hexarelin and Fibrosis

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide. Growth hormone secretagogues (GHS) have been shown to improve cardiac function in models of IHD. This study determined whether hexarelin (HEX), a synthetic GHS, preserves cardiac function and morphology in a mouse model of myocardial infarction (MI). MI was induced by ligation of the left descending coronary artery in C57BL/6J mice followed by vehicle (VEH; n = 10) or HEX (0.3 mg/kg/day; n = 11) administration for 21 days. MI-injured and sham mice (treated with VEH; n = 6 or HEX; n = 5) underwent magnetic resonance imaging for measurement of left ventricular (LV) function, mass and infarct size at 24 h and 14 days post-MI. MI-HEX mice displayed a significant improvement (P < 0.05) in LV function compared with MI-VEH mice after 14 days treatment. A significant decrease in LV mass, interstitial collagen and collagen concentration was demonstrated with chronic HEX treatment (for 21 days), accompanied by a decrease in TGF-β1 expression, myofibroblast differentiation and an increase in collagen-degrading MMP-13 expression levels. Furthermore, heart rate variability analysis demonstrated that HEX treatment shifted the balance of autonomic nervous activity toward a parasympathetic predominance and sympathetic downregulation. This was combined with a HEX-dependent decrease in troponin-I, IL-1β and TNF-α levels suggestive of amelioration of cardiomyocyte injury. These results demonstrate that GHS may preserve ventricular function, reduce inflammation and favorably remodel the process of fibrotic healing in a mouse model of MI and hold the potential for translational application to patients suffering from MI.

Topics: Animals; Blood Pressure; Disease Models, Animal; Fibrosis; Heart; Inflammation; Male; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Oligopeptides; Ventricular Remodeling

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.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Collagen Type I; Collagen Type III; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Heart Diseases; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardium; Oligopeptides; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Ghrelin; RNA, Messenger; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Ventricular Dysfunction, Left; Ventricular Function, Left