Transcriptome profiling reveals that the SM22α-regulated molecular pathways contribute to vascular pathology

Smooth muscle cell marker, SM22 alpha, was down-regulated in the pathogenesis of arterial diseases including atherosclerosis, restenosis and abdominal aortic aneurysms. However, the question still exists whether this down-regulation actively contributes to the pathogenesis of vascular diseases. In an ongoing effort to understand the role of SM22 alpha, here we explored transcriptome profiling by RNA-Seq from arteries of SM22 alpha(-/-) and SM22 alpha(+/+) mice. Analysis revealed that the most enriched pathways caused by SM22 alpha-knockout were hematopoiesis, inflammation and lipid metabolism, respectively, and NF-kappa B, RXR alpha and PPAR alpha were the major upstream regulators. The candidate genes involved in inflammation and lipid metabolism were clustered in atherosclerosis. Thus we suspected that the molecular basis in SM22 alpha(-/-) mice was already prepared for the initiation of atherosclerosis. Further analysis suggested the up-regulated TNF caused NF-kappa B pathway activation. Our results showed loss of SM22 alpha exacerbated TNF-alpha-mediated NF-kappa B activation and increased the expression levels of ApoCI in vitro, while overexpression of SM22 alpha suppressed TNF-a-mediated NF-kappa B activation. In addition, disruption of SM22 alpha enhanced injury-induced neointimal hyperplasia, and increased expression levels of molecules related with cellular adhesion and extracellular matrix degradation. Taken together, these findings not only suggested down-regulation of SM22 alpha can actively contribute to the pathogenesis of atherosclerosis from the molecular basis, but also further confirmed that the vascular cells of SM22 alpha(-/-) mice may become more sensitive to extracellular stimulation, increasing its tendency to develop vascular diseases. Meanwhile, rescuing SM22 alpha expression may provide a novel therapeutic strategy for arterial diseases. (C) 2014 The Authors. Published by Elsevier Ltd.