NRF2 Regulates Contractile Vascular Smooth Muscle Cells Phenotypic Switching In Abdominal Aortic Aneurysm

OBJECTIVE Evidence from previous studies has demonstrated that NRF2 can protect cardiovascular progression,which prompted us to study if NRF2 is involved in AAA development. APPROACH AND RESULTS The difference and function of NRF2 in AAA were verified on human aortic tissues combined with scRNA-seq samples.We then used angiotensin II (Ang II) infusion mouse model with VSMCs-specific knockout to study the role of NRF2 in AAA formation.Primary cultured VSMCs were used to study how NRF2 regulates contractile VSMCs phenotype.Patient specimens were obtained to investigate the relevance of NRF2 expression to human AAA disease. NRF2 was induced in abdominal aortic VSMCs in both mouse and human AAA tissues. VSMCs-specific NRF2 knockout increased experimental AAA formation. Mechanistically, NRF2 regulates the contractile VSMCs phenotypic through miRNA145, leading to increased classic contractile protein level to prevent the development of AAA. CONCLUSIONS NRF2 is a negative regulator of AAA development, and thus may represent a potentially new therapeutic target to inhibit AAA growth and rupture.