AMP Activated Protein Kinase-alpha 2 Deficiency Exacerbates Pressure-Overload-Induced Left Ventricular Hypertrophy and Dysfunction in Mice

作者：Zhang Ping; Hu Xinli; Xu Xin; Fassett John; Zhu Guangshuo; Viollet Benoit; Xu Wayne; Wiczer Brian; Bernlohr David A; Bache Robert J; Chen Yingjie^*

来源：Hypertension, 2008, 52(5): 918-924.

DOI：10.1161/HYPERTENSIONAHA.108.114702

• hypertrophy
• congestive heart failure
• mTOR

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 AMPK alpha 2 protects the heart against systolic overload-induced ventricular hypertrophy and dysfunction, we studied the response of AMPK alpha 2 gene deficient (knockout [KO]) mice and wild-type mice subjected to 3 weeks of transverse aortic constriction (TAC). Although AMPK alpha 2 KO had no effect on ventricular structure or function under control conditions, AMPK alpha 2 KO significantly increased TAC-induced ventricular hypertrophy (ventricular mass increased 46% in wild-type mice compared with 65% in KO mice) while decreased left ventricular ejection fraction (ejection fraction decreased 14% in wild-type mice compared with a 43% decrease in KO mice). AMPK alpha 2 KO also significantly exacerbated the TAC-induced increases of atrial natriuretic peptide, myocardial fibrosis, and cardiac myocyte size. AMPK alpha 2 KO had no effect on total S6 ribosomal protein (S6), p70 S6 kinase, eukaryotic initiation factor 4E, and 4E binding protein-1 or their phosphorylation under basal conditions but significantly augmented the TAC-induced increases of p-p70 S6 kinase(Thr389), p-S6(Ser235), and p-eukaryotic initiation factor 4E(Ser209). AMPK alpha 2 KO also enhanced the TAC-induced increase of p-4E binding protein-1(Thr46) to a small degree and augmented the TAC-induced increase of p-Akt(Ser473). These data indicate that AMPK alpha 2 exerts a cardiac protective effect against pressure-overload-induced ventricular hypertrophy and dysfunction. (Hypertension. 2008;52:918-924.)

• 出版日期2008-11