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

Rosemeire M. Kanashiro-Takeuchi, Luca Szalontay, Andrew V. Schally, Lauro M. Takeuchi, Petra Popovics, Miklos Jaszberenyi, Irving Vidaurre, Marta Zarandi, Ren Zhi Cai, Norman L. Block, Joshua M. Hare, Ferenc G. Rick

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)9728-9739
Number of pages12
JournalOncotarget
Volume6
Issue number12
StatePublished - 2015
Externally publishedYes

Keywords

  • Cardioprotection
  • Growth hormone-releasing hormone
  • Heart failure
  • Myocardial infarction
  • Remodeling

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Kanashiro-Takeuchi, R. M., Szalontay, L., Schally, A. V., Takeuchi, L. M., Popovics, P., Jaszberenyi, M., Vidaurre, I., Zarandi, M., Cai, R. Z., Block, N. L., Hare, J. M., & Rick, F. G. (2015). New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor. Oncotarget, 6(12), 9728-9739.