Study Of The Effect Of P38MAPK Pathway In Autogenous Vein Graft Restenosis

Objective Autologous vein graft is the most common surgical method treating coronary heart disease (CHD) and vascular occlusive disease in clinical. Restenosis of vein grafts have a serious impact on short and long term patency of grafts after coronary artery bypass grafting. Restenosis of grafts is complexly and multi-factor involve in the vascular remodeling process. The exact mechanism remain to know. The study aiming to explore the mechanism of the p38MAPK pathway in restenosis of vein grafts after arterialized vein grafts,through a jugular vein arterialized model simulating the physiological process after CABG, using highly selective p38MAPK inhibitor CBS3830 to intervent.Methods 80 SD rats were randomly divided into four groups: control group (n=20), sham-operated group (n=20), single doses group (n=20) and double doses group (n=20). Sham-operated group, only simulated surgical procedure,without vascular grafts and drug intervention; control group, jugular vein to carotid artery, and given the solvent (Solvent, methyl cellulose) 2h before transplantation once, 3mg/kg intervention; sigle doses group only once,3mg/kg(CBS3830), 2h before transplantation;double doses group twice, 3mg/kg(CBS3830) per time, 2h before transplantation and 4d after transplantation. Taking blood samples at time points of 0h, 24h, 48h, 4d, 1w and 2w. Enzyme-linked immunosorbent assay (ELSIA) was used to detect the serum levels of TNF-α, IL-1βand IL-6. HE staining was used to detect the pathological changes of vien grafts intima,medial and adventitia (1w,2w,4w) in each group. Immunohistochemical staining was used to detect the expression of proliferating cell nuclear antigen (PCNA) of vascular specimens each group. RT-PCR was used to detect the expression of p38 andβ-actin; Western blotting was used to detect the expression of p38, p-p38,β-actin.Results There was no operative mortality in each group. TNF-αrised in 0 ~ 24h and single-dose group and double-dose group at 48h ~ 2w showed a clear downward trend.single-dose group, double-dose group show significant differences (p=.003)compare to sham-operated group, the control group.while the single-dose group compare to double-dose group showing no difference; The IL-1βlevels of single and double group at 24h reach to maximum, show gradual declining trend in 48h ~ 4d, 4d ~ 2w levels increase again, the lowest in the 4d, and show a significant statistical difference (p<0.01) compare to the control group and sham group; the levels of IL-6 of control group appears bimodal changes in the 24h and 4d ~ 1w have increased twice. The single-and double-dose group at 0 ~ 24h experiencing a downward trend in first and then rise again and then declined. Only at 24h double dose group compared with the control group, there are significant differences, while not the rest of the time points. Single and double dose group intimal, medial thickening was significantly lower than the control group at each time piont trough HE staining, the difference was statistically significant (p <0.05 or p <0.01); Single and double dose group intima and media thickness is significantly higher than sham group, there was significant difference (p <0.01), but there is no difference between single and two-dose group at each time point(p> 0.05). Expression of PCNA in control group increased 1w after operation, reached its peak 2w after operation and 4w began to decline. The expression of PCNA in single-dose group and two-dose group at each time point was significantly lower than the control group (p <0.01), but the single and double dose groups showed no differences at each time point. PCNA in the sham group slightly increased at 1w,2w with little changing at each time point,but significantly less than the control group, single-dose group, double-dose group(p <0.01). The p38 expression in vein grafts of single and double dose group was significantly lower than the control group, sham group through RT-PCR 1w after trasplantation. Western blotting detection of p38 and P-p38 showed the single and double dose group significant less than the control group, sham group.Conclusion The p38MAPK pathway involved in the venous arterialized grafts restenosis, CBS3830 can significantly reduce inflammation and intimal hyperplasia. The p38MAPK pathway activation is a critical part of vein graft vascular remodeling. It is expected a new target for preventing and treating restenosis and vein graft occlusion after CABG through further study it.