Role of the alpha2-isoform of AMP-activated protein kinase in the metabolic response of the heart to no-flow ischemia.
AMP-activated protein kinase (AMPK) is a major sensor and regulator of the energetic state of the cell. Little is known about the specific role of AMPKalpha(2), the major AMPK isoform in the heart, in response to global ischemia. We used AMPKalpha(2)-knockout (AMPKalpha(2)(-/-)) mice to evaluate the consequences of AMPKalpha(2) deletion during normoxia and ischemia, with glucose as the sole substrate. Hemodynamic measurements from echocardiography of hearts from AMPKalpha(2)(-/-) mice during normoxia showed no significant modification compared with wild-type animals. In contrast, the response of hearts from AMPKalpha(2)(-/-) mice to no-flow ischemia was characterized by a more rapid onset of ischemia-induced contracture. This ischemic contracture was associated with a decrease in ATP content, lactate production, glycogen content, and AMPKbeta(2) content. Hearts from AMPKalpha(2)(-/-) mice were also characterized by a decreased phosphorylation state of acetyl-CoA carboxylase during normoxia and ischemia. Despite an apparent worse metabolic adaptation during ischemia, the absence of AMPKalpha(2) does not exacerbate impairment of the recovery of postischemic contractile function. In conclusion, AMPKalpha(2) is required for the metabolic response of the heart to no-flow ischemia. The remaining AMPKalpha(1) cannot compensate for the absence of AMPKalpha(2).
Zarrinpashneh
Elham
E
Division of Cardiology, Université catholique de Louvain, B-1200 Brussels, Belgium.
Carjaval
Karla
K
Beauloye
Christophe
C
Ginion
Audrey
A
Mateo
Philippe
P
Pouleur
Anne-Catherine
AC
Horman
Sandrine
S
Vaulont
Sophie
S
Hoerter
Jacqueline
J
Viollet
Benoit
B
Hue
Louis
L
Vanoverschelde
Jean-Louis
JL
Bertrand
Luc
L
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000225:Adenine / Q000032:analysis; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006003:Glycogen / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology; D007773:Lactates / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology; D017202:Myocardial Ischemia / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D005227:Fatty Acids; D007527:Isoenzymes; D007773:Lactates; D009097:Multienzyme Complexes; D000255:Adenosine Triphosphate; D006003:Glycogen; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D000225:Adenine