厄贝沙坦抑制兔动脉球囊损伤后再狭窄的作用及机理研究

目的观察国产血管紧张素1型受体拮抗剂厄贝沙坦抑制兔颈动脉球囊损伤后再狭窄(RS)的作用,探讨 RS 可能的机理。方法将48只大耳白兔随机分为实验7、14、28 d 组并各设对照组(每组8只),以球囊损伤左颈总动脉,建立再狭窄模型。术后7、14、28 d 不同时点取材。实验组术前3 d 喂饲厄贝沙坦(35 mg/kg)至处死。病理 HE 染色观察动脉壁内、中膜面积、管腔面积;免疫组化法测定核因子-κB(NF-κB)、核增殖抗原(PCNA)核易位阳性细胞率;实时荧光定量聚合酶链反应(PCR)测定κB抑制蛋白(I-κB)、单核细胞趋化蛋白 mRNA 表达。结果厄贝沙坦实验组与对照组相比,术后7 d 时明显抑制内膜的增生(0.34 mm~2±0.15 mm~2 vs 1.05 mm~2±0.38 mm~2,P<0.05),28 d 时管腔面积明显较大(4.25 mm~2±0.29 mm~2 vs 2.56 mm~2±1.02 mm~2,P<0.05)。术后7 d 时厄贝沙坦明显抑制 NF-κB p65核易位(P<0.05)和 PCNA 的表达(P<0.05)。术后7 d 时厄贝沙坦实验组 I-κB mRNA 含量明显较低(7.2拷贝/μl±0.9拷贝/μl vs 15.6拷贝/μl±0.7拷贝/μl,P<0.05),厄贝沙坦实验组在各时相点均明显抑制 MCP-1 mRNA 的表达(P<0.05)。结论厄贝沙坦通过抑制NF-κB的激活而调控 MCP-1、PCNA 的表达,有效抑制再狭窄的发生发展。

Inhibitory effect of irbesartan on restenosis after balloon angioplasty and mechanism thereof: experiment with rabbits

OBJECTIVE: To investigate the inhibitory effect of irbesartan on the restenosis after balloon angioplasty and mechanism thereof. METHODS: Forty-eight Harbin white rabbits underwent balloon angioplasty at the left common carotid artery to establish models of restenosis (RS) and then were randomly divided into 3 groups of 8 rabbits: 7 d, 14 d, and 28 d to be fed with the diet with 35 mg/kg irbesartan till the day when the rabbits were to be killed, each group with 4 controls fed with normal diet At the scheduled days the rabbits were killed and their left common carotid arteries, livers, and kidneys were taken out to undergo morphological examination. The areas of the tunica intima, tunica media, and lumen of the common carotid artery were measured. Immunohistochemistry was used to detect the nuclear factor-kappaB p65 (NF-kappaB p65) and proliferating cell nuclear antigen (PCNA) protein. RT-PCR was used to detect the mRNA expression of inhibitor-kappaB (I-kappaB) and monocyte chemoattractant protein-1 (MCP-1). RESULTS: No abnormality was found in the specimens of liver and kidney. Measurement showed that the area of tunica intima of the 7 d irbesartan group was 0.34 mm(2) +/- 0.15 mm(2), significantly smaller than that of the controls (1.05 mm(2) +/- 0.38 mm(2), P < 0.05), and the area of arterial lumen of the 28 d group was 4.25 mm(2) +/- 0.29 mm(2), significantly larger than that of the controls (2.56 mm(2) +/- 1.02 mm(2), P < 0.05). Immunohistochemistry showed that the rates of NF-kappaB p65 positive cell and PCNA positive cell of the 7 d irbesartan group were both significantly lower than those of the controls (both P < 0.05). The mRNA expression of I-kappaB in the vascular wall of the 7 d irbesartan group was significantly lower than that of the controls. The mRNA expression levels of MCP-1 at different time points were all significantly lower than those of the corresponding controls (all P < 0.05). CONCLUSION: Irbesartan inhibits the RS after injury of arterial wall by balloon angioplasty via suppressing the activation of NF-kappaB p65 which controls the expression of I-kappaB and MCP-1.