Proc Natl Acad Sci U S A 114:12033-12038
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
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
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Hatzistergos, Konstantinos E; Saur, Dieter; Seidler, Barbara et al. (2016) Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. Circ Res 119:921-30
Florea, Victoria; Balkan, Wayne; Schulman, Ivonne Hernandez et al. (2016) Cell Therapy Augments Myocardial Perfusion and Improves Quality of Life in Patients With Refractory Angina. Circ Res 118:911-5
Kulandavelu, Shathiyah; Karantalis, Vasileios; Fritsch, Julia et al. (2016) Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine. J Am Coll Cardiol 68:2454-2464
Hatzistergos, Konstantinos E; Takeuchi, Lauro M; Saur, Dieter et al. (2015) cKit+ cardiac progenitors of neural crest origin. Proc Natl Acad Sci U S A 112:13051-6

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