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Vildagliptin Reduces Stenosis of Injured Carotid Artery in Diabetic Mouse Through Inhibiting Vascular Smooth Muscle Cell Proliferation via ER Stress/NF-κB Pathway.

ABSTRACT: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel anti-hyperglycemic drugs for type 2 diabetes. It has been reported that DDP-4 inhibitor could exert pleiotropic effects on cardiovascular system. This study was to explore the effect and mechanism of vildagliptin on the stenosis of injured carotid artery in diabetic mouse. Twenty six-week-old male db/db mice (BKS) were randomized into vildagliptin treated and vehicle control groups. Ligation injury was first performed in left carotid arteries of all diabetic mice, then oral vildagliptin or equal amount of PBS was correspondingly administered to the mice from the next day to ligation injury for 4 weeks. Effects on proliferation were detected via histological and morphometric analysis. Endoplasmic reticulum (ER) stress and nuclear factor kappa B (NF-κB) markers were determined by immunoblot analysis. After 4 weeks of vildagliptin delivery, it was observed that the intimal area and neointimal thickness of the ligated carotid arteries were significantly reduced as compared to the control group. In vivo, vildagliptin suppressed the expressions of PCNA and α-SMA, phospho-p65, phospho-IKKα/β, GRP78 and CHOP, as well as IRE-1 in vascular smooth muscle cells (VSMCs). In vitro, the proliferation and hypertrophy of VSMCs were significantly inhibited by blocking the IRE-1 pathway, and the inhibition of phospho-IRE-1 expression down-regulated the expression of phospho-IKKα/β in VSMCs. Vildagliptin reduced the stenosis of injured carotid arteries in diabetic mice, and this effect was achieved via inhibiting the activation of ER stress/NF-κB pathway.

SUBMITTER: Ji Y

PROVIDER: S-EPMC6397934 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Patients with contralateral carotid occlusion (CCO) have been excluded from randomized clinical trials because of a deemed high risk for adverse neurologic outcomes with carotid endarterectomy (CEA). Evidence for this rationale is limited and conflicting. Therefore, we aimed to compare outcomes after CEA between patients with and without CCO and varying degrees of contralateral carotid stenosis (CCS).We identified patients undergoing CEA from 2003 to 2015 in the Vascular Study Group of New England (VSGNE) registry. Patients were stratified by preoperative symptom status and presence of CCO. Multivariable analysis was used to account for differences in demographics and comorbidities. Our primary outcome was 30-day stroke/death risk.Of 15,487 patients we identified who underwent CEA, 10,377 (67%) were asymptomatic. CCO was present in 914 patients, of whom 681 (75%) were asymptomatic. Overall, the 30-day stroke/death was 2.0% for symptomatic patients (CCO: 2.6%) and 1.1% for asymptomatic patients (CCO: 2.3%). After adjustment, including symptom status, CCO was associated with higher 30-day stroke/death (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4-3.3; P = .001), any in-hospital stroke (OR, 2.8; 95% CI, 1.7-4.6; P < .001), in-hospital ipsilateral stroke (OR, 2.2; 95% CI, 1.2-4.0; P = .02), in-hospital contralateral stroke (OR, 5.1; 95% CI, 2.2-11.4; P < .001), and prolonged length of stay (OR, 1.6; 95% CI, 1.3-1.9; P < .001). CCS of 80% to 99% was only associated with a prolonged length of stay (OR, 1.3; 95% CI, 1.1-1.6; P = .01), not with in-hospital stroke. Neither CCO nor CCS was associated with 30-day mortality.Although CCO increases the risk of 30-day stroke/death, in-hospital strokes, and prolonged length of stay after CEA, the 30-day stroke/death rates in symptomatic and asymptomatic patients with CCO remain within the recommended thresholds set by the 14 societies' guideline document. Thus, CCO should not qualify as a high-risk criterion for CEA. Moreover, there is no evidence that patients with CCO have lower stroke/death rates after carotid artery stenting than after CEA. We believe that CEA remains a valid and safe option for patients with CCO and that CCO should not be applied as a criterion to promote carotid artery stenting per se.

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Vildagliptin Reduces Stenosis of Injured Carotid Artery in Diabetic Mouse Through Inhibiting Vascular Smooth Muscle Cell Proliferation via ER Stress/NF-κB Pathway.

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