The effect and molecular mechanism of statins on the expression of human anti-coagulation genes

• Published in: Cellular and molecular life sciences : CMLS Vol. 76; no. 19; pp. 3891 - 3898
• Main Authors: Chang, Sheng-Nan, Wu, Cho-Kai, Lai, Ling-Ping, Chiang, Fu-Tien, Hwang, Juey-Jen, Tsai, Chia-Ti
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-10-2019; Springer Nature B.V
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; C gene; Cell Biology; Clinical trials; Coagulation; Gene expression; Gene regulation; Guanosine triphosphatases; Hep G2 Cells; Hepatocyte Nuclear Factor 1-alpha - metabolism; Hepatocytes; Hepatoma; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Life Sciences; Lipids; Medical research; Molecular modelling; Original; Original Article; Promoter Regions, Genetic - drug effects; Protein C; Protein C - genetics; Protein C - metabolism; Proteins; rac1 GTP-Binding Protein - genetics; Rac1 protein; Rats, Wistar; Simvastatin; Simvastatin - pharmacology; Statins; Thromboembolism; Thrombosis; Transcription; Transcription, Genetic - drug effects; HNF 1α; Protein C; Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase; Rac1; Anti-coagulation; Gene
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03100-w

Statins are potent lipid-lowering drugs. Large prospective clinical trials have shown the anti-thrombotic effect of statins, e.g., preventing deep vein thrombosis. However, the mechanism underlying the beneficial effect of statins in reducing thrombus formation remains to be established. We, thus, conduct this study to investigate the potential molecular mechanisms. The cultured human hepatoma cells (HepG2) were used as the in vitro model. The human protein C gene promoter was cloned into the luciferase reporter to study the transcriptional regulation of human protein C gene. Wistar rats fed with simvastatin (5 mg/kg day) were used as the in vivo model. We found that simvastatin increased the expression of protein C in hepatocytes (361 ± 64% and 313 ± 59% after 2 h and 6 h of stimulation, respectively, both
p
 < 0.01). In the animal study, the serum protein C levels were increased in the simvastatin-treated group (7 ± 2.2 unit/ml vs 23.4 ± 19.3 unit/ml and 23.4 ± 18.2 unit/ml and 1 and 2 weeks of treatment, respectively, both
p
 < 0.05). Regarding the possible molecular mechanism, we found that the level of hepatocyte nuclear factor 1α (HNF1α) was also increased in both the in vivo and in vitro models. We found that the protein C promoter activity was increased by simvastatin, and this effect was inhibited by HNF1α knockdown and constitutively active Rac1. Therefore, stains may modulate protein C expression through small GTPase Rac 1 and HNF1α.