Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Abstract

Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.

Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway

“…Although [D-Lys3]-GHRP-6 has been suggested to exert activities such as stimulation of calcium increase (15), decrease in food intake (1), and reduction of alcohol intake in mice (24), it is unlikely that [D-Lys3]-GHRP-6 would have beneficial effects on the doxorubicin-treated heart. Nonetheless, [D-Lys3]-GHRP-6 has been reported to abolish the antifibrotic effect of hexarelin on interstitial and perivascular fibrosis in the heart of spontaneously hypertensive rats (58), whereas the decrease in cardiac fibrosis induced by desacyl ghrelin in the doxorubicin-treated heart in this study was not found to be abolished by [D-Lys3]-GHRP-6 (Fig. 2, A and B).…”

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

“…So, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation [168].…”

“…weeks from an age of 16 weeks significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts [168].…”

Activation of growth hormone secretagogue receptor induces time-dependent clock phase delay in mice

“…For example, the regulatory role of growth hormone secretagogues (GHSs) and their receptors (GHSR), a newly found branch of the endocrine system, on the circadian clock is still elusive. GHSs are known to have effects on many physiological activities, including pituitary hormone secretion, pancreatic endocrine, gastric acid secretion, regulation of appetite, energy metabolism, and cardiovascular functions (6,13,16,33,46,47). Some investigators reported that GHSs could also influence the circadian rhythm and sleeping, but their findings are inconsistent or even contradictory.…”