New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor

// Rosemeire M. Kanashiro-Takeuchi 1, 2, * , Luca Szalontay 3, * , Andrew V. Schally 1, 3, 4, 5, 6 , Lauro M. Takeuchi 1 , Petra Popovics 3, 7, 8 , Miklos Jaszberenyi 3, 4 , Irving Vidaurre 3 , Marta Zarandi 3 , Ren-Zhi Cai 3, 4 , Norman L. Block 1, 3, 4, 5, 6 , Joshua M. Hare 1, 8 , Ferenc G. Rick 3, 9 1 Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida, United States of America 2 Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Florida, United States of America 3 Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida, United States of America 4 Department of Pathology, University of Miami, Miller School of Medicine, Miami, Florida, United States of America 5 Department of Medicine, Divisions of Hematology/Oncology and Endocrinology, University of Miami, Miller School of Medicine, Miami, Florida, United States of America 6 Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, United States of America 7 Department of Medicine III, Medical Faculty Carl Gustav Carus, TU Dresden, Germany 8 Department of Medicine, Division of Cardiology, University of Miami, Miller School of Medicine, Miami, Florida, United States of America 9 Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America * These authors have contributed equally to this work Correspondence to: Ferenc G. Rick, e-mail: ferencrick@gmail.com Keywords: growth hormone-releasing hormone, myocardial infarction, heart failure, remodeling, cardioprotection Received: January 27, 2015 Accepted: February 08, 2015 Published: March 14, 2015 ABSTRACT Background: We previously showed that growth hormone-releasing hormone (GHRH) agonists are cardioprotective following myocardial infarction (MI). Here, our aim was to evaluate the in vitro and in vivo activities of highly potent new GHRH agonists, and elucidate their mechanisms of action in promoting cardiac repair. Methods and Results: H9c2 cells were cultured in serum-free medium, mimicking nutritional deprivation. GHRH agonists decreased calcium influx and significantly improved cell survival. Rats with cardiac infarction were treated with GHRH agonists or placebo for four weeks. MI size was reduced by selected GHRH agonists (JI-38, MR-356, MR-409); this accompanied an increased number of cardiac c-kit + cells, cellular mitotic divisions, and vascular density. One week post-MI, MR-409 significantly reduced plasma levels of IL-2, IL-6, IL-10 and TNF-α compared to placebo. Gene expression studies revealed favorable outcomes of MR-409 treatment partially result from inhibitory activity on pro-apoptotic molecules and pro-fibrotic systems, and by elevation of bone morphogenetic proteins. Conclusions: Treatment with GHRH agonists appears to reduce the inflammatory responses post-MI and may consequently improve mechanisms of healing and cardiac remodeling by regulating pathways involved in fibrosis, apoptosis and cardiac repair. Patients with cardiac dysfunction could benefit from treatment with novel GHRH agonists.