AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice.
AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice.
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DOI：
10.1161/hypertensionaha.108.114702
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
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作者：
Zhang P;Hu X;Xu X;Fassett J;Zhu G;Viollet B;Xu W;Wiczer B;Bernlohr DA;Bache RJ;Chen Y
AMP激活蛋白激酶（AMPK）在调节心肌代谢和蛋白质合成中发挥着重要作用。 AMPK 的激活可减弱培养的心肌细胞的肥大，但 AMPK 在调节慢性压力超负荷引起的心肌肥大发展中的作用尚不清楚。为了验证 AMPKα2 保护心脏免受收缩超负荷引起的心室肥大和功能障碍的假设，我们研究了 AMPKα2 基因缺陷 (KO) 小鼠和野生型 (WT) 小鼠在接受 3 周主动脉横缩 (TAC) 后的反应。尽管AMPKα2 KO在对照条件下对心室结构或功能没有影响，但AMPKα2 KO显着增加了TAC诱导的心室肥大（WT小鼠的心室质量增加了46％，而KO小鼠的心室质量增加了65％），同时降低了左心室射血分数（WT小鼠的射血分数减少了14％，而KO小鼠的射血分数减少了43％）。 AMPKα2 KO 还显着加剧了 TAC 诱导的心房钠尿肽、心肌纤维化和心肌细胞大小的增加。 AMPKα2 KO 对总 S6 核糖体蛋白 (S6)、p70 S6 激酶 (70S6K)、真核起始因子 4E (eIF4e) 和 4E 结合蛋白 1 (4EBP1) 或其在基础条件下的磷酸化没有影响，但显着增强了 TAC 诱导的 p-70S6KThr389、p-S6Ser235 和 p-S6Ser235 的增加。 p-eIF4eSer209。 AMPKα2 KO 还小程度增强了 TAC 诱导的 p-4EBP1Thr46 的增加，并增强了 TAC 诱导的 p-AktSer473 的增加。这些数据表明 AMPKα2 对压力超负荷引起的心室肥厚和功能障碍发挥心脏保护作用。
AMP activated protein kinase (AMPK) plays an important role in regulating myocardial metabolism and protein synthesis. Activation of AMPK attenuates hypertrophy in cultured cardiac myocytes, but the role of AMPK in regulating the development of myocardial hypertrophy in response to chronic pressure overload is not known. To test the hypothesis that AMPKα2 protects the heart against systolic overload induced ventricular hypertrophy and dysfunction, we studied the response of AMPKα2 gene deficient (KO) mice and wild type (WT) mice subjected to 3 weeks of transverse aortic constriction (TAC). Although AMPKα2 KO had no effect on ventricular structure or function under control conditions, AMPKα2 KO significantly increased TAC-induced ventricular hypertrophy (ventricular mass increased 46% in WT mice compared to 65% in KO mice), while decreasing left ventricular ejection fraction (ejection fraction decreased 14% in WT mice compared to a 43% decrease in KO mice). AMPKα2 KO also significantly exacerbated the TAC–induced increases of atrial natriuretic peptide, myocardial fibrosis and cardiac myocyte size. AMPKα2 KO had no effect on total S6 Ribosomal Protein (S6), p70 S6 kinase (70S6K), eukaryotic initiation factor 4E (eIF4e) and 4E binding protein-1 (4EBP1) or their phosphorylation under basal conditions, but significantly augmented the TAC-induced increases of p-70S6KThr389, p-S6Ser235, and p-eIF4eSer209. AMPKα2 KO also enhanced the TAC-induced increase of p-4EBP1Thr46 to a small degree and augmented the TAC-induced increase of p-AktSer473. These data indicate that AMPKα2 exerts a cardiac protective effect against pressure overload induced ventricular hypertrophy and dysfunction.