Liu Rong, Ma Shixin, Lu Zhigang, Shen Hong, Sun Leiqing, Wei Meng
Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, China.
Cardiovasc Drugs Ther. 2015 Feb;29(1):23-9. doi: 10.1007/s10557-014-6561-6.
ADP plays an important part in platelet aggregation by activating P2Y1 and P2Y12 receptors. The ADP antagonist MRS2179 has been used in thrombosis-related treatments but its effects on vein graft (VG) remodeling is undefined. We examined the effect of MRS2179 on VG intimal hyperplasia and explored the mechanism of action.
A mouse model of VG transplantation was established. Mice underwent surgery and received MRS2179 by intraperitoneal injection every other day for 3 weeks. VG remodeling was assessed 4-weeks later. Vascular smooth muscle cells (VSMCs) were isolated and treated with MRS2179. The effect of MRS2179 on the proliferation, migration and inflammatory-cytokine expression of VSMCs was also evaluated.
MRS2179 significantly inhibited VSMC proliferation compared with the control group. Significant inhibitory effects of MRS2179 on VSMC migration was observed in two-dimensional and three-dimensional models. The extent of intimal hyperplasia was significantly less in MRS2179 treated mice than in controls. Reduced migration of macrophage was found in MRS2179 treated mice. Expression of the inflammatory cytokines IL-1β and TNF-α was decreased significantly in the MRS2179 treated group. In addition, decreased phosphorylation was found on Akt, Erk1/2 and p38.
These data demonstrate that MRS2179 inhibits neointima formation in VGs by regulating the proliferation, and migration of VSMCs, macrophage migration, inflammatory-cytokine secretion and related signaling pathway. Our study provides novel insights regarding purinergic signaling in SMCs in vivo. The P2Y1 receptor may serve as a therapeutic target in neointima formation.
二磷酸腺苷（ADP）通过激活P2Y1和P2Y12受体在血小板聚集中起重要作用。ADP拮抗剂MRS2179已用于血栓形成相关治疗，但其对静脉移植物（VG）重塑的影响尚不清楚。我们研究了MRS2179对VG内膜增生的影响并探讨其作用机制。
建立小鼠VG移植模型。小鼠接受手术，每隔一天腹腔注射MRS2179，持续3周。4周后评估VG重塑情况。分离血管平滑肌细胞（VSMC）并用MRS2179处理。还评估了MRS2179对VSMC增殖、迁移和炎性细胞因子表达的影响。
与对照组相比，MRS2179显著抑制VSMC增殖。在二维和三维模型中均观察到MRS2179对VSMC迁移有显著抑制作用。MRS2179处理的小鼠内膜增生程度明显低于对照组。在MRS2179处理的小鼠中发现巨噬细胞迁移减少。MRS2179处理组中炎性细胞因子白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的表达显著降低。此外，发现Akt、细胞外信号调节激酶1/2（Erk1/2）和p38的磷酸化水平降低。
这些数据表明，MRS2179通过调节VSMC的增殖和迁移、巨噬细胞迁移、炎性细胞因子分泌及相关信号通路，抑制VG中新内膜的形成。我们的研究为体内平滑肌细胞中嘌呤能信号传导提供了新的见解。P2Y1受体可能是新内膜形成的治疗靶点。
