Suppressor of Cytokine Signaling 3 Is a Negative Regulator for Neointimal Hyperplasia of Vein Graft Stenosis

Abstract

Coronary artery bypass graft (CABG) surgery is one of the most effective treatments for coronary artery disease. However, neointimal hyperplasia and ultimate luminal occlusion that is caused by vascular smooth muscle cell (VSMC) migration, proliferation and inflammatory response impede the long-term prognosis. The SOCS3 protein is involved in modulating various autoimmune and inflammatory diseases. However, the role of SOCS3 in vein graft disease is still unclear. We found that the mRNA and protein expression levels of IL-1β, IL-6, MCP-1, ICAM-1, TNF-α, STAT3, P-STAT3 and SOCS3 were significantly higher in the graft samples compared to normal veins. After transfecting the recombinant adenovirus carrying the rat SOCS3 gene into cultured rat VSMCs or grafting veins in rat, SOCS3 overexpression was found to significantly inhibit VSMC migration and proliferation in vitro and neointimal hyperplasia in vivo, respectively. Furthermore, SOCS3 overexpression inhibited VSMC migration and growth in vitro and alleviated VSMC inflammation in vitro by inhibiting STAT3 activation and phosphorylation. In conclusion, SOCS3 is a crucial physiological negative regulator for vein graft failure and provides a novel target for vein graft stenosis therapy after CABG.

The future of EPAC-targeted therapies: agonism versus antagonism

“…Moreover, IL-6 has been reported to promote acute and chronic inflammatory disease in the absence of SOCS3 [62] and conditional deletion of SOCS3 in VECs results in pathological angiogenesis [63] . By contrast, either overexpression of SOCS3 or introduction of SOCS-derived peptides has been shown to suppress JAK–STAT signalling, acute inflammation, and the development of atherosclerosis and NH, illustrating the important protective role of SOCS3 [64–66] .…”

Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3) Function and Expression

“…Approaches to achieve this have included administration of recombinant SOCS3 adenovirus [70] or purified SOCS3 protein modified with a membrane-translocating motif from a hydrophobic signal sequence derived from fibroblast growth factor 4 to confer cell permeability [71]. As proof of concept, preliminary studies already suggest that SOCS3 gene therapy is effective in reducing neointimal hyperplasia in a rat vein grafting model, and can inhibit aortic SMC inflammation, migration and proliferation responses in vitro [72]. The identification of E3 ligases controlling SOCS3 ubiquitylation and degradation may give rise to the development of specific inhibitors or peptide disruptors that could ultimately stabilise the expression of SOCS3 in the vasculature.…”

MicroRNA‐365 promotes the contractile phenotype of venous smooth muscle cells and inhibits neointimal formation in rat vein grafts

“…Nevertheless, unlike striated muscle cells and cardiac muscle cells, vascular SMCs retain the ability to switch between contractile and synthetic phenotypes in response to internal and external environmental factors, and this is accompanied by increased SMC proliferation, migration, and extracellular matrix deposition . Ultimately, these pathological changes promote the development of neointimal formation, which results in vein graft failure . Therefore, prevention of pathological vein graft remodeling needs to concentrate on the regulation of SMC function, for example, cell phenotype modulation, proliferation, and migration.…”