Abstract 311: Poly(ADP-ribose) Polymerase-1 Inhibition Prevents High Fat Diet-induced Cardiac Hypertrophy by Modulating Matrix-destabilizing Proteases and Oxidative Stress
Background: We recently showed that PARP-1 is activated within atherosclerotic plaques and that inhibition of this enzyme, exerts protective effects against high fat diet-induced atherogenesis. Given the tight association between atherosclerosis and cardiac pathologies, we examined, whether PARP-1 is an active participant in high fat diet-induced cardiac hypertrophy and whether PARP-1 gene knockout prevents such pathological abnormalities.
Methods: Apolipoprotein (ApoE)−/− mice fed a high-fat diet were used as a model of atherosclerosis. C57BL/6 ApoE−/− mice that are deficient in PARP-1 (ApoE-PARP-1d−/−) were generated in our laboratory. Hemodynamic parameters were obtained by a small animal-adapted ultrasound imaging system.
Results: Hemodynamic parameters revealed that ApoE−/− mice on regular diet exhibited markers of cardiac hypertrophy. PARP-1 gene knockout markedly protected against dyslipidemia-induced cardiac hypertrophy. An increase in dyslipidemia burden further exacerbated the latter parameters in ApoE−/− mice. Inhibition of PARP-1 by gene deletion provided a significant protection against the parameters of cardiac hypertrophy. Histology showed enlarged hypertrophied cardiac myocytes in ApoE−/− mice with typical “boxcar-shaped” nuclei and high-fat diet caused separation of the myocardial fibers suggestive of dilated cardiomyopathy in these mice. PARP-1 gene deletion maintained the structural integrity of cardiac myocytes. MMP activity, measured by zymography, was dramatically increased in heart and aorta of ApoE−/− mice on high-fat diet compared to ApoE-PARP-1d−/− mice on similar diet regimen, which was accompanied by increased collagen degradation and mast cell degranulation. PARP-1 gene knockout was associated with increased TIMP-2 expression in various cells of vascular origin which seemed to neutralize the degenerative effects of MMP activity.
Discussion: Our results demonstrate that PARP-1 gene deletion protects against dyslipidemia-induced cardiac hypertrophy and dilatations. We also provide evidence that PARP-1 inhibition protects against these pathologies by increasing expression of TIMP-2 and subsequent inhibition of tissue-degrading proteases in a mouse model of atherosclerosis.