Abstract
The maintenance of normal heart function requires proper control of protein turnover. The ubiquitin-proteasome system is a principal regulator of protein degradation. Mdm2 is the main E3 ubiquitin ligase for p53 in mitotic cells thereby regulating cellular growth, DNA repair, oxidative stress and apoptosis. However, which of these Mdm2-related activities are preserved in differentiated cardiomyocytes has yet to be determined. We sought to elucidate the role of Mdm2 in the control of normal heart function. We observed markedly reduced Mdm2 mRNA levels accompanied by highly elevated p53 protein expression in the hearts of wild type mice subjected to myocardial infarction or trans-aortic banding. Accordingly, we generated conditional cardiac-specific Mdm2 gene knockout (Mdm2f/f;mcm) mice. In adulthood, Mdm2f/f;mcm mice developed spontaneous cardiac hypertrophy, left ventricular dysfunction with early mortality post-tamoxifen. A decreased polyubiquitination of myocardial p53 was observed, leading to its stabilization and activation, in the absence of acute stress. In addition, transcriptomic analysis of Mdm2-deficient hearts revealed that there is an induction of E2f1 and c-Myc mRNA levels with reduced expression of the Pgc-1a/Ppara/Esrrb/g axis and Pink1. This was associated with a significant degree of cardiomyocyte apoptosis, and an inhibition of redox homeostasis and mitochondrial bioenergetics. All these processes are early, Mdm2-associated events and contribute to the development of pathological hypertrophy. Our genetic and biochemical data support a role for Mdm2 in cardiac growth control through the regulation of p53, the Pgc-1 family of transcriptional coactivators and the pivotal antioxidant Pink1.
Highlights
Heart failure occurs when the heart is unable to adequately pump blood to meet the demands of the body at normal filling pressures
When compared to mRNA isolated from healthy hearts, murine double-minute 2 (Mdm2) gene expression was significantly decreased in samples from patients with idiopathic dilated cardiomyopathy (DCM), ischemic cardiomyopathy and chemotherapy-induced cardiomyopathy (P < 0.05) (Fig 1), suggesting a correlation between Mdm2 expression and end-stage HF of these etiologies
To elucidate the potential function of the p53/Mdm2 circuitry in cardiomyocytes, we examined their protein expression and mRNA levels in left ventricular samples derived from C57BL/6J wild-type mice subjected to myocardial infarction (MI) or trans-aortic banding (TAB)
Summary
Heart failure occurs when the heart is unable to adequately pump blood to meet the demands of the body at normal filling pressures. Mdm targets many proteins regulating pleiotropic biological processes including cell growth, proliferation and apoptosis, such as the tumor suppressors Trp (p53), retinoblastoma (Rb1) or the transcription factor E2f1 and targets them for proteasomal degradation [32,33,34]. The loss of Mdm severely impacts redox homeostasis and mitochondrial function through activation of the transcription factors c-Myc and E2f1, both known for their ability to induce apoptosis and inhibit antioxidative systems. Under these conditions, negative regulation of the Pgc-1a/ Ppar/Esrr axis and Pink evoked oxidative stress, energy deprivation and cardiac dysfunction. Our data identify Mdm as a regulator of cardiac homeostasis through the persistent upregulation of ROS-detoxifying systems and mitochondrial energy metabolism
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