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. 2008 Nov;52(5):918-24.
doi: 10.1161/HYPERTENSIONAHA.108.114702. Epub 2008 Oct 6.

AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice

Ping Zhang  1 , Xinli Hu, Xin Xu, John Fassett, Guangshuo Zhu, Benoit Viollet, Wayne Xu, Brian Wiczer, David A Bernlohr, Robert J Bache, Yingjie Chen
Affiliations

AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice

Ping Zhang et al. Hypertension. 2008 Nov.

Abstract

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 AMPKalpha2 protects the heart against systolic overload-induced ventricular hypertrophy and dysfunction, we studied the response of AMPKalpha2 gene deficient (knockout [KO]) mice and wild-type mice subjected to 3 weeks of transverse aortic constriction (TAC). Although AMPKalpha2 KO had no effect on ventricular structure or function under control conditions, AMPKalpha2 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). AMPKalpha2 KO also significantly exacerbated the TAC-induced increases of atrial natriuretic peptide, myocardial fibrosis, and cardiac myocyte size. AMPKalpha2 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). AMPKalpha2 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 AMPKalpha2 exerts a cardiac protective effect against pressure-overload-induced ventricular hypertrophy and dysfunction.

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Figures

Figure 1
Figure 1
AMPKα2 KO exacerbates TAC-induced ventricular hypertrophy (A), pulmonary congestion (B), decrease of LV ejection fraction (C), increase of mortality rate (D), myocardial fibrosis (E), and cardiac myocyte hypertrophy (F). *p<0.05 compared to the corresponding control; #p<0.05 compared to WT-TAC mice.
Figure 2
Figure 2
Alterations of myocardial total-AMPKα (A,B), AMPKα1 (A,C), p-ACCSer79 (A,D), AMPKα2 activity (E), and ANP protein (F) and mRNA content (G) under control conditions and after TAC for 3 weeks. *P<0.05 compared to the corresponding control; #p<0.05 compared to corresponding WT mice. Mean value was obtained from 5 to 6 samples each group.
Figure 3
Figure 3
Effect of AMPKα2 KO on TAC-induced increases of p-p70s6kThr389, p-s6Ser235/236, p-elf4eSer209, p-Akt Ser473, p-eEF2 Thr56, and p-4EBP1Thr46. *P<0.05 compared to the corresponding control; #p<0.05 compared to corresponding WT mice. Mean value was obtained from 5 to 6 samples each group.
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