The Effect Of The Transsignaling Of Interleukin-6 On Intimal Nyperplasia And Phenotypic Transition Of VSMCs

Objectives:The rate of 1 year restenosis (RS) in patients with lower extremity peripheral arterial disease (PAD) undergoing percutaneous transluminal angioplasty (PTA) is up to 20-50%. The phenotypic transition of vascular smooth muscle cells (VSMCs) form contractile phenotype to synthetic phenotype is an essential process involved in the development of restenosis after angioplasty. The theory of inflammation after vascular injury has been got more and more attention. The research was going to focus on one of the most representative pro-inflammatory factors-interleukin-6. Firstly, the predictive value of the levels of IL-6 in patients’ serum to the development of RS will be determined. Secondly, the effect of the transsignaling of IL-6 on intimal hyperplasia and phenotypic transition of VSMCs would be investigated in the femoral artery cuff injury model of mice.Methods:Part 1:In order to determine the predictive value of the levels of IL-6 in patients’ serum to the development of RS,68 participants with TASCⅡC/D femoropopliteal lesions were involved in the study who were incharged to receive endovascular treatment from August 2013 to March 2014. IL-6 and high sensitivity C reactive protein (hsCRP) levels at baseline and 24 hours post-intervention were examined. Logistic regression analysis was performed to assess the independent association of serum levels of IL-6 and hs-CRP with the occurrence of RS after clinical and angiographic Data collection and 6 months follow-up. Part 2:For evaluating the effect of IL-6 transsignaling on intimal hyperplasia and phenotypic transition of VSMCs, a mice femoral artery cuff injury model was established. A IL-6 transsignaling inhibitor sgp130Fc was used in the study. The thickness and area of intima and intima/media ratio were calculated in morphometric examination. Primary antibodies against proliferating cell nuclear antigen, smooth muscle α-actin, and calponin were used in immunohistochemistry analysis.Results:Serum levels of IL-6 and hs-CRP in the 68 participants significantly increased at 24 hours post-intervention compared to baseline. In-stent restenosis of the femoropopliteal artery was diagnosed in 15 patients (22.1%). Baseline IL-6,24-hour IL-6, relative increase in IL-6 [AIL-6 0 to 24 (rel%)] and 24-hour hs-CRP levels were independently associated with 6-month post-intervention outcome. Hs-CRP at baseline and relative increase in hs-CRP levels [AIL-6 0 to 24 (rel%)] did not show an independent association with RS. Significantly neointima formation was obsersed in femoral arteries harvested 3 weeks after the induction of cuff injury [intimal area:27.39±8.67 vs 9.65±3.49 (×104, μm2), P<0.001]. Less PCNA positive cells (P=0.009), more a-SMA (P=0.001) and calponin (P<0.009) positive units were observed after treatment with sgp130Fc without affecting weight gain and liver function.Conclusions:Peripheral revascularization in the form of PTA and stent implantation would cause a significant systemic inflammatory response. Baseline, post-interventional, and relative increase in IL-6[AIL-6 0 to 24 (rel%)]levels were significant predictors of in-stent restenosis at intermediate-term. Sgp130Fc could depress restenosis though inhibiting VSMCs phenotype transition and hyperplasia without leading to side effect.