Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10755021 | Biochemical and Biophysical Research Communications | 2014 | 6 Pages |
Abstract
Cereblon (CRBN) was originally identified as a target protein for a mild type of mental retardation in humans. However, recent studies showed that CRBN acts as a negative regulator of AMP-activated protein kinase (AMPK) by binding directly to the AMPK catalytic subunit. Because AMPK is implicated in myocardial ischemia-reperfusion (I-R) injury, we reasoned that CRBN might play a role in the pathology of myocardial I-R through regulation of AMPK activity. To test this hypothesis, wild-type (WT) and crbn knockout (KO) mice were subjected to I-R (complete ligation of the coronary artery for 30Â min followed by 24Â h of reperfusion). We found significantly smaller infarct sizes and less fibrosis in the hearts of KO mice than in those of WT mice. Apoptosis was also significantly reduced in the KO mice compared with that in WT mice, as shown by the reduced numbers of TUNEL-positive cells. In parallel, AMPK activity remained at normal levels in KO mice undergoing I-R, whereas it was significantly reduced in WT mice under the same conditions. In rat neonatal cardiomyocytes, overexpression of CRBN significantly reduced AMPK activity, as demonstrated by reductions in both phosphorylation levels of AMPK and the expression of its downstream target genes. Collectively, these data demonstrate that CRBN plays an important role in myocardial I-R injury through modulation of AMPK activity.
Keywords
ACCinfarcted areaTriphenyltetrazoliumCRBN5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranosidepoly (ADP-ribose) polymerase 1SREBP1PARP1PGC1αCPT1AARAMPKAICARTTCeNOSAMP-activated protein kinaseCereblonIschemia–reperfusion injuryacetyl-CoA carboxylaseischemia–reperfusionLeft ventricularTerminal deoxynucleotidyl transferase dUTP nick end labelingTUNELendothelial nitric oxide synthaseHeartknockoutwild-typesterol regulatory element-binding protein 1Carnitine palmitoyltransferase 1
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Authors
Jooyeon Kim, Kwang Min Lee, Chul-Seung Park, Woo Jin Park,