4.8 Article

Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo

Journal

CIRCULATION
Volume 134, Issue 22, Pages 1752-1765

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.116.017949

Keywords

endothelial cells; GTP cyclohydrolase; hydroxymethylglutaryl-CoA reductase inhibitors; MIRN133 microRNA, rat; nitric oxide synthase type III

Funding

  1. National 973 Basic Research Program of China [2013CB530700, 2015CB553600]
  2. National Natural Science Foundation of China [81320108004, 91439201, 81370411, 81470591, 81570723, 81673423, 31372409]
  3. Science and Technology Research Project of Henan Province [121100910300, 132102310247]
  4. Program for New Century Excellent Talents in University [NCET-13-0351]
  5. Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry
  6. Program of Clinical Investigation (Nanshan Group), Qilu Hospital, Shandong University [2014QLKY15]

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BACKGROUND: GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. METHODS: Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization. RESULTS: We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin. CONCLUSIONS: Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.

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