Gasdermin D affects aortic vascular smooth muscle cell pyroptosis and Ang II-induced vascular remodeling

Abstract

Vascular smooth muscle cells (VSMCs) are primarily responsible for vasoconstriction and the regulation of blood pressure1. Pyroptosis, a particular form of regulated cell death, is involved in multiple vascular injuries, including hypertensive vascular dysfunction. This pyroptotic cell death is mediated by the pore-forming protein of Gasdermin D (GSDMD). This study was designed to examine the direct effect of GSDMD on smooth muscle cell pyroptosis and vascular remodeling. Findings revealed that GSDMD was activated in Angiotensin (Ang) II- treated aortas. We then showed that genetic deletion of Gsdmd reduced vascular remodeling and aorta pyroptosis induced by Ang II <i>in vivo</i>. Aberrant expression of GSDMD by recombinant AAV9 virus carrying Gsdmd cDNA aggravated the level of pyroptosis in aortas of Ang II mice. Gain- and loss-of- function analysis further confirmed that GSDMD regulated the pyroptosis of murine aortic vascular smooth muscle cells (MOVAS) in an <i>in vitro</i> model of tumor necrosis factor (TNF)-α treatment, which was achieved by transfecting expressing plasmid or siRNA, respectively. Overall, this study provided evidence supporting the active involvement of GSDMD in smooth muscle cell pyroptosis and Ang II-induced mice vascular injury. This finding lends credence to GSDMD as a potential therapeutic target for hypertensive vascular remodeling via inhibiting pyroptosis.