MicroRNA-126 inhibits endothelial permeability and apoptosis in apolipoprotein E-knockout mice fed a high-fat diet

Abstract

Endothelial dysfunction and apoptosis have key roles in the initiation and progression of atherosclerosis (AS). AS has been demonstrated to be associated with a high-fat diet, which may increase endothelial permeability and apoptosis; however, the exact mechanisms underlying the development of AS remain poorly understood. MicroRNAs (miRNAs) are vital for the regulation of cardiovascular disease, and dysregulated miRNAs have been implicated in AS. The present study investigated whether miRNA (miR)-126 regulates high-fat diet-induced endothelial permeability and apoptosis by targeting transforming growth factor β (TGFβ), a secreted protein that controls cellular proliferation and apoptosis. In the present study, apolipoprotein E (apoE)−/− mice were fed a high-fat diet in order to establish a model of AS. Mice were subcutaneously injected with a miR-126 mimic, a miR-126 antagomir or control miRNA. Reverse transcription-quantitative polymerase chain reaction was used to assess miR-126 expression, and a fluorometric assay was used to evaluate caspase-3 activity. The effects of miR-126 on the endothelial permeability of the aortic intima were also explored. Western blotting and immunohistochemical analysis were used to investigate the effects of miR-126 on B-cell lymphoma-2 (Bcl-2) and transforming growth factor (TGF) β protein expression levels. Furthermore, a luciferase assay was performed to verify whether TGFβ may be a direct target gene of miR-126. In apolipoprotein E-knockout mice, a high-fat diet reduced miR-126 expression and induced apoptosis as determined by the upregulation of caspase-3 activity. A miR-126 antagomir increased endothelial permeability and apoptosis in mice fed a high-fat diet. By contrast, an miR-126 mimic attenuated endothelial permeability and apoptosis. The reduction in miR-126 was associated with a reduction in protein expression levels of Bcl-2 and an increase of TGFβ in mice fed a high-fat diet. In addition, the present study demonstrated that miR-126 reduced TGFβ expression following binding to the 3′-untranslated region of TGFβ mRNA. The current study demonstrated a role for miR-126 in AS and identified TGFβ as a direct target of miR-126. Furthermore, the present study demonstrated that miR-126 contributed to endothelial permeability and apoptosis, and suggested that the downregulation of TGFβ may be involved in the molecular mechanisms underlying the actions of miR-126. miR-126 may therefore have potential as a novel therapeutic target for the treatment of AS.

MicroRNAs as Potential Mediators for Cigarette Smoking Induced Atherosclerosis

“…However, we need further studies since no significant changes were observed in the expression level of miR-126 after exposure to CS. Consistent with the present study, previous studies have shown that the miR-126 level was decreased in the aortas of ApoE KO mice fed a high-fat diet [ 45 ]. Conversely, other previous studies have shown that the miR-126 level was increased in the aortas of ApoE KO mice with superimposed chronic kidney disease [ 46 ].…”

The role of miRNAs in the diagnosis of stable atherosclerosis of different arterial territories: A critical review

“…In fact, endothelial dysfunction is considered an early marker of atherosclerosis development (14). Different miRNAs, such as miR-21 (21), miR-126 (22)(23)(24), miR-146a (25) and miR-221 (26), regulate endothelial cell senescence, proliferation, and migration and influence inflammatory pathways initiated in endothelial cells. Members of the miR-181 family have been shown to suppress the inflammatory response of endothelial cells by targeting mediators of NF-kB pathways (27)(28)(29).…”

Role of microRNAs in the Development of Cardiovascular Disease in Systemic Autoimmune Disorders

“…There is growing evidence that miRNAs control these pathologic processes including endothelial dysfunction (miR let-7g, mir-17-3p, miR-31, miR-146a, miR-155, miR-181 family, miR-221/-222,) [170][171][172][173][174][175], oxidative stress (miR-let-7a/b, miR-19b, miR-20a, miR-98, miR-126, miR-142-3p, miR-199a-3p and -5p, miR-200c, miR-221, miR-222, miR-328) [176][177][178][179][180][181][182][183][184][185][186][187][188][189], monocyte recruitment, differentiation and activation (miR-21, miR-23a-5p, miR-27a/b, miR-33, miR-34, miR-146a, miR-155, miR-212, miR-451, miR-590, miR-758-5p, [190][191][192][193][194][195][196][197][198][199][200][201] and inflammation/secretion of inflammatory cytokines (miR let-7g, miR-17-3p, miR-31, miR-146a, miR-155, miR-181a-3p/-5p, miR-181b, miR-221 and miR-222) [171,202,203]. Interestingly, a number of them are simultaneously involved in all those processes, suggesting common and/or cooperative activities, and underlying their relevance in the physiopathology of CVD.…”