Let-7g Improves Multiple Endothelial Functions Through Targeting Transforming Growth Factor-Beta and SIRT-1 Signaling

• Published in: Journal of the American College of Cardiology Vol. 63; no. 16; pp. 1685 - 1694
• Main Authors: Liao, Yi-Chu, Wang, Yung-Song, Guo, Yuh-Cherng, Lin, Wen-Lien, Chang, Ming-Hung, Juo, Suh-Hang Hank
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 29.04.2014; Elsevier; Elsevier Limited
• Subjects: Angiogenesis; Animals; Atherosclerosis; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Cardiovascular Diseases - genetics; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - physiopathology; Cell adhesion & migration; Coronary vessels; Disease Models, Animal; endothelial function; Endothelium; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Experiments; Female; Gene Expression Regulation; Heart; Humans; Let-7g; Male; Medical sciences; Mice; Mice, Knockout; MicroRNAs - genetics; PAI-1; Plasmids; Polymerase Chain Reaction; Proteins; RNA - genetics; Senescence; Signal Transduction; SIRT-1; Sirtuin 1 - biosynthesis; Sirtuin 1 - genetics; Studies; TGF-β pathway; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Vasodilation - genetics; United States > US; California; endothelial function; SMAD2; IL; ADMA; THBS1; SIRT-1; VCAM; TGF-β pathway; TGF; Let-7g; PAI-1; HUVEC; miRNA; PAI; qPCR; MCP; EC; SIRT; human umbilical endothelial cell; microribonucleic acid; SMAD family member 2; sirtuin; interleukin; plasminogen activator inhibitor; quantitative real-time polymerase chain reaction; monocyte chemotactic protein; endothelial cell; asymmetric dimethyl arginine; vascular cell adhesion molecule; transforming growth factor; thrombospondin-1; Improvement; Multiple; Targeting; Transforming growth factor β; Cardiovascular disease; Circulatory system; Endothelial function; Cardiology
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2013.09.069

The present study aimed to explore the role of microribonucleic acid (miRNA) Let-7g in regulating endothelial functions. Derangement of miRNAs is implicated in the pathogenesis of cardiovascular diseases. Because the transforming growth factor (TGF)-β pathway plays a regulatory role in endothelial functions, miRNAs targeted at TGF-β signal cascade might affect vascular health. Bioinformatics software predicted that Let-7g can influence the TGF-β pathway by targeting 3 genes. The Let-7g's effects on multiple endothelial functions were first tested in endothelial cells (ECs) and then in apolipoprotein E knockout mice. Blood samples from lacunar stroke patients were also examined to further support Let-7g's effects on human subjects. Let-7g was experimentally confirmed to knock down the THBS1, TGFBR1, and SMAD2 genes in the TGF-β pathway. PAI-I, one of the downstream effectors of the TGF-β pathway, was also down-regulated by Let-7g. Let-7g decreased EC inflammation and monocyte adhesion and increased angiogenesis via the TGF-β pathway. Furthermore, Let-7g reduced EC senescence through increasing SIRT-1 protein. Venous injection of Let-7g inhibitor into apolipoprotein E knockout mice caused overgrowth of vascular intima-media, overexpression of PAI-1, increased macrophage infiltration, and up-regulation of TGF-β downstream genes in the carotid arteries. Let-7g's beneficial effects on EC were reduced, whereas the TGF-β pathway was suppressed by ribonucleic acid interference. Restoration of the TGF-β pathway also attenuated the effects of Let-7g overexpression. Low serum levels of Let-7g were associated with increased circulating PAI-1 levels. Decreased Let-7g levels impair endothelial function and increase the risks of cardiovascular diseases through targeting TGF-β and SIRT-1 signaling.