Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction

Abstract

Whether the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear.Here we tested the hypothesis that growth hormone-releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH/IGF-1 independent fashion. After experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4-week period, either placebo (n = 14), rat recombinant GH (n = 8) or JI-38 (n = 8; 50 µg/kg per day), a potent GHRH agonist. JI-38 did not elevate serum levels of GH or IGF-1, but it markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, and circulating GH and IGF-1, but it did not offset the decline in cardiac structure and function. Whereas both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased antiapoptotic gene expression. The receptor for GHRH was detectable on myocytes, supporting direct activation of cardiac signal transduction. Collectively, these findings demonstrate that within the heart, GHRH agonists can activate cardiac repair after MI, suggesting the existence of a potential signaling pathway based on GHRH in the heart. The phenotypic profile of the response to a potent GHRH agonist has therapeutic implications.cardiac stem cells | apoptosis | remodeling | heart failure C ongestive heart failure remains a leading cause of morbidity and mortality in developed countries. Despite major therapeutic advances, current therapies fail to fully reverse heart failure and/or left ventricular (LV) dysfunction. One major therapeutic avenue is that of cytokine and/or hormonal signaling pathways, and in this regard, various experimental and clinical studies have suggested an important role for the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the regulation of cardiac growth and function (1, 2). Moreover, several clinical studies have tested the impact of GH replacement on the failing human heart, with controversial results (3, 4).In addition to GH itself and IGF-1, GH-releasing peptides such as ghrelin and synthetic GH secretagogues (GHS) are also suggested to have cardiac effects (5-8), and growth hormone-releasing hormone (GHRH) mRNA is detected in peripheral tissues, including the heart (9, 10), consistent with widespread biologic signaling potential beyond the hypothalamic-pituitary axis.Recently, Granata et al. (10) reported that rat GHRH (1-44) promoted survival of cardiomyocytes in vitro and protected rat hearts from ischemia-reperfusion injury. The detection of the GHRH receptor (GHRHR) on the cardiomyocyte sarcolemmal membrane supports the view that GHRH may elicit direct signal transduction within the heart, independent of the GH/IGF-1 axis per se (10). Ghrelin and other GHS may have pharmacologic potential (10) but also have pleiotropic actions with a high possibility...

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

“…Although peripheral tissues rarely express full-length GHRH-R, splice variants can also be found (21). Thus, GHRH-R and splice variant SV1 are present not only in tumors but also in myocardium, pancreatic β-islet cells, and fibroblasts (22)(23)(24). Nonpituitary GHRH can modulate cell proliferation, especially in malignant tissues (18), promote healing of skin wounds, inhibit cardiomyocyte apoptosis, and reduce infarct size in isolated rat heart after ischemia reperfusion and in vivo after myocardial infarction (21)(22)(23)(24)(25).…”

“…Nonpituitary GHRH can modulate cell proliferation, especially in malignant tissues (18), promote healing of skin wounds, inhibit cardiomyocyte apoptosis, and reduce infarct size in isolated rat heart after ischemia reperfusion and in vivo after myocardial infarction (21)(22)(23)(24)(25). Moreover, GHRH agonists were shown to stimulate cardiac myocytes, to accelerate regeneration of the heart in rats after myocardial infarct, to stimulate pancreatic β-islet cells, and to accelerate wound healing in mice (21)(22)(23)(24).…”

Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists

“…These findings suggest the potential for the development of new therapeutic paradigms in the treatment of brain cancers using agonistic as well as antagonistic analogs of hypothalamic GHRH. These GHRH analogs (2,4,6,11,(20)(21)(22), may augment the direct cytotoxic effect of traditional chemotherapeutic drugs, by stimulation and maturation of stem cells and eliciting cellular synchronization of the cell cycle. To further investigate this phenomenon, other studies are necessary to assess the outcome of the combination of GHRH analogs and improved forms of chemotherapeutic agents such as liposomal doxorubicin.…”

“…Previous studies also suggested that growth factors such as EGF or agonistic analogs of LHRH serving as carriers for cytotoxic analogs and functioning as growth factors may sensitize cancer cells to cytotoxic treatments (10,19) through the activation of maturation processes. We therefore hypothesized that pretreatment with one of our GHRH agonists, such as JI-34 (20), which has shown effects on growth and differentiation in other cell lines (17,18,21,22), might decrease the pluripotency and the adaptability of GBM cells and thereby increase their susceptibility to cytotoxic treatment.…”

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

“…Hypothalamic growth hormone-releasing hormone (GHRH) stimulates production and release of GH from the pituitary gland, exerts some of its effects through the GH/IGF axis, and also directly affects extrapituitary cells expressing GHRH receptors by activating these receptors. GHRH receptor(s) have been detected in various tumor cells, stem cells, and other tissues including pancreatic β cells (12)(13)(14)(15)(16). Understanding the action of GHRH on its target cells is important for potential application in the use of synthetic GHRH analogs, with prolonged half-lives, which may provide a promising pharmacologic therapy in various fields.…”