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

Abstract

Smooth muscle cell marker, SM22α, 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 SM22α, here we explored transcriptome profiling by RNA-Seq from arteries of SM22α(-/-) and SM22α(+/+) mice. Analysis revealed that the most enriched pathways caused by SM22α-knockout were hematopoiesis, inflammation and lipid metabolism, respectively, and NF-κB, RXRα and PPARα 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 SM22α(-/-) mice was already prepared for the initiation of atherosclerosis. Further analysis suggested the up-regulated TNF caused NF-κB pathway activation. Our results showed loss of SM22α exacerbated TNF-α-mediated NF-κB activation and increased the expression levels of ApoCI in vitro, while overexpression of SM22α suppressed TNF-α-mediated NF-κB activation. In addition, disruption of SM22α 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 SM22α can actively contribute to the pathogenesis of atherosclerosis from the molecular basis, but also further confirmed that the vascular cells of SM22α(-/-) mice may become more sensitive to extracellular stimulation, increasing its tendency to develop vascular diseases. Meanwhile, rescuing SM22α expression may provide a novel therapeutic strategy for arterial diseases.

SM22α inhibits lamellipodium formation and migration via Ras-Arp2/3 signaling in synthetic VSMCs

“…The present study provided evidence that overexpression of SM22␣ inhib-C765 SM22␣ IN VSMC LAMELLIPODIUM FORMATION its PDGF-BB-induced cell migration in synthetic VSMCs and that disruption of SM22␣ promotes migratory responses after artery ligation. This result is similar to the previously reported effects of SM22␣ on proliferation (10), oxidative stress (27), and proinflammation responses (6,37,39), suggesting that there is a causal relationship between decreased expression of SM22␣ and pathological changes during vascular disease. SM22␣ exerts a dual regulatory action on VSMC migration in a phenotype-dependent manner.…”

“…The upregulation of migration and adhesion-related molecule expression, including MMPs, VCAM-1, and ICAM-1, offers the molecular basis for VSMC migration (15). Our previous study had shown that the expression of these proteins in the arteries of Sm22 Ϫ/Ϫ mice was significantly elevated compared with wild-type mice at baseline (6). Using IHC, we found that the expression of ICAM-1, VCAM-1, MMP-2, MMP-9, OPN, and integrin ␤ 3 in the media and neointima of Sm22␣ Ϫ/Ϫ mice was approximately 2-3 times higher than that in their Sm22␣ ϩ/ϩ littermates (Fig.…”

SM22α inhibits vascular inflammation via stabilization of IκBα in vascular smooth muscle cells

“…Our data confirm that SM22α is a direct regulator of NF-κB. SM22α −/− mice may be a sensitive model of early vascular inflammation [16]. Importantly, these findings may also shed more light on the role of downregulation of SM22α in cancers, abdominal aortic aneurysm, atherosclerosis and other inflammatory vascular diseases.…”

“…Our findings suggest that SM22α may act as an adapter or scaffold protein to modulate signaling. More recently, the aortic transcriptomes of SM22α −/− mice reveal that loss of SM22α can actively contribute to the pathogenesis of atherosclerosis, because the knockout of Sm22α results in an increased expression of pro-inflammatory genes in the aortas which are controlled by NF-κB (RelA) [16]. However, the mechanism by which disruption of SM22α activates NF-κB is not fully understood.…”

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

“…16,29,30 These findings suggest a functional link between SM22α and VSMC phenotypes. The current study uncovers a biochemical mechanism by which G6PD is activated subsequent to TRAF6-mediated SM22α ubiquitination, which promotes G6PD membrane translocation and glucose metabolism via the PPP.…”