Abstract 12829: Ablation of Pink1 Evokes Spontaneous Early-Onset Cardiac Left Ventricular Hypertrophy and Hypersensitivity to Biomechanical Stress
Introduction: Mutations in the protein kinase Pink1 are associated with autosomal recessive Parkinson's disease. Pink1 protects cells against oxidative stress such that Pink1 inactivation leads to mitochondrial dysfunction, increased sensitivity to reactive oxygen species (ROS) and apoptosis. Increased ROS impair cardiac function and promote heart failure (HF). Preliminary western blotting revealed that Pink1 protein was markedly decreased in human pathological left ventricular (LV) samples as compared to normal tissue, linking an altered Pink1 level to human HF.
Hypothesis: Genetic depletion of Pink1 in mouse models of HF will increase oxidative stress and promote pathologic cardiac hypertrophy.
Methods and Results: Wild type (WT) and Pink1-deficient (KO) mice were examined at 2 and 6 months of age for concentric hypertrophy. The heart weight/body weight ratio (WT vs KO; 17.9% vs 35.4%) and cardiomyocyte (CM) cross-sectional area (14.2% vs 26.5%) were increased in KO mice. Transcripts of biochemical markers of hypertrophy (ANF, BNP, α-MHC. β-MHC) were also elevated as analyzed by qPCR. At 2 months, KO mice exhibited impaired cardiac function (fractional shortening (FS); 40±6% vs 31.4±4%) as determined by echocardiography. At 6 months, LVEDd and LVESd in KO mice had increased by an additional 21% and 64%, respectively, whereas FS had further declined. Numbers of apoptotic CM were markedly enhanced in KO vs WT, as were indicators of oxidative stress (lipid peroxidation, 8-OhdG), but activities of antioxidant enzymes (aconitase, MnSOD, CuZnSOD) were reduced. After 4 weeks of trans-aortic banding (TAB), KO mice showed significantly impaired cardiac contractility (FS; 34±2% vs 27±1%) and increased collagen deposition (26.3±3.8 vs 36.5±3.4% of myocardial surface) compared to the WT.
Conclusions: Our data show that (i) Pink1 is important for proper postnatal myocardial development; (ii) elimination of Pink1 is sufficient to cause post-natal pathophysiologic hypertrophy; and (iii) Pink1 KO mice are sensitized to biomechanical stress signals that induce enhanced cardiac hypertrophy. Thus, Pink1 is a novel signal-responsive suppressor of cardiac hypertrophy and HF.
- © 2010 by American Heart Association, Inc.