Abstract 10426: Inactivation of DJ-1/Park7 Promotes Pathologic Cardiac Hypertrophy by Inhibiting Hif-1α and Promoting Myocyte Apoptosis During Biomechanical Stress
Introduction: Mutation of DJ-1/Park7 (DJ), an autosomal recessive gene associated with familial Parkinson's disease, causes mitochondrial dysfunction and increased sensitivity to reactive oxygen species (ROS). Increased ROS contributes to the development of heart failure (HF). While DJ is highly expressed in the heart, its physiologic function in this organ has not been studied. Preliminary western blot data revealed that DJ protein was markedly decreased in human pathological left ventricular (LV) samples as compared to normal tissue, linking an altered DJ protein level to human HF.
Hypothesis: Genetic deletion of DJ in murine models of HF will lead to an enhanced oxidative stress response that results in exaggerated cardiac hypertrophy.
Methods and Results: Adult DJ-null (KO) mice were viable and fertile with no baseline cardiac abnormalities. After 3 days trans-aortic banding (TAB), numbers of apoptotic cardiomyocytes (CM) were significantly increased in KO vs WT (TUNEL: 18.9±0.9 vs 7.5±0.7%; Ρ<0.001) as were indicators of oxidative stress (lipid peroxidation, 8-OhdG). In contrast, activities of antioxidant enzymes (aconitase, MnSOD, CuZnSOD) were decreased in KO vs WT. Although quantitative RT-PCR revealed no differences in transcript levels of biochemical markers of hypertrophy (ANF, BNP, Sk-Actin, β-MHC), KO mice did exhibit increased septal wall thickening (0.99±0.08 vs 0.84±0.09mm; Ρ<0.05), impaired cardiac function (FS 27±3.1 vs 34±2.9%; Ρ<0.05) as determined by echocardiography and increased collagen deposition (33.9±4.4 vs 41.8±3.6% of myocardial surface) as assessed by immunofluorescence microscopy. TAB also decreased the number of microvessels/CM in KO vs WT (1.12±0.06 vs 1.37±0.04; Ρ<0.01) and markedly reduced Hif-1α mRNA. Vascular endothelial growth factor and angiopoietin-1 mRNAs were also significantly downregulated by TAB in KO vs WT, with a concomitant increase in p53 protein in KO.
Conclusions: Our study demonstrates that loss of DJ results in increased oxidative stress in CM and suggests that the physiologic function of DJ in the heart is to attenuate CM apoptosis by inhibiting p53 and promoting angiogenesis through Hif-1α induction.
- © 2010 by American Heart Association, Inc.