Abstract 467: The Histone Acetyltransferases P300 And Cbp Coordinate Distinct Chromatin Remodeling Programs In Vascular Smooth Muscle Plasticity

Vascular smooth muscle cell (VSMC) phenotypic switching contributes to cardiovascular diseases. Epigenetic regulation is emerging as a key regulatory mechanism, with the methyl cytosine dioxygenase TET2 acting as a master regulator of SMC phenotype. The histone acetyltransferases (HATs) p300 and CBP are highly homologous and often considered to be interchangeable, and their roles in SMC phenotypic regulation are not known. We assessed the roles of p300 and CBP in human VSMC with knockdown, in inducible smooth muscle-specific knockout mice ( p300 iKO or CBP iKO ), and in human intimal hyperplasia. P300, CBP, and histone acetylation were differently regulated in VSMCs undergoing phenotypic switching and in injury-induced vessel remodeling. Knockdown experiments revealed opposing effects of p300 and CBP in VSMC phenotype: p300 promoted contractile protein expression and inhibited migration, but CBP inhibited contractile genes and enhanced migration. p300 iKO mice exhibited severe intimal hyperplasia following arterial injury while CBP iKO mice were entirely protected. In normal aorta, p300 iKO reduced, but CBP iKO enhanced, contractile proteins and contractility. Mechanistically, we found that these HATs oppositely regulate histone acetylation, DNA hydroxy methylation, and RNA PolII binding to promoters of differentiation-specific contractile genes. We report p300 and TET2 function together, as p300 was required for TET2-dependent hydroxy methylation of contractile promoters, and TET2 was required for p300-dependent acetylation of these loci. TET2 co-immunoprecipitated with p300 and this interaction was enhanced by rapamycin but repressed by PDGF, with p300 promoting TET2 protein stability. CBP did not associate with TET2, instead facilitated recruitment of histone deacetylases (HDAC2, HDAC5) to contractile gene promoters. Immunostaining revealed, p300 expression is repressed but CBP is induced in human intimal hyperplasia. This work reveals that p300 and CBP serve non-redundant and opposing functions in VSMC phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with TET2 or HDACs. Targeting specific HATs may hold therapeutic promise for cardiovascular diseases.