Low dose of alcohol attenuates pro-atherosclerotic activity of thrombin

Masaaki Toda; Toshiaki Totoki; Chizu Nakamura; Taro Yasuma; Corina N D' Alessandro-Gabazza; Rumi Mifuji-Moroka; Kota Nishihama; Motoh Iwasa; Noriyuki Horiki; Esteban C Gabazza; Yoshiyuki Takei

doi:10.1016/j.atherosclerosis.2017.09.005

Low dose of alcohol attenuates pro-atherosclerotic activity of thrombin

Atherosclerosis. 2017 Oct:265:215-224. doi: 10.1016/j.atherosclerosis.2017.09.005. Epub 2017 Sep 5.

Affiliations

¹ Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan.
² Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan.
³ Suntory Business Expert Ltd., Seikadai, Seika-cho Soraku-gun, Kyoto, 619-0284, Japan.
⁴ Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan; Department of Diabetes and Metabolism, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan.
⁵ Department of Diabetes and Metabolism, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan.
⁶ Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan. Electronic address: gabazza@clin.medic.mie-u.ac.jp.

PMID: 28923781
DOI: 10.1016/j.atherosclerosis.2017.09.005

Abstract

Background and aims: Thrombin, the active enzyme of the coagulation system, plays a critical role in the pathogenesis of atherosclerosis. Vascular repair promoted by stromal cell-derived factor-1 is a protective process in atherosclerosis. Consumption of low amount of alcohol is believed to reduce the risk of atherosclerotic cardiovascular disease but the mechanism is unclear. This study evaluated whether alcohol can modulate the expression of stromal cell-derived factor-1 and the pro-atherosclerotic activity of thrombin.

Methods: Hepatocytes, monocytes, vascular endothelial and vascular smooth muscle cells were pre-treated with increasing concentrations of ethanol before stimulation with thrombin. The expression of cytokines, chemokines, cell adhesion molecules and epigenetic factors, including histone deacetylases and sirtuins, was evaluated.

Results: Thrombin stimulation significantly enhanced the expression of pro-inflammatory cytokines, chemokines and cell adhesion molecules, but significantly decreased the expression of stromal cell-derived factor-1. Pre-treatment of cells with a low dose of ethanol significantly decreased thrombin-induced production of pro-inflammatory cytokines and chemokines, and significantly increased the production of stromal cell-derived factor-1 compared to cells treated with thrombin alone. Ethanol significantly counteracted the decreased expression of histone deacetylases and sirtuins induced by thrombin. Inhibition of histone deacetylase-2 with trichostatin A or with specific siRNA abolished the stimulatory activity of low-dose ethanol on stromal cell-derived factor-1.

Conclusions: Low-dose of ethanol attenuates the inflammatory response and counteracts the reduced expression of stromal cell-derived factor-1 induced by thrombin via an epigenetic mechanism, providing a potential explanation for the protective activity of low dose of alcohol in atherosclerosis.

Keywords: Alcohol; Atherosclerosis; Chemokines; Coagulation system; Thrombin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis / etiology*
Atherosclerosis / prevention & control
Blood Coagulation / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Ethanol / administration & dosage*
Ethanol / pharmacology
Ethanol / therapeutic use
Humans
Inflammation / prevention & control
Mice
Thrombin / drug effects*
Thrombin / physiology*

Substances

Ethanol
Thrombin