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

Abstract

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.

• Authors: Peng Li, Ya-Ling Yin, Tao Guo, Xue-Ying Sun, Hui Ma, Mo-Li Zhu, Fan-Rong Zhao, Ping Xu, Yuan Chen, Guang-Rui Wan, Fan Jiang, Qi-Sheng Peng, Chao Liu, Li-Ying Liu, Shuang-Xi Wang
• Journal: Circulation (Circulation) Vol. 134 Issue 22 Pg. 1752-1765 (Nov 29 2016) ISSN: 1524-4539 [Electronic] United States
• PMID: 27765794 (Publication Type: Journal Article)
• Copyright: © 2016 The Authors.

Chemical References

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• MIRN133 microRNA, rat
• MicroRNAs
• RNA, Messenger
• Nitric Oxide
• Lovastatin
• Nitric Oxide Synthase Type III
• GTP Cyclohydrolase
• Gch1 protein, mouse

Topics

• Animals
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism)
• GTP Cyclohydrolase (deficiency, genetics, metabolism)
• HEK293 Cells
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Lovastatin (pharmacology)
• Mice
• MicroRNAs (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• RNA, Messenger (genetics)
• Rats
• Risk Factors
• Up-Regulation