18 April 2020 : Animal Research
Effect of Aldosterone on Senescence and Proliferation Inhibition of Endothelial Progenitor Cells Induced by Sirtuin 1 (SIRT1) in Pulmonary Arterial Hypertension
Yue Wang1A, Bin Zhong2B, Qiyong Wu2C, Jichun Tong2D, Tao Zhu2E, Ming Zhang2F*DOI: 10.12659/MSM.920678
Med Sci Monit 2020; 26:e920678
Abstract
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 β-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.
Keywords: Aldosterone, Hypertension, Sirtuin 1, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21, endothelial progenitor cells, pulmonary arterial hypertension, Tumor Suppressor Protein p53
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