p38 MAPK inhibitor, CBS3830 limits vascular remodelling in arterialised vein grafts

Abstract

Objective: Following bypass surgery vein grafts undergo a remodelling process that can lead to restenosis and ultimately vein graft failure. Signalling through mitogen activated protein kinases (MAPKs) is a key mechanism involved in vein graft failure. Here, we investigated whether CBS3830 (c-a-i-r biosciences GmbH, Tübingen, Germany), a new highly selectively inhibitor of p38 MAPK, has a significant effect on inhibiting intimal, medial and adventitial hyperplasia.

Methods: Sixty specific pathogen free Sprague Dawley male rats were randomly divided into three groups. The control group with a reversed right jugular vein, which is common to carotid artery interposition graft, was compared with sham-operated, and CBS3830 treated animals. Intimal, medial and adventitia morphometric examinations and expression of proliferating cell nuclear antigen (PCNA) were analysed after one, two and four weeks for vein grafts.

Results: Intimal, medial and adventitia thickening in CBS3830 group were significantly lower than in the control group at each time point. Moreover, CBS3830 significantly reduced the phosphorylation of p38 MAPK and PCNA expression compared to the control.

Conclusion: On the basis of the present work, intima, media and adventitia of saphenous vein grafts undergo vascular remodelling after surgery. The new, highly selective p38 MAPK inhibitor, CBS3830, ameliorates intimal, medial, and adventitial remodelling by varying degrees.

Keywords: AVGs; Adventitia hyperplasia; Arterio-venous bypass; CHD; Con; EC; ERK; IH; Intimal hypeplasia; MAPKs; Medial hyperplasia; NIH; PCNA; PDGF-BB; PRRs; SMC; Sham; Vein graft; arterialized vein grafts; control; coronary heart disease; endothelial cells; extracellular-signal regulated kinas; intimal hyperplasia; mitogen activated protein kinases; neointimal hyperplasia; p38 MAPK; p38 MAPK-inhibitor; p38 mitogen activated protein kinases; pattern recognition receptors; platelet derived growth factor BB; proliferating cell nuclear antigen; sham-operated; smooth muscle cells.