Abstract
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. 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. 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.
Highlights
Current management of congestive heart failure (HF) serves to maximize the effectiveness of the remaining heart tissue in order to maintain an adequate cardiac output
Treatment with growth hormone-releasing hormone (GHRH) agonists appears to reduce the inflammatory responses post-myocardial infarction (MI) and may 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
Summary
Current management of congestive heart failure (HF) serves to maximize the effectiveness of the remaining heart tissue in order to maintain an adequate cardiac output. Secretory events which occur in cardiomyocytes and fibroblasts play a critical role in the progression of myocardial remodeling leading to heart failure [3]. Both of these cell types secrete a variety of growth factors, cytokines, and hormones that influence cardiomyocyte growth and fibroblast activation in paracrine and autocrine manners. Our group reported recently that receptors for growth hormone-releasing hormone (GHRH-R) are present on the cell membranes of both cardiomyocytes [4, 5] and fibroblasts [6], and mediate the direct effects of this hormone. 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
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