Circulating Toll-like receptor 4-responsive microRNA panel in patients with coronary artery disease: results from prospective and randomized study of treatment with renin-angiotensin system blockade.
The extracellular miRNAs circulate in the bloodstream and may serve as novel diagnostic and therapeutic biomarkers. The aim of the present study was to investigate circulating Toll-like receptor 4 (TLR4)-responsive miRNA expression in patients with coronary artery disease (CAD) and to examine the effects of renin-angiotensin system (RAS) blockade and statins on miRNA levels. This study included 41 patients with CAD and 20 subjects without CAD (non-CAD). Plasma TLR4-responsive miRNA samples were analysed using a microarray assay for 1700 human miRNA. The candidate miRNAs were verified with real-time reverse transcription (RT)-PCR. Patients with CAD were randomized to 12 months of combined treatment with either telmisartan and atorvastatin [angiotensin II receptor blocker (ARB)] or enalapril and atorvastatin [angiotensin-converting enzyme inhibitor (ACEI)]. Plasma samples were obtained from peripheral blood at baseline and after 12 months. The microarray assay showed significant differences in seven TLR4-responsive miRNAs between the CAD and non-CAD groups (P<0.05). Real-time PCR verified that miR-31, miR-181a, miR-16 and miR-145 were significantly lower in the CAD group than in the non-CAD group (P<0.01). Levels of TLR4 protein were higher in the CAD group than in the non-CAD group (P<0.01) and were negatively correlated with levels of TLR4-responsive miRNAs. Receiver operating characteristic (ROC) curve analysis revealed that a panel of these four miRNAs was sensitive and specific enough to distinguish CAD from non-CAD [area under the curve (AUC)=0.93, 95% CI (confidence interval)=0.99-0.87]. Both ARB and ACEI groups showed increased TLR4-responsive miRNAs and diminished levels of TLR4 protein (P<0.05). Changes in miRNAs and TLR4 levels were greater in the ARB group than in the ACEI group (P<0.05). Circulating TLR4-responsive miRNAs including miR-31, miR-181a, miR-16 and miR-145 were significantly lower in patients with CAD compared with controls and these miRNAs may be involved in the pathogenesis of CAD.
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Mamoru
M
Satoh
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Yuji
Y
Takahashi
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Tsuyoshi
T
Tabuchi
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Makiko
M
Tamada
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Kan
K
Takahashi
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Tomonori
T
Itoh
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Yoshihiro
Y
Morino
*Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Division of Cardioangiology, Nephrology and Endocrinology and Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
Motoyuki
M
Nakamura
D000368:Aged; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000097:blood*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D035683:MicroRNAs; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4