title: Ablation of cereblon attenuates myocardial ischemia-reperfusion injury.
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 30 min followed by 24h 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.
authors.affiliation: Global Research Laboratory, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: Jooyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: Kwang Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: Chul-Seung
authors.initials: CS
authors.lastname: Park
authors.affiliation: Global Research Laboratory, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea. Electronic address: woojinpark@me.com.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D049069:ATP-Dependent Proteases; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; C503910:CRBN protein, rat; D002352:Carrier Proteins; C549921:Crbn protein, mouse; D009419:Nerve Tissue Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D055372:AMP-Activated Protein Kinases; D010447:Peptide Hydrolases; D049069:ATP-Dependent Proteases
keywords: AMPK; Cereblon; Heart; Ischemia–reperfusion injury