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 infarc- tion. Heart failure can develop at any age, but increases in prevalence with age. Moreover, individuals of ad- vanced 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 as- sociated morbidity and mortality. Our novel and potent family of synthetic peptide analogues of Growth Hor- mone 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 periph- eral 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 re- main 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 combi- nation of in vivo and ex vivo approaches to test the central hypothesis that activation of GHRHR signaling re- stores 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 reg- ulates cardiomyocyte function; 2) GHRH-A therapy prevents cardiovascular changes and/or restores cardio- vascular 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 therapeu- tic approaches tailored to improve cardiac performance in patients with HFpEF and other cardiovascular dis- eases.

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107110-07
Application #
9402118
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2011-01-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
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
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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
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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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