胰岛素信号和PHLPP-1的相互作用对心衰大鼠Akt通路的影响

Mutual Inhibition of Insulin Signaling and PHLPP-1 Influences Akt Pathway in Experimental Rats with Heart Failure

目的研究胰岛素信号和PHLPP-1的相互抑制作用在心衰大鼠中对Akt通路的影响。方法成年雄性SD大鼠30只,随机分为3组:正常对照组、心衰模型组、胰岛素组。心衰模型组和胰岛素组采用腹腔注射阿霉素法建造大鼠心衰模型,胰岛素组给予诺和灵R腹腔注射。6周后行心脏彩超检测大鼠心功能;ELISA法检测大鼠血清尿钠肽(BNP)含量;HE染色检测大鼠心肌组织病理学改变;免疫蛋白印迹法(Western blot)检测p-Akt Ser473和PHLPP-1蛋白的表达。结果与正常对照组比较,心衰模型组心功能明显衰竭,心腔扩大,LVEF值降低(P<0.05),血清BNP含量显著增加,心肌细胞坏死、肌纤维排列紊乱、炎细胞浸润,心肌p-Akt Ser473含量降低,PHLPP-1含量增加(P<0.05);与心衰模型组比较,胰岛素组左室扩张、心功能降低明显改善,血清BNP含量降低,心肌细胞形态、纤维排列、炎症细胞浸润有所改善,p-Akt Ser473含量增加,PHLPP-1含量降低(P<0.05)。结论胰岛素信号可通过抑制PHLPP-1阻止Akt去磷酸化,从而减少心肌细胞凋亡,延缓心衰进展。

Objective To investigate the influence of insulin signaling and PHLPP-1 mutual inhibition on Akt pathway in experi- mental rats with heart failure. Methods Thirty senior male SD rats were randomly divided into 3 groups：control group,DOX group and Insu- lin group. The heart failure model was established by injection of DOX. The insulin group was given intraperitoneal injection of Novolin R. Af- ter 6 weeks,echocardiography was performed to observe the cardiac function, the morphology of myocardium was observed by HE staining, the level of BNP in serum was detected with ELISA,and p-Akt Ser473 and PHLPP-I protein expression was measured with Western blot. Results Compared with control group, the rats in DOX group showed cardiac function failure, cardiac chamber enlargement, decreased LVEF （ P 〈 0. 05 } ,lower serum BNP level, myocardial necrosis, muscle fiber disorder, inflammatory cell infiltration, decreased p-Akt Ser473 and increased PHLPP-1 （ P 〈 0.05 ）. Compared with DOX group, insulin group showed the enlargement of left ventricular and improvement of heart function, the level of serum BNP was higher, the myocardial cell morphology,fiber arrangemen and inflammatory cell infiltration were improved,the ex- pression of p-Akt Ser473 was increased and PHLPP-1 was decreased （ P 〈 0.05 ）. Conclusion Insulin signaling can prevent Akt dephospho- rylation by inhibiting PHLPP-1, thereby reducing myocardial apoptosis and delaying the progression of heart failure.