Downregulation of HDAC1 suppresses media degeneration by inhibiting the migration and phenotypic switch of aortic vascular smooth muscle cells in aortic dissection.

Although much progress has been made in the diagnosis and treatment of thoracic aortic dissection (TAD), the overall morbidity and mortality rates of TAD are still high. Therefore, the molecular pathogenesis and etiology of TAD need to be elucidated. In this study, we found that histone deacetylase 1 (HDAC1) expression is dramatically higher in the aortic wall of patients with TAD (than that in a normal group) and negatively correlates with the levels of the vascular smooth muscle cell (SMC) contractile-phenotype markers. Knockdown of HDAC1 upregulated both smooth muscle 22 α (SM22α) and α-smooth muscle actin (α-SMA) in platelet-derived growth factor (PDGF)-BB-treated and -untreated SMCs. In addition, the knockdown of HDAC1 markedly decreased SMC viability and migration in contrast to the control group under the conditions of quiescence and PDGF-BB treatment. We also showed that the expression of polycystic kidney disease 1 (PKD1) is decreased in the aortic wall of patients with TAD and negatively correlates with HDAC1 expression. Overexpressed PKD1 obviously increased SM22α and α-SMA expression and reduced the viability and migration of SMCs, but these effects were attenuated by HDAC1. Furthermore, we demonstrated that HDAC1 serves as an important modulator of the migration and phenotypic switch of SMCs by suppressing the PKD1- mammalian target of the rapamycin signaling pathway. HDAC1 downregulation inhibited media degeneration and attenuated the loss of elastic-fiber integrity in a mouse model of TAD. Our results suggest that HDAC1 might be a new target for the treatment of a macrovascular disease such as TAD.