Expression ofmiR-146a/bis associated with the Toll-like receptor 4 signal in coronary artery disease: effect of renin–angiotensin system blockade and statins onmiRNA-146a/band Toll-like receptor 4 levels

Abstract

The TLR4 (Toll-like receptor 4) signal plays an important role in immunity in CAD (coronary artery disease). miR-146a/b (where miR is microRNA) regulates the TLR4 downstream molecules IRAK1 (interleukin-1-receptor-associated kinase 1) and TRAF6 (tumour-necrosis-factor-receptor-associated factor 6). It has also been reported that statins and RAS (renin-angiotensin system) inhibition and have anti-atherosclerotic properties. In the present study, we have investigated whether miR-146a/b was expressed with the TLR4 signal in CAD patients, and whether combined treatment with a statin and RAS inhibition might affect these levels. A total of 66 patients with CAD and 33 subjects without CAD (non-CAD) were enrolled. Patients with CAD were randomized to 12 months of combined treatment with atorvastatin and telmisartan [an ARB (angiotensin II receptor blocker)] or atorvastatin and enalapril [an ACEI (angiotensin-converting enzyme inhibitor)]. PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 12 months. Levels of miR-146a/b, IRAK1 mRNA, TRAF6 mRNA and TLR4 mRNA/TLR4 protein were significantly higher in the CAD group than in the non-CAD group (all P<0.01). Levels of miR-146a/b were positively correlated with IRAK1 mRNA and TRAF6 mRNA levels. After 12 months of treatment, these levels were markedly decreased in the ARB and ACEI groups, with the decrease in the ARB group being greater than that in the ACEI group (all P<0.05). In our 12-month follow-up study, high levels of miR-146a and TLR4 mRNA/TLR4 protein at baseline were independent predictors of cardiac events. The present study demonstrates that combined treatment with an ARB and a statin decreases miR-146a/b and the TLR4 signal in CAD patients, possibly contributing to the anti-atherogenic effects of ARBs and statins in this disorder.

MicroRNAs in the Atherosclerotic Plaque

“…fering from CAD has been replicated, in 2 independent studies (69,70 ). miRNAs have also been seen as direct drug targets.…”

“…Most importantly, statins have become widely used for lowering LDL concentrations. Statins have been shown to decrease the expression of miR-146a and -146b (70 ) and to increase let-7i (71 ) expression in the PBMCs of CAD patients. More specifically, atorvastatin has been demonstrated to decrease miR-221/222 (80 ) and miR-34a (81 ) in circulating endothelial progenitor cells, whereas pravastatin or rosuvastatin did not have this effect.…”

Apolipoprotein E Epsilon 4 Enhances the Association between the rs2910164 Polymorphism of miR-146a and Risk of Atherosclerotic Cerebral Infarction

“…MiR-146a is recognized for its ability to silence multiple inflammatory targets, including IRAK1 and TRAF6, and suppress TLRdriven NF-B signaling in macrophages and other haematopoietic cells. Reduction of miR-146a levels in these cell lines could enhance the susceptibility to atherosclerosis and sepsis [12][13][14] . The current evidence supports the hypothesis that miR-146a operates as an important epigenetic regulator in various pathways involved in atherosclerosis and stroke.…”

“…Mechanistically, ApoE increases the expression of the transcription factor PU.1, which increases miR-146 levels to suppress NF-B signaling. Li et al demonstrated that ApoE regulates the expression of miR-146a in monocytes and macrophages to repress NF-B signaling in these cells, and intravascular delivery of miR-146a mimetics can inhibit atherogenesis in mouse models 13) . However, the 4 gene polymorphism causes strong dysfunction of ApoE, which suppresses the level of miR146a 13,38,50) .…”

“…Li et al demonstrated that ApoE regulates the expression of miR-146a in monocytes and macrophages to repress NF-B signaling in these cells, and intravascular delivery of miR-146a mimetics can inhibit atherogenesis in mouse models 13) . However, the 4 gene polymorphism causes strong dysfunction of ApoE, which suppresses the level of miR146a 13,38,50) . Based on the finding that ApoE 4 induced decreasing expression of miR-146a in ACI patients, we suggest that the downregulation of NF-B-dependent pathways by miR-146a through a critical negative feedback regulatory loop was attenuated by the effects of ApoE 4.…”