Activation of growth hormone releasing hormone (GHRH) receptor stimulates cardiac reverse remodeling after myocardial infarction (MI)

Abstract

Both cardiac myocytes and cardiac stem cells (CSCs) express the receptor of growth hormone releasing hormone (GHRH), activation of which improves injury responses after myocardial infarction (MI). Here we show that a GHRH-agonist (GHRH-A; JI-38) reverses ventricular remodeling and enhances functional recovery in the setting of chronic MI. This response is mediated entirely by activation of GHRH receptor (GHRHR), as demonstrated by the use of a highly selective GHRH antagonist (MIA-602). One month after MI, animals were randomly assigned to receive: placebo, GHRH-A (JI-38), rat recombinant GH, MIA-602, or a combination of GHRH-A and MIA-602, for a 4-wk period. We assessed cardiac performance and hemodynamics by using echocardiography and micromanometry derived pressure-volume loops. Morphometric measurements were carried out to determine MI size and capillary density, and the expression of GHRHR was assessed by immunofluorescence and quantitative RT-PCR. GHRH-A markedly improved cardiac function as shown by echocardiographic and hemodynamic parameters. MI size was substantially reduced, whereas myocyte and nonmyocyte mitosis was markedly increased by GHRH-A. These effects occurred without increases in circulating levels of growth hormone and insulin-like growth factor I and were, at least partially, nullified by GHRH antagonism, confirming a receptor-mediated mechanism. GHRH-A stimulated CSCs proliferation ex vivo, in a manner offset by MIA-602. Collectively, our findings reveal the importance of the GHRH signaling pathway within the heart. Therapy with GHRH-A although initiated 1 mo after MI substantially improved cardiac performance and reduced infarct size, suggesting a regenerative process. Therefore, activation of GHRHR provides a unique therapeutic approach to reverse remodeling after MI.heart failure | cardiac stem cells | cardiac regeneration

cKit + cardiac progenitors of neural crest origin

“…Following the seminal description by Beltrami et al (16) of clusters of cKit cells in the postnatal mammalian heart, several laboratories, including ours, suggested that cKit marks CPs (16)(17)(18)(19), a finding that led to the clinical testing of these cells for heart repair (20). Recently, a straightforward genetic fate-mapping study showed that a relatively small proportion of murine myocardium is derived from cKit + CPs, leading to the conclusion that the cardiomyogenic capacity of cKit + CPs is functionally insignificant (21).…”

Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

“…Our group recently demonstrated that JI-38, a synthetic agonist of the growth hormone-releasing hormone receptor (GHRH-R), has cardioprotective effects and also stimulates cardiac reverse remodeling in a rodent model of myocardial infarction (22,35,36). These findings were associated with an increase in the number of CSCs in vivo.…”

Inhibition of GHRH aggravated acetaminophen-induced acute mice liver injury through GH/IGF-I axis

“…The anesthesia agent was the mixture of ketamine (100 mg/kg) and xylazine (10 mg/kg). The pre-treatment period and dosage of MZ-5-156 and JI-38 were optimized by previous studies [15,16]. Serum and plasma samples were obtained from whole blood by centrifugation at 3,000 rpm for 15 min.…”