miR-26a inhibits atherosclerosis progression by targeting TRPC3

Abstract

BackgroundAtherosclerosis, a chronic multi-factorial vascular disease, has become a predominant cause of a variety of cardiovascular disorders. miR-26a was previously reported to be involved in atherosclerosis progression. However, the underlying mechanism of miR-26a in atherosclerosis remains to be further explained.MethodsHigh-fat diet (HFD)-fed apolipoprotein E (apoE)−/− mice and oxidized low-density lipoprotein (ox-LDL)-stimulated human aortic endothelial cells (HAECs) were established as in vivo and in vitro models of atherosclerosis. RT-qPCR and western blot analysis were performed to measure the expression of miR-26a and transient receptor potential canonical 3 (TRPC3), respectively. Binding between miR-26a and TRPC3 was predicted with bioinformatics software and verified using a dual luciferase reporter assay. The effects of miR-26a on the lipid accumulation, atherosclerotic lesion, and inflammatory response in HFD-fed apoE−/− mice were investigated by a colorimetric enzymatic assay system, hematoxylin–eosin and oil-Red-O staining, and ELISA, respectively. Additionally, the effects of miR-26a or combined with TRPC3 on cell viability, apoptosis and the nuclear factor-kappa B (NF-κB) pathway in ox-LDL-stimulated HAECs were evaluated by MTT assay, TUNEL assay, and western blot, respectively.ResultsmiR-26a was downregulated in HFD-fed apoE−/− mice and ox-LDL-stimulated HAECs. miR-26a overexpression inhibited the pathogenesis of atherosclerosis by attenuating hyperlipidemia, atherosclerotic lesion and suppressing inflammatory response in HFD-fed apoE−/− mice. Moreover, miR-26a overexpression suppressed inflammatory response and the NF-κB pathway, promoted cell viability and inhibited apoptosis in ox-LDL-stimulated HAECs. Additionally, TRPC3 was demonstrated to be a direct target of miR-26a. Enforced expression of TRPC3 reversed the effects of miR-26a on cell viability, apoptosis, and the NF-κB pathway in ox-LDL-treated HAECs.ConclusionsmiR-26a alleviated the development of atherosclerosis by regulating TRPC3, providing a potential target for atherosclerosis treatment.

RNA-seq analysis reveals TRPC genes to impact an unexpected number of metabolic and regulatory pathways

“…In addition, TRPC1 appears to contribute to the regulation of the epithelial-mesenchymal transition (EMT) in cancer; its inhibition suppresses TGF-β1-induced EMT 96,97 . TRPC3 is expressed in various immune cells and has been proposed to contribute to vascular inflammation [98][99][100] . Also, the brain-derived neurotrophic factor (BNDF) has the effect of upregulating TRPC3 in the cell membrane.…”

Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis

“…In contrast, Feng et al showed that overexpression of miR‐26a suppressed an inflammatory response and inhibited atherosclerosis progression by regulating transient receptor potential canonical 3 (TRPC3). They also reported that, in humans, upregulated miR‐26a promoted cell viability and inhibited apoptosis in Ox‐LDL‐stimulated aortic endothelial cells . It has been reported that with atherosclerosis induced by ApoE deficiency, upregulated miR‐133 expression is positively correlated with levels of insulin‐like growth factor 1 receptor (IGF‐1R) and promotes VSMC growth and migration, thereby increasing intimal thickness .…”

TRPC and TRPV Channels’ Role in Vascular Remodeling and Disease

“…TRPC3 deletion in macrophages reduces their presence in the atheroma plaque [96]. TRPC3 inhibition suppresses the NF-κB pathway, promotes cell viability and inhibits apoptosis in ECs [97].…”