GSH And L-Arg Mitigate Diabetic Heart Dysfunction: Mitochondria Protection In Diabetic Rats

Aims:It has confirmed the greater incidence and prevalence of heart failure in diabetes.Heart disease is a leading cause of death in diabetes. The aim of this study was to examine the mechanism of Diabetic cardiopathy and the effect of GSH and L-arginine(L-Arg) on functional, metabolic,structural changes and the activity of mitochondria in heart of streptozotocin(STZ) induced-diabetic rats.Methods:Adult male Sprague-Dawley rats,randomized into control and experimental groups which were divided into diabetes group induced by STZ(65 mg/kg b.wt.) and therapeutic groups following with GSH or L-Arg treatment.Left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS) were determined by echocardiography after 8 weeks;MPA multichannel biology signal analysis system assayed the systolic blood pressure(SBP),diastolic blood pressure(DBP),mean blood pressure(MBP) and heart rate(HR);creatine kinase(CK) and serum lactate dehydrogenase(LDH) were detected to determine the heart function.Histomorphologic changes were observed by optics microscope and electron microscope,respectively.Serum me(?)abolic parameters of Triglyeride(TG),Total Cholesterol(TC), high-density lipoprotein cholesterol(HDL-c),low-density lipoprotein cholesterol(LDL-c) and blood glucose were detected.Stringent state was observed by Malondialdehyde(MDA) and superoxide dismutase(SOD). The mitochondrial function was detected by assessment of mitochondrial SOD,SDH,mitochondrial swelling and mitochondrial membrane potential(MMP).The expression of Voltage-dependent anion channel (VDAC),apoptosis inducing factor(AIF) and second mitochondrial activator of caspase(Smac) was detected by immunohistochemistry.Results:1.Firstly,a significant decrease in LVFF,LVFS and HR, marked elevation in BP,CK and LDH activities were found in the DM rats;Histopathological studies revealed that DM rat heart tissues showed muscle plasma agglutination and hyalinization.Meanwhile,TG,TC and glucose levels of DM rats were significantly higher than those of the normal rats;SOD was significantly decreased and MDA had a significant increase in heart of DM rats.Except these,significantly collapse of MMP and attenuation of Ca²⁺-induced mitochondrial swelling,SOD and SDH were showed in heart mitochondria of DM rats.The mitochondria presented in the heart from the DM rats,were quite different from that of the mitochondria from normal rat hearts,which were vague of mitochondrial crista,dislocated,calcified,smaller.At last,hearts of normal rats showed a strong signal for VDAC and a weak one for Smac, and diabetes rat showed a significant change.2.It was found that treatment with GSH orally(500 mg/kg,for 8 weeks) significantly increased LVEF and HR,decreased blood pressure, blocked the marked elevation in serum CK and serum LDH activity of diabetic rats.And L-Arg significantly decreased the levels of TG compared with DM rats.Meanwhile,a significant increase in MDA and decrease in SOD activities,in heart,was observed in diabetic rats and this was significantly attenuated by GSH.On the other hand,treatment with GSH could significantly inhibit the significantly collapse of the MMP and strengthen Ca²⁺-induced mitochondrial swelling in heart of diabetes rats.3.It was found that treatment with L-Arg orally(125 mg/kg b.wt.,for 8 weeks) significantly increased LVEF,LVFS and heart rate,decreased blood pressure,blocked the marked elevation in serum CK and serum LDH activity of diabetic rats;50 mg/kg L-Arg treatment significantly attenuated the change of LVFS,heart rate,CK and LDH,but there was no significant change on LVEF and blood pressure.And 125 mg/kg L-Arg significantly decreased the levels of TG compared with DM rats.During 125 mg/kg L-Arg treatment,abnormal histologic and ultrastructural characteristics were reduced.Meanwhile,a significant increase in MDA, in heart,was observed in diabetic rats and this was significantly attenuated by 50 mg/kg and 125 mg/kg L-Arg,and a significant decrease in SOD activities could be attenuated by 125 mg/kg L-Arg.On the other hand,treatment with 125 mg/kg L-Arg could significantly inhibit the significantly collapse of the mitochondrial SDH,SOD activities,MMP and strengthen Ca²⁺-induced mitochondrial swelling in heart of diabetes rats,recover VDAC,AIF and Smac protein expression.Conclusion:Both GSH and L-Arg protected the heart of STZ induced-diabetic rats.The mechanism may improve the function of mitochondria and inhibite oxidative stress in heart to reduce heart injury induced by diabetes.