Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis
Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis
复制标题
DOI：
10.1124/jpet.104.070839
复制
发表时间：
2004-12
影响因子：
3.5
通讯作者：
Y. Takada;Masami Hashimoto;J. Kasahara;K. Aihara;K. Fukunaga
中科院分区：
文献类型：
--
作者：
Y. Takada;Masami Hashimoto;J. Kasahara;K. Aihara;K. Fukunaga
在心肌缺血性梗死的大鼠模型中，原钒酸钠可使细胞免受缺血/再灌注损伤。通过阻断左冠状动脉使大鼠心肌缺血30分钟，随后再灌注24小时。原钒酸钠进行后处理可剂量依赖性地减小梗死面积。原钒酸钠处理还能改善再灌注72小时后左心室的收缩功能障碍。原钒酸钠处理的细胞保护作用与抑制血影蛋白降解密切相关。由于原钒酸钠是蛋白酪氨酸磷酸酶的强效抑制剂，从而激活酪氨酸激酶和磷脂酰肌醇3 - 激酶（PI3K）通路，我们研究了心肌细胞中PI3K的下游靶点蛋白激酶B（Akt）的活性。原钒酸钠诱导的细胞保护作用与心肌梗死后降低的Akt活性的部分恢复有关。原钒酸钠处理使Akt活性恢复，这与心肌细胞中糖原合成酶激酶 - 3β和Bad磷酸化增加呈正相关。此外，原钒酸钠处理可抑制缺血诱导的半胱天冬酶 - 3激活。综上所述，原钒酸钠后处理通过激活Akt和抑制血影蛋白降解，使心肌细胞免受缺血/再灌注损伤，从而抑制细胞凋亡。
In a rat model of myocardial ischemic infarction, sodium orthovanadate rescued cells from ischemia/reperfusion injuries. Rats underwent 30 min of myocardial ischemia by occluding the left coronary artery followed by 24 h of reperfusion. Post-treatment with orthovanadate reduced infarct size in a dose-dependent manner. Orthovanadate treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. The cytoprotective action of orthovanadate treatment was closely associated with inhibition of fodrin breakdown. Since orthovanadate is a potent inhibitor for protein tyrosine phosphatases, thereby activating tyrosine kinases and phosphatidylinositol 3-kinase (PI3K) pathways, we investigated activities of protein kinase B (Akt), a downstream target of PI3K in cardiomyocytes. Orthovanadate-induced cytoprotection was associated with partial restoration of reduced Akt activity following myocardial infarction. Restoration of Akt activity by orthovanadate treatment correlated positively with increased phosphorylation of glycogen synthase kinase-3β and Bad in cardiomyocytes. Furthermore, orthovanadate treatment inhibited caspase-3 activation induced by ischemia. Taken together, orthovanadate post-treatment rescued cardiomyocytes from ischemia/reperfusion injuries via Akt activation and inhibition of fodrin breakdown, thereby inhibiting apoptosis.