Abstract
Apelin, identified as the endogenous ligand of APJ, exerts various cardiovascular effects. However, the molecular mechanism underlying the regulation of apelin expression in vascular cells is poorly described. Pioglitazone (PIO) and Krüppel-like factor 4 (KLF4) exhibit specific biological functions on vascular physiology and pathophysiology by regulating differentiation- and proliferation-related genes. The present study aimed to investigate the roles of PIO and KLF4 in the transcriptional regulation of apelin in a high-fat diet/streptozotocin rat model of diabetes and in PIO-stimulated vascular smooth muscle cells (VSMCs). Immunohistochemistry, qRT-PCR, and Western blotting assays revealed that the aorta of the Type 2 diabetes mellitus (T2DM) rat models had a high expression of apelin, PIO could decrease the expression of apelin in the PIO-treated rats. In vitro, Western blotting assays and immunofluorescent staining results showed that the basal expression of apelin was decreased but that of KLF4 was increased when VSMCs were stimulated by PIO treatment. Luciferase and chromatin immunoprecipitation assay results suggested that KLF4 bound to the GKLF-binding site of the apelin promoter and negatively regulated the transcription activity of apelin in VSMCs under PIO stimulation. Furthermore, qRT-PCR and Western blotting assay results showed that the overexpression of KLF4 markedly decreased the basal expression of apelin, but the knockdown of KLF4 restored the PIO-induced expression of apelin. In conclusion, PIO inhibited the expression of apelin in T2DM rat models to prevent diabetic macroangiopathy, and negatively regulated the gene transcription of apelin by promoting transcription of KLF4 in the apelin promoter.
Highlights
The incidence of Type 2 diabetes mellitus (T2DM) is currently very high, with several young individuals acquiring the disease over recent years
To the best of our knowledge, the results reported in the present study showed that for the first time the serum levels of apelin could be reduced by PIO in T2DM rats
Previous studies have shown that the expression of apelin in vivo and in vitro is upregulated by hypoxia-inducible factor 1-α (HIF1-α), all-trans retinoic acid (ATRA), and insulin [22,34,35] and down-regulated by TNF-α and the activating transcription factor 4 in different cell types [23,36]
Summary
The incidence of Type 2 diabetes mellitus (T2DM) is currently very high, with several young individuals acquiring the disease over recent years. T2DM complications are mainly caused by vasculopathy and include coronary heart diseases, cerebrovascular diseases, hypertension, and retinal hemorrhage. It can be developed from microangiopathy, and macroangiopathy. Apelin is an endogenous peptide that comprises a ligand for the APJ (angiotensin II receptor like-1, AT-1) Both apelin and APJ have been shown to regulate cardiovascular actions such as blood pressure regulation, neovascularization, and cardiac function [1,2,3,4,5].
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