Abstract
Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are associated with the pathogenesis of atherosclerosis (AS). Eplerenone (EPL), a novel selective aldosterone receptor blocker, plays a substantial role in the treatment of cardiovascular disease. The G protein-coupled estrogen receptor (GPER) is a target of EPL as the STITCH website predicated. We aimed to investigate the roles of EPL in AS and identify its potential mechanisms of action. Oxidized low-density lipoprotein (ox-LDL) was employed to stimulate VSMCs to establish a cellular model of AS. The ability of cell proliferation was examined using a Cell Counting Kit-8, and the expression of proliferation-related proteins was tested using immunofluorescence staining and western blot analysis. Subsequently, cell migration and the expression of migration-associated proteins were evaluated with a wound healing assay, transwell assay and western blot analysis. Then, GPER expression was determined using western blot analysis in the absence or presence of EPL. To explore the regulatory mechanisms of EPL in ox-LDL-stimulated VSMCs, GPER was overexpressed, followed by measurement of cell proliferation and migration. The Ox-LDL stimulation notably upregulated GPER expression, whereas EPL treatment downregulated GPER expression in a dose-dependent manner. Additionally, EPL markedly inhibited proliferation and migration of VSMCs, and the highest dose of EPL resulted in the most marked effect. By contrast, GPER overexpression reversed the inhibitory effects of EPL on proliferation and migration of VSMCs. Eplerenone suppressed ox-LDL-induced proliferation and migration of VSMCs partly through downregulation of GPER, providing a new mechanism of support for EPL use in the clinical treatment of AS.
Highlights
Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are associated with the pathogenesis of atherosclerosis (AS)
G protein-coupled estrogen receptor (GPER) overexpression reversed the inhibitory effects of EPL on proliferation and migration of VSMCs
EPL markedly downregulated the expression of minichromosome maintenance-2 (MCM-2) and proliferating cell nuclear antigen (PCNA), which are key proliferation-related proteins, in Oxidized low-density lipoprotein (ox-LDL)-exposed VSMCs (Fig. 1D)
Summary
Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are associated with the pathogenesis of atherosclerosis (AS). Eplerenone (EPL), a novel selective aldosterone receptor blocker, plays a substantial role in the treatment of cardiovascular disease. The G protein-coupled estrogen receptor (GPER) is a target of EPL as the STITCH website predicated. Atherosclerosis (AS), a chronic degenerative disease of the arterial wall, is the leading cause of peripheral vascular disease and cardiac-cerebral vascular disease.[1] It is well known to cause high morbidity and mortality in aged individuals worldwide.[2,3] Vascular smooth muscle cells (VSMCs) are involved in the reconstruction of arterial wall by maintaining blood flow in affected vessels due to atherosclerotic alteration.[4] A growing body of literature has shown that abnormal proliferation and migration of VSMCs are closely associated with AS progression.[5,6] Oxidized low-density lipoprotein (ox-LDL), a well-established risk factor for AS, can induce proliferation and migration of VSMCs, thereby contributing to atherosclerotic plaque formation and progression.[7] ox-LDL was employed in the present study to stimulate VSMCs to establish an AS cell model, providing a similar environment to explore the regulatory mechanisms involved in AS
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