Institute of Biomedicine, University of Helsinki, Finland.
Cardiovasc Diabetol. 2010 Jan 27;9:5. doi: 10.1186/1475-2840-9-5.
Diabetes is associated with changes in myocardial stress-response pathways and is recognized as an independent risk factor for cardiac remodeling. Using spontaneously diabetic Goto Kakizaki rats as a model of type 2 DM we investigated whether post-translational modifications in the Akt - FOXO3a pathway, Sirt1 - p53 pathway and the mitogen activated protein kinase p38 regulator are involved in post-infarct cardiac remodeling
Experimental myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in spontaneously diabetic Goto-Kakizaki rats and non-diabetic Wistar controls. Cardiac function was studied by echocardiography. Myocardial hypertrophy, cardiomyocyte apoptosis and cardiac fibrosis were determined histologically 12 weeks post MI or Sham operation. Western blotting was used to study Caspase-3, Bax, Sirt1, acetylation of p53 and phosphorylation of p38, Akt and FOXO3a. Electrophoretic mobility shift assay was used to assess FOXO3a activity and its nuclear localization.
Post-infarct heart failure in diabetic GK rats was associated with pronounced cardiomyocyte hypertrophy, increased interstitial fibrosis and sustained cardiomyocyte apoptosis as compared with their non-diabetic Wistar controls. In the GK rat myocardium, Akt- and FOXO3a-phosphorylation was decreased and nuclear localization of FOXO3a was increased concomitantly with increased PTEN protein expression. Furthermore, increased Sirt1 protein expression was associated with decreased p53 acetylation, and phosphorylation of p38 was increased in diabetic rats with MI.
Post-infarct heart failure in diabetic GK rats was associated with more pronounced cardiac hypertrophy, interstitial fibrosis and sustained cardiomyocyte apoptosis as compared to their non-diabetic controls. The present study suggests important roles for Akt-FOXO3a, Sirt1 - p53 and p38 MAPK in the regulation of post-infarct cardiac remodeling in type 2 diabetes.
糖尿病与心肌应激反应途径的变化有关，被认为是心脏重构的独立危险因素。本研究使用自发性糖尿病 Goto Kakizaki 大鼠作为 2 型糖尿病模型，探讨 Akt-FOXO3a 通路、Sirt1-p53 通路和丝裂原活化蛋白激酶 p38 调节物的翻译后修饰是否参与梗死后心脏重构。
通过左前降支冠状动脉结扎诱导自发性糖尿病 Goto-Kakizaki 大鼠和非糖尿病 Wistar 对照大鼠实验性心肌梗死（MI）。通过超声心动图研究心功能。MI 或假手术后 12 周，通过组织学方法测定心肌肥厚、心肌细胞凋亡和心肌纤维化。Western blot 检测 Caspase-3、Bax、Sirt1、p53 乙酰化和 p38、Akt 和 FOXO3a 的磷酸化。电泳迁移率变动分析用于评估 FOXO3a 活性及其核定位。
与非糖尿病 Wistar 对照相比，糖尿病 GK 大鼠梗死后心力衰竭与明显的心肌肥厚、间质纤维化和持续的心肌细胞凋亡有关。在 GK 大鼠心肌中，Akt 和 FOXO3a 的磷酸化减少，FOXO3a 的核定位增加，同时伴有 PTEN 蛋白表达增加。此外，Sirt1 蛋白表达增加与 p53 乙酰化减少有关，p38 磷酸化增加。
与非糖尿病对照相比，糖尿病 GK 大鼠梗死后心力衰竭与更明显的心肌肥厚、间质纤维化和持续的心肌细胞凋亡有关。本研究表明，Akt-FOXO3a、Sirt1-p53 和 p38 MAPK 在 2 型糖尿病梗死后心脏重构的调节中具有重要作用。
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