Notch1 gene promoter methylation promotes phenotypic transformation and functional alteration of VSMCs to regulate...

Acute type A aortic dissection (ATAAD) is a life-threatening cardiovascular emergency. A key driver of disease progression is dysfunction of vascular smooth muscle cells (VSMCs), whose loss of contractile phenotype and increased matrix degradation contribute to aortic wall weakening. Aberrant DNA methylation patterns have been observed in thoracic aortic disease and linked to VSMCs dysfunction and extracellular matrix degradation. This study aimed to investigate the change of DNA methylation in ATAAD and the mechanism underlying notch receptor 1 (Notch1) promoter methylation regulating VSMCs transition in phenotype. In this study, ATAAD patients showed higher DNA methylation levels in the ascending aortic wall than control patients. The levels of DNA methyltransferase (DNMT), MMP2, and MMP9 were increased, Notch1, α-SMA, and SM22α were decreased, and the levels of Notch1 promoter methylation were increased in tissue samples from ATAAD patients and cellular models. Overexpression of Notch1 promoted α-SMA and SM22α expressions, inhibited MMP2 and MMP9 expressions, and suppressed cell migration, and invasion, as well as facilitated Notch intracellular domain (NICD) and hes family bHLH transcription factor 1 (Hes1) expressions in VSMCs. Inhibition of DNA methylation in VSMCs can inhibit the levels of the Notch1 promoter methylation and thus promote Notch1 expression exerting similar results as overexpression of Notch1, whereas knockdown Notch1 has the opposite effect. In conclusion, Notch1 gene promoter methylation region regulates ATAAD by phenotypic transformation and functional alteration of VSMCs. These findings identify Notch1 promoter methylation as a pivotal epigenetic switch in ATAAD pathogenesis and suggest its therapeutic and biomarker potential.