Despite therapeutic advances, no current treatment fully reverses impaired heart function. Heart failure often develops in individuals with coronary artery disease; high blood pressure or have suffered a myocardial infarction. Heart failure can develop at any age, but increases in prevalence with age. Moreover, individuals of advanced age also develop a syndrome of heart failure with preserved ejection fraction (HFpEF). Experimental models of aging as well as human studies suggest that endogenous repair capabilities become depleted with age. Therefore, novel interventions that preserve cardiac homeostasis are essential to reduce heart failure associated morbidity and mortality. Our novel and potent family of synthetic peptide analogues of Growth Hormone Releasing Hormone (GHRH) receptor agonists (GHRH-As) produce a comprehensive repair program in two models of heart failure associated with ischemic heart disease. Treatment with GHRH-A improved cardiac function and attenuated remodeling in both acute and chronic models of ischemic injury, and improved peripheral vascular function. These effects are mediated by direct activation of GHRH receptor signaling, promoting endogenous cell survival and repair mechanisms. However, the cellular targets and mechanisms involved remain to be elucidated. The long-term goal of this proposal is to identify the mechanisms underlying GHRH- mediated cardiac protection and apply GHRH-targeted therapeutics to prevent HFpEF. We propose a combination of in vivo and ex vivo approaches to test the central hypothesis that activation of GHRHR signaling restores cardiac structure and function in HFpEF by promoting cardiomyocyte proliferation and reducing fibrosis and apoptosis.
The specific aims of this grant are to test the hypotheses that 1) GHRH Receptor signaling regulates cardiomyocyte function; 2) GHRH-A therapy prevents cardiovascular changes and/or restores cardiovascular function in Ang II-induced mouse models of HFpEF; and 3) GHRH-As prevent and/or reverse HFpEF in a porcine model of chronic kidney disease. Together this series of aims will provide novel insights into the mechanisms by which GHRH-As are cardioprotective and to the development of novel and effective therapeutic approaches tailored to improve cardiac performance in patients with HFpEF and other cardiovascular diseases.

Public Health Relevance

Heart failure with preserved ejection fraction (HFpEF) represents a leading cause of death and disability worldwide, yet there are no current therapies that directly treat this challenging clinical syndrome. In this proposal, we will explore the mechanisms through which Growth Hormone Releasing Hormone analogs act to protect the heart from injury. Our findings will have implications for developing new therapeutic strategies for HFpEF and other related cardiovascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Internal Medicine/Medicine
Schools of Medicine
Coral Gables
United States
Zip Code
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