The Protective Effect Of Glycine On Cardiac Hypertrophy And Heart Failure Induced By Stress Load

Glycine is a non-essential but the simplest amino acid.It exists in most tissues playing a key role in the metabolism of one-carbon fragments,proteins,peptides,nucleotides,porphyrins,and bile salts.Glycine is one of the main components that mediate fast inhibitory neurotransmission in the central nervous system(CNS).Activation of glycine-gated ion channels(GlyRs)leads to postsynaptic hyperpolarization induced by chloride influx,or a shunt effect characterized by a drop in membrane resistance consecutive to enhanced chloride conductance.It has been reported that prophylactic and therapeutic administration of glycine can protect organs and tissues from several pathological impairs.Recent studies from our laboratory have suggested that glycine attenuates myocardial ischemia-reperfusion injury by inhibiting myocardial apoptosis in rats.However,little is known about the role of glycine in cardiomyopathy,especially in cardiac hypertrophy and heart failure.We hypothesized that glycine may benefically impact on the pressure overload-induced myocardial remodeling and,thus,prevents the development of dilated cardiomyopathy and ultimately heart failure.In vivo studies,mice underwent transverse aortic constriction,and the characteristics of cardiac remodeling were analyzed by echocardiography,histology,and gene expression four weeks after surgery.Pretreatment with glycine attenuated the development of myocardial fibrotic remodelling and inhibited cardiac Raf/MEK/ERK and GATA-4 activities.We also found that glycine therapy significantly improved left ventricular function.Moreover,administration of glycine one week after aortic banding prevented cardiac remodelling by inhibiting myocyte hypertrophy.In vitro experiments were performed in neonatal rat ventricular cardiomyocytes.Treatment of cardiac myocytes with glycine inhibited angiotensin II induced cardiac myocytes hypertrophy through inhibiting ERK activity.Glycine receptor a2(GlyRa2)subunit transcripts and proteins were detected in cardiomyocytes in this study.The effect of glycine was significantly dampened by SiRNA-mediated knockdown of GlyRa2.In conclusion,this study demonstrats for the first time the protective role of glycine on pressure overload induced myocardial remodeling.The effect of glycine might be mediated via glycine receptor a2 linking to the Raf/MEK/ERK/GATA-4 signaling.Thus,glycine may in the future serve as a therapeutic molecule for treatment of heart failure.