Contribution of acid sphingomyelinase to angiotensin II-induced vascular adventitial remodeling via membrane rafts/Nox2 signal pathway

Aims: Vascular adventitial fibroblasts (AFs) in the vascular remodeling during atherosclerosis are increasing arousing attention. Acid sphingomyelinase (ASM) is a soluble glycoprotein which is involved in the development and progression of atherosclerosis. However, it remains unknown if ASM is expressed in vascular AFs and regulates vascular adventitial remodeling and underlying mechanisms. Main methods and key findings: ASM downregulation with gene silencing was used in the rat AFs treated with angiotensin (Ang) II, which is universally demonstrated to induce vascular adventitia remodeling. It was showed that ASM was indeed expressed in vascular AFs and ASM downregulation resulted in a significant decrease in the protein level of PCNA and collagen I and cell migration under Ang II stimulation. Such improvement of adventitial remodeling was not further augmented by Ang-(1-7), which is deemed as an endogenous Ang II blocker. We further found that ASM downregulation blocked the Nox2-dependent superoxide (O-2(-center dot)) generation, which regulated vascular remodeling in AFs under Ang II. ASM siRNA decreased the aggregation of membrane rafts (MRs) and the consequent recruiting of ceramide and Nox2 in MRs. Significance: In conclusion, these results suggested that ASM downregulation could improve vascular adventitial remodeling which was attributed to inhibiting MRs/Nox2 redox signaling pathway in AFs. Thus, these data supported the idea that ASM is a potential therapeutic target for diabetic vascular complication.