The effect of adenovirus-mediated anti-extracellular signal regulated kinase 2 gene therapy on intimal change in transplant arteriosclerosis

Abstract

Objective To explore the mechanisms of intimal injury underlying transplant arteriosclerosis (TA) and to clarify the treatment effect of adenovirus-mediated anti-extracellular signal regulated kinase 2 (Adanti-ERK2) gene therapy on TA. Methods The Brown-Norway (BN)-Lewis TA model was employed. According to different gene therapy, the recipients were divided into isograft group, control group, LacZ group, which were used as control, and Adanti-ERK2 group (5 × 109 pfu Adanti-ERK2 was transferred into the graft before transplant, 6 cases in each group). The grafts were harvested on the day60 post-transplantation to evaluate the intimal injury and calculate the ratio of intima/( intima + media). The staining of α-actin and PDGF-BB was performed to analyze proliferation and secretion of vascular smooth muscle cells (VSMCs). The angingenesis was evaluated and the cyclooxygenase-2 (COX-2) staining was detected. Results The intima was normal in the isograft group but a typical intimal proliferation was observed in the control group and the LacZ group. A mild intima injury was obtained in the Adanti-ERK2 group. The ratio of intima/( intima + media) was 7.6%, 81.4%, 85.9% and 15.9% in isograft, control, LacZ and Adanti-ERK2 groups, respectively. The α-actin staining-positive cells, which indicated VSMCs, were counted per vision-field as 0, 71.3 ± 9.2, 76. 4 ± 11.3 and 34. 8 ± 5.3, respectively. The platelet derived growth factor-BB (PDGF-BB) positive cells were counted as 0. 9 ± 0. 5, 28.4 ± 3.4,29. 1 ± 3.2 and 8.6 ± 1.7, respectively. The angiogenesis was detected as none, abundant, abundant and few, and COX-2 positive cells were counted as 0, 36. 3 ± 8. 3, 40. 9 ± 9. 2 and 10. 4 ± 3.9, respectively (P ＜ 0. 05 between Adanti-ERK2 group and other groups). Conclusion Intimal proliferation, luminal narrow, VSMCs recruitment and differentiation induced by PDGF-BB in intima and the following angiogenesis are the important pathophysiological process of TA. Adanti-ERK2 gene therapy modulates the process and then ameliorates TA. Key words: Transplant arteriosclerosis; Intima; Angiogenesis; ERK2; Gene therapy