PARP‐1 inhibition, pharmacologically or genetically, reduces plaque size and promotes factors of plaque stability in an ApoE−/− mouse model of atherosclerosis

Abstract

We have established a critical role for PARP-1 in cell death and the overall process of inflammation. Using an ApoE−/− mouse model of high fat diet (HF)-induced atherosclerosis, we report a positive correlation between apoptotic DNA damage within necrotic cores of atherosclerotic plaques and the activation of PARP-1 suggesting a role for this enzyme in the onset of disease. Administration of the potent PARP-1 inhibitor TIQ-A, twice a week, moderately reduced plaque size after 12 weeks of HF. Increasing TIQ-A injections to thrice a week significantly reduced plaque sizes. Plaques from TIQ-A treated mice contained thicker fibrous caps enriched with an abundance of smooth muscle cells (SMCs) and atrophic foam cells. Though lipid profile in sera and overall collagen synthesis in aortas were not different, marked reduction in macrophage recruitment, increase in SMC transmigration into the intimal space with concomitant increase in collagen content in plaques of TIQ-A treated mice was observed. Such traits are cardinal for atherosclerotic plaque integrity. These results were corroborated by the similar effect PARP-1 heterozygocity exerted on plaque size and structure in ApoE−/− mice. Using an in vitro model of vascular inflammation, we found that PARP-1 inhibition, by TIQ-A or gene knockout, conferred significant protection to ex vivo-generated foam cells and SMC after H2O2 treatment. Our results suggest that PARP-1 inhibition not only reduces plaque size, but may have an important role in plaque structure and stability through its modulation of cell death Support: NIH-1P20RR18766 and HL072889 to H. B.