Xiong Shunbin, Van Pelt Carolyn S, Elizondo-Fraire Ana C, Fernandez-Garcia Belen, Lozano Guillermina
Department of Cancer Genetics, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Circulation. 2007 Jun 12;115(23):2925-30. doi: 10.1161/CIRCULATIONAHA.107.689901. Epub 2007 May 28.
Although several loci for familial dilated cardiomyopathy (DCM) have been mapped, the origin of a large percentage of DCM remains unclear. Mdm2, a p53-negative regulator, protects cardiomyocytes from ischemic and reperfusion-induced cell death. Mdm4, a homolog of Mdm2, inhibits p53 activity in numerous cell types. It is unknown whether Mdm4 plays a role in the inhibition of p53 in fully differentiated tissues such as adult cardiomyocytes and whether this role is associated with DCM.
The conditional knockout of Mdm4 in the heart by use of cardiomyocyte-specific Cre (alphaMyHC-Cre) allele does not result in any developmental defects. With time, however, mice with deletion of Mdm4 in the adult heart developed DCM and had a median survival of 234 days. More interestingly, the onset of DCM occurs significantly earlier in male mice than in female mice, which mimics human DCM disease. DCM in Mdm4 mutant mice was caused by loss of cardiomyocytes by apoptosis, and it was p53-dose dependent.
Activity of p53 was inhibited by Mdm4 even in the fully differentiated cardiomyocyte. Elevated apoptosis mediated by the p53 pathway in cardiomyocytes may be a mechanism for DCM.
尽管已经定位了几个家族性扩张型心肌病（DCM）的基因座，但很大一部分DCM的病因仍不清楚。Mdm2是一种p53负调节因子，可保护心肌细胞免受缺血和再灌注诱导的细胞死亡。Mdm4是Mdm2的同源物，在多种细胞类型中抑制p53活性。尚不清楚Mdm4在成年心肌细胞等完全分化组织中是否在抑制p53方面发挥作用，以及这种作用是否与DCM相关。
利用心肌细胞特异性Cre（αMyHC-Cre）等位基因在心脏中条件性敲除Mdm4不会导致任何发育缺陷。然而，随着时间的推移，成年心脏中缺失Mdm4的小鼠发展为DCM，中位生存期为234天。更有趣的是，雄性小鼠DCM的发病明显早于雌性小鼠，这与人类DCM疾病相似。Mdm4突变小鼠的DCM是由心肌细胞凋亡导致的损失引起的，并且是p53剂量依赖性的。
即使在完全分化的心肌细胞中，p53的活性也受到Mdm4的抑制。心肌细胞中由p53途径介导的凋亡增加可能是DCM的一种机制。
