Propofol inhibits lipopolysaccharide-induced tumor necrosis factor-alpha expression and myocardial depression through decreasing the generation of superoxide anion in cardiomyocytes.

Jing Tang,Chun-Shui Lin,Jia-Ni Liang,You-Tan Liu,Ji-Jie Hu,Jin-Fang Xiao,Zai-Sheng Qin,Chun-Hua Lu

doi:10.1155/2014/157376

Abstract

TNF-α has been shown to be a major factor responsible for myocardial depression in sepsis. The aim of this study was to investigate the effect of an anesthetic, propofol, on TNF-α expression in cardiomyocytes treated with LPS both in vivo and in vitro. In cultured cardiomyocytes, compared with control group, propofol significantly reduced protein expression of gp91phox and phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) and p38 MAPK, which associates with reduced TNF-α production. In in vivo mice studies, propofol significantly improved myocardial depression and increased survival rate of mice after LPS treatment or during endotoxemia, which associates with reduced myocardial TNF-α production, gp91phox, ERK1/2, and p38 MAPK. It is concluded that propofol abrogates LPS-induced TNF-α production and alleviates cardiac depression through gp91phox/ERK1/2 or p38 MAPK signal pathway. These findings have great clinical importance in the application of propofol for patients enduring sepsis.

Highlights

Endotoxemia or sepsis is a major consequence of infectious diseases, which causes multiple organ injury, including injury of the cardiovascular system, and becomes one of the leading causes of death in patients in the intensive care unit (ICU) [1, 2]
Our results showed that propofol could inhibit NADPH oxidase expression and NADH oxidase activity to downregulate the phosphorylation of p38 MAPK and extracellular regulated protein kinases 1/2 (ERK1/2) and to decrease LPS-induced TNF-α expression
We demonstrate that (i) propofol inhibits LPS-induced increased TNF-α production in cardiomyocytes, (ii) the inhibitory effect of propofol on TNF-α production in cardiomyocytes relies on its ability of suppressing the activity of NADH oxidase to decrease the generation of O2− and phosphorylation of p38 MAPK and ERK1/2, (iii) propofol alleviates myocardial dysfunction in mice with endotoxemia, and (iv) propofol protects mice with endotoxemia from death

Summary

Introduction

Endotoxemia or sepsis is a major consequence of infectious diseases, which causes multiple organ injury, including injury of the cardiovascular system, and becomes one of the leading causes of death in patients in the intensive care unit (ICU) [1, 2]. It has been demonstrated that cardiomyocytes are the major local source of TNF-α, a proinflammatory cytokine, in the myocardium during sepsis and TNF-α is responsible for LPS induced cardiac function [3] and for myocardial depression induced by endotoxemia [4, 5]. Previous studies have proven that gp91phox-containing NADPH oxidase activity plays a pivotal role in LPS-induced TNF-α expression in the heart. This signaling pathway involves O2− generation and activation of ERK1/2 and p38 MAPK. Gp91phox-containing NADPH oxidase contributes to myocardial dysfunction during endotoxemia [7]

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