School of Pharmaceutical Engineering and Life Science and School of Nursing, Changzhou University, Changzhou, Jiangsu, China (mainland).
Department of Thoracic and Cardiovascular Surgery, Changzhou No. 2 People's Hospital, Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China (mainland).
Med Sci Monit. 2020 Apr 18;26:e920678. doi: 10.12659/MSM.920678.
BACKGROUND Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary circulatory resistance. Pulmonary vascular endothelial dysfunction is one of the main causes of primary PAH. Endothelial progenitor cells (EPCs) can proliferate and differentiate into vascular endothelial cells and play an important role in maintaining normal endothelial function. Mineralocorticoid receptor inhibitor has been reported to be used in the treatment of PAH. However, the role and the underlying mechanism of aldosterone (ALDO) in PAH remains unclear. MATERIAL AND METHODS Rats were divided to 4 groups (n=10 per group) and treated with 0.9% normal saline, monocrotaline (MCT), spironolactone (SP), or MCT combined with SP. After the rats were sacrificed with an overdose of pentobarbital sodium, hematoxylin and eosin staining was performed to observe the pulmonary artery pathology section. Sirtuin 1 (SIRT1), p53, and p21 protein expression was detect by western blot. Immunofluorescence staining was performed to verify EPCs. EPCs were treated with different concentrations of ALDO. MTT assay and senescence-associated ß-galactosidase staining were used to measure cell viability and senescence. RESULTS MCT increased the vascular arterial wall thickness and wall area, inhibited SIRT1 protein expression and increased p53 and p21 protein expression in the lung tissue of rats, while SP partially reversed this effect. In addition, ALDO inhibited EPCs viability and induced senescence. The expression of p53 and p21 proteins in the EPCs were upregulated and the senescence was accelerated when EPCs were transfected with SIRT1 siRNA. CONCLUSIONS ALDO promoted EPCs senescence and inhibited EPCs proliferation by downregulating SIRT1, which regulates the p53/p21 pathway, thus promoting PAH.
肺动脉高压（PAH）的特征是肺循环阻力逐渐增加。肺血管内皮功能障碍是原发性 PAH 的主要原因之一。内皮祖细胞（EPCs）可以增殖并分化为血管内皮细胞，在维持正常内皮功能方面发挥重要作用。已报道醛固酮（ALDO）受体抑制剂可用于治疗 PAH。然而，ALDO 在 PAH 中的作用及其潜在机制尚不清楚。
将大鼠分为 4 组（每组 10 只），分别用 0.9%生理盐水、野百合碱（MCT）、螺内酯（SP）或 MCT 联合 SP 处理。用过量戊巴比妥钠处死大鼠后，进行苏木精和伊红染色以观察肺动脉病理切片。通过 Western blot 检测 Sirtuin 1（SIRT1）、p53 和 p21 蛋白表达。通过免疫荧光染色验证 EPCs。用不同浓度的 ALDO 处理 EPCs。用 MTT 测定法和衰老相关β-半乳糖苷酶染色法测量细胞活力和衰老。
MCT 增加了大鼠肺组织中的血管动脉壁厚度和壁面积，抑制了 SIRT1 蛋白表达，增加了 p53 和 p21 蛋白表达，而 SP 部分逆转了这种作用。此外，ALDO 抑制了 EPCs 的活力并诱导了衰老。当 EPCs 转染 SIRT1 siRNA 时，p53 和 p21 蛋白的表达上调，衰老加速。
ALDO 通过下调 SIRT1 促进 EPCs 衰老和抑制 EPCs 增殖，从而调节 p53/p21 通路，促进 PAH。
