ELEVATED p53 EXPRESSION IS ASSOCIATED WITH DYSREGULATION OF THE UBIQUITIN-PROTEASOME SYSTEM IN DILATED CARDIOMYOPATHY.

Cardiovasc Res. 2008 Mar 28;

Authors: Birks EJ, Latif N, Enesa K, Folkvang T, Luong LA, Sarathchandra P, Khan M, Ovaa H, Terracciano CM, Barton PJ, Yacoub MH, Evans PC

AIMS: The molecular mechanisms that regulate cardiomyocyte apoptosis and their role in human heart failure (HF) are uncertain. Expression of the apoptosis regulator p53 is governed by MDM2, an E3 enzyme that targets p53 for ubiquitination and proteasomal processing, and by the deubiquitinating enzyme HAUSP which rescues p53 by removing ubiquitin chains from it. Here we examined whether elevated expression of p53 was associated with dysregulation of ubiquitin-proteasome system (UPS) components and activation of downstream effectors of apoptosis in human dilated cardiomyopathy (DCM). Methods and Results Left ventricular myocardial samples were obtained from patients with DCM (n=12) or from non-failing (donor) hearts (n=17). Western blotting and immunohistochemistry revealed that DCM tissues contained elevated levels of p53 and its regulators MDM2 and HAUSP (all p<0.01) compared to non-failing hearts. DCM tissues also contained elevated levels of polyubiquitinated proteins and possessed enhanced 20S-proteasome chymotrypsin-like activities (p<0.04) as measured in vitro using a fluorogenic substrate. DCM tissues contained activated caspases-9 and -3 (p<0.001) and reduced expression of the caspase substrate PARP-1 (p<0.05). Western blotting and immunohistochemistry revealed that DCM tissues contained elevated expression levels of caspase-3 activated DNAse (CAD; p<0.001) which is a key effector of DNA fragmentation in apoptosis and also contained elevated expression of a potent inhibitor of CAD (ICAD-S; p<0.01). CONCLUSION: Expression of p53 in human DCM is associated with dysregulation of UPS components that are known to regulate p53 stability. Elevated p53 expression and caspase activation in DCM was not associated with activation of both CAD and its inhibitor ICAD-S. Our findings are consistent with the concept that apoptosis may be interrupted and therefore potentially reversible in human HF.

PMID: 18375498 [PubMed - as supplied by publisher]