肾去交感神经术调节PI3K/AKT/GSK-3β通路改善糖尿病性心肌病大鼠心功能及心肌重构

Renal denervation improves cardiac function and myocardial remodeling in rats with diabetic cardiomyopathy by regulation of PI3K/AKT/GSK-3β pathway

目的 :探究肾去交感神经术(renal denervation, RDN)对糖尿病性心肌病(diabetic cardiomyopathy, DCM)大鼠心功能及心肌重构的影响及相关机制。方法:28只雄性SD大鼠随机分为对照组(8只)、DCM组(10只)及RDN组(10只),利用高脂高热量饲料+链尿佐霉素(streptozotocin, STZ)构建DCM模型,STZ注射后8周行RDN术。STZ注射后12周,心超检测心功能,Masson染色检测心肌纤维化水平,TUNEL免疫荧光染色检测凋亡水平,Western Blot检测凋亡相关蛋白半胱天冬酶-3(caspase-3, C3)、活性半胱天冬酶-3(cleaved caspase-3, CC3)的表达,以及通路蛋白磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase, PI3K)、丝氨酸/苏氨酸激酶(serine/threonine kinase, AKT)、糖原合成酶激酶-3β(glycogen synthase kinase-3β, GSK-3β)的表达。结果:与DCM组相比,RDN治疗显著升高了大鼠的左室射血分数(left ventricular ejection fraction, LVEF)及左室短轴缩短率(left ventricular fractional shortening, LVFS),降低了左室收缩期内径(left ventricular end systolic diameter, LVDs)及舒张期内径(left ventricular end diastolic diameter, LVDd),减少了心肌胶原容积分数(collagen volume fraction, CVF),降低了心肌细胞凋亡率(cardiac myocyte apoptosis rate, CMAR)及凋亡相关蛋白表达水平,同时有效升高了PI3K/AKT/GSK-3β通路的蛋白表达水平。结论:RDN可有效改善DCM模型大鼠的心功能及心肌重构,其机制可能与调节PI3K/AKT/GSK-3β通路抑制心肌细胞凋亡有关。

Objective:To investigate the effect of renal denervation(RDN)on cardiac function and myocardial remodeling in rats with diabetic cardiomyopathy(DCM)and the underlying mechanism.Methods:A total of 28 male Sprague-Dawley(SD)rats were randomly divided into the control group(n=8),the DCM group(n=10)and the RDN group(n=10).The DCM model was constructed using high-fat diet with streptozotocin(STZ)injection,and RDN surgery was performed 8 weeks after STZ injection.All rats were sacrificed at 12 weeks after STZ injection.Echocardiography was used to evaluate cardiac function.Masson staining was performed to evaluate myocardial fibrosis.TUNEL staining was performed to evaluate myocardial apoptosis.Western Blot was used to detect the expression of apoptosis-related proteins caspase-3(C3)and cleaved caspase-3(CC3),as well as pathway proteins phosphatidylinositol-3-kinase(PI3 K),serine/threonine kinase(AKT)and glycogen synthase kinase-3β(GSK-3β).Results:Compared with the DCM group,rats in the RDN group showed increased left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS),decreased left ventricular end diastolic diameter(LVDd)and left ventricular end systolic diameter(LVDs),reduced collagen volume fraction(CVF),lower cardiac myocyte apoptosis rate(CMAR),as well as decreased expression of apoptosis-related protein.Meanwhile,RDN also increased the protein expression of PI3 K/AKT/GSK-3βpathway.Conclusion:RDN could improve cardiac function and myocardial remodeling in rats with DCM,which might be related to its regulation of PI3 K/AKT/GSK-3βpathway.