雷帕霉素对大鼠心房纤维化的影响

目的:探讨雷帕霉素(rapamycin，RAPA)对盐酸异丙肾上腺素(isoproterenol，ISO)诱导的大鼠心房纤维化的影响及其可能的机制。方法: 雄性Wistar 大鼠27只，随机分为空白对照组(对照组)、 ISO组和ISO+RAPA组，每组9只(n=9)。皮下注射ISO建立大鼠心房纤维化模型，给予RAPA干预。实验的第15天，处死大鼠并取心房组织，用放射免疫测定法检测AngⅡ的含量，用免疫组化染色法及Western blot法检测缺氧诱导因子-1α(hypoxia-inducible factor-1alpha，HIF-1α)和转化生长因子-β1(transforming growth factor-beta 1，TGF-β1)的表达。将心房组织切片经Masson染色后，观察心房纤维化程度即胶原容积分数(CVF)。结果: ①AngⅡ含量，与对照组(36.452±3.262) ng/L相比，ISO组(147.328±6.889) ng/L及ISO+RAPA组(142.252±4.968) ng/L明显升高(P<0.01)。对照组的CVF为(16.334±1.447)%，无心房纤维化，ISO组心房纤维化的程度明显(P<0.01)，ISO+RAPA组(17.021±1.341)%较ISO组(85.692±2.430)%心房纤维化的程度明显减轻(P<0.01)。②免疫组化染色法及Western blot的结果显示，ISO组HIF-1α(0.264±0.017) A和TGF-β1(0.343±0.018) A的表达较对照组［分别为(0.160±0.012) A和(0.129±0.012) A］均明显升高(P<0.01)，ISO+RAPA组［分别为(0.174±0.013) A和(0.139±0.014) A］较ISO组明显降低(P<0.01)，且与纤维化的程度呈正相关(r值分别0.949和0.987，P<0.01)；HIF-1α与TGF-β1的表达亦呈正相关(r值为0.945，P<0.01)。结论: RAPA可能通过抑制HIF-1α、TGF-β1的表达而使ISO诱导的大鼠心房纤维化减轻。

Effects of rapamycin on atrial fibrosis in rats

AIM:To explore the effects of rapamycin (RAPA) on atrial fibrosis in rats treated with high isoproterenol (ISO). METHODS: Twenty-seven male Wistar rats were randomly divided into control group, ISO group ［5 mg/(kg·day) for 7 days］ and ISO+RAP group ［3 mg/(kg·day) for 2 weeks］. Mice were sacrificed after 15 days. Angiotensin II (AngII) content in myocardial tissue was measured by radioimmunoassay, HIF-1α and TGF-β1 were detected by immunohistochemistry and Western blot, and atrial fibrosis was determined on H-E and Masson stained heart sections. RESULTS: Compared with the control group, AngII content increased in ISO group and ISO+RAP group (P<0.01). The degree of atrial fibrosis in ISO+RAP group was significantly lower than that in ISO group (P<0.01) and no atrial fibrosis was seen in control group. HIF-1α and TGF-β1 expressions of myocardium increased in ISO group compared with those in control group (P<0.01) and decreased in ISO+RAP group compared with those in ISO group (P<0.01). CONCLUSION: HIF-1α may be involved in atrial fibrosis and RAPA can efficiently improve atrial fibrosis by repressing the expressions of HIF-1α and TGF-β1.