Sm22 Alpha (Smooth Muscle 22 Alpha) Prevents Aortic Aneurysm Formation By Inhibiting Smooth Muscle Cell Phenotypic Switching Through Suppressing Reactive Oxygen Species/Nf-Kappa B (Nuclear Factor-Kappa B)

Objective-Vascular smooth muscle cell phenotypic transition plays a critical role in the formation of abdominal aortic aneurysms (AAAs). SM22 alpha (smooth muscle 22 alpha) has a vital role in maintaining the smooth muscle cell phenotype and is downregulated in AAA. However, whether manipulation of the SM22 alpha gene influences the pathogenesis of AAA is unclear. Here, we investigated whether SM22 alpha prevents AAA formation and explored the underlying mechanisms. Approach and Results-In both human and animal AAA tissues, a smooth muscle cell phenotypic switch was confirmed, as manifested by the downregulation of SM22 alpha and alpha-SMA (alpha-smooth muscle actin) proteins. The methylation level of the SM22a gene promoter was dramatically higher in mouse AAA tissues than in control tissues. SM22a knockdown in ApoE-/( apolipoprotein E-deficient) mice treated with Ang II (angiotensin II) accelerated the formation of AAAs, as evidenced by a larger maximal aortic diameter and more medial elastin degradation than those found in control mice, whereas SM22 alpha overexpression exerted opposite effects. Similar results were obtained in a calcium chloride-induced mouse AAA model. Mechanistically, SM22 alpha deficiency significantly increased reactive oxygen species production and NF-kappa B (nuclear factor.B) activation in AAA tissues, whereas SM22 alpha overexpression produced opposite effects. NF-kappa B antagonist SN50 or antioxidant N-acetyl-L-cysteine partially abrogated the exacerbating effects of SM22 alpha silencing on AAA formation. Conclusions-SM22 alpha reduction in AAAs because of the SM22 alpha promoter hypermethylation accelerates AAA formation through the reactive oxygen species/ NF-kappa B pathway, and therapeutic approaches to increase SM22 alpha expression are potentially beneficial for preventing AAA formation.