AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice.
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.
Cardiovascular Division, University of Minnesota, Minneapolis, MN 55455, USA.
Ping
P
Zhang
Xinli
X
Hu
Xin
X
Xu
John
J
Fassett
Guangshuo
G
Zhu
Benoit
B
Viollet
Wayne
W
Xu
Brian
B
Wiczer
David A
DA
Bernlohr
Robert J
RJ
Bache
Yingjie
Y
Chen
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010656:Phenylephrine; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013318:Stroke Volume / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C499527:Eif4ebp1 protein, mouse; C491779:Elf4 protein, mouse; D039642:Eukaryotic Initiation Factors; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; D014157:Transcription Factors; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases