The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

Abstract

SummaryHexarelin, a synthetic growth hormone-releasing peptide, has been proven to possess cardioprotective actions through its binding to the growth hormone secretagogue receptor (GHSR) 1a and the non-GHSR receptor CD36. However, its effect on myocardial ischemia/reperfusion (I/R) injury has not been fully clarified in vivo. We aimed to determine whether hexarelin treatment could protect cardiomyocytes from I/R injury and to examine the underlying mechanisms. In vivo hearts of male SD rats underwent 30 minutes of ischemia by left coronary artery ligation followed by reperfusion. The rats were then treated subcutaneously twice daily with hexarelin [100 μg/kg·day], ghrelin [400 μg/ kg·day], or saline for 7 days. Echocardiography, malondialdehyde detection, and histochemical staining were performed after treatment. In addition, Western blot was used to examine the expression levels of IL-1β, IL-1Ra, and IL-1RI. Our study showed that hexarelin treatment improved cardiac systolic function, decreased malondialdehyde production, and increased the number of surviving cardiomyocytes. The beneficial effects of hexarelin treatment were slightly superior to those of equimolar ghrelin treatment. We meanwhile confirmed that hexarelin induced down-regulation of IL-1β expression and up-regulation of IL-1Ra expression in I/R myocardium, which could be neutralized by the GHSR antagonist A cute myocardial infarction, which is caused by a sudden embolism of the coronary arteries, is a leading cause of mortality. As the primary clinical therapy for treatment of myocardial infarction, myocardial reperfusion can also aggravate cardiac injury. 1) Its mechanism includes calcium overload, cardiomyocyte apoptosis, and reactive oxygen species (ROS) accumulation.2-5) Finding a strategy to alleviate myocardial I/R injury has become a hot research field in cardiology.In vivo I/R models can cause regional myocardial I/R injury by ligating the left anterior descending coronary artery, which have been widely used to mimic the process of myocardial infarction and subsequent reperfusion.6) Compared to the in vitro global I/R models, in vivo I/R models can not only reveal changes in hemodynamics, and cardiac structure and function after I/R, but also display the impact of molecules in reperfusion flow on I/R myocardium, such as ROS and inflammation cytokines.7) The in vivo I/R models are more consistent with the pathophysiological process of myocardial I/R injury.Ghrelin, a growth hormone-releasing peptide produced in the stomach, is an endogenous ligand of growth hormone secretagogue receptor (GHSR) 1a. Previous studies have demonstrated the cardioprotective effects of exogenous ghrelin administration. 8) Hexarelin, a synthetic analog of ghrelin, shows effects similar to those of ghrelin and is more chemically stable, making it a potential alternative to ghrelin. Its beneficial action on the cardiovascular system has been reported by a lot of research, including inhibition of cardiomyocyte apoptosis, [9][10][11] anti-atherosclerosis, 12,13) impro...

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