Rac1 mediates sex difference in cardiac tumor necrosis factor-α expression via NADPH oxidase–ERK1/2/p38 MAPK pathway in endotoxemia

Zhu, Huaqing; Shan, Limei; Peng, Tianqing

doi:10.1016/j.yjmcc.2009.05.002

« Previous Next »Journal of Molecular and Cellular Cardiology
Volume 47, Issue 2 , Pages 264-274, August 2009

Rac1 mediates sex difference in cardiac tumor necrosis factor-α expression via NADPH oxidase–ERK1/2/p38 MAPK pathway in endotoxemia

Huaqing Zhu
- Critical Illness Research, Lawson Health Research Institute, London Health Sciences Center, London, Ontario, Canada N6A 4G5
- Department of Medicine, University of Western Ontario, London, Ontario, Canada N6A 4G5
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, China
Limei Shan
- Critical Illness Research, Lawson Health Research Institute, London Health Sciences Center, London, Ontario, Canada N6A 4G5
- Department of Medicine, University of Western Ontario, London, Ontario, Canada N6A 4G5
Tianqing Peng
- Critical Illness Research, Lawson Health Research Institute, London Health Sciences Center, London, Ontario, Canada N6A 4G5
- Department of Medicine, University of Western Ontario, London, Ontario, Canada N6A 4G5
- Department of Pathology, University of Western Ontario, London, Ontario, Canada N6A 4G5
- Corresponding author. Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ontario, Canada N6A 4G5. Tel.: +1 519 685 8300x55441; fax: +1 519 685 8341.

Received 30 January 2009; received in revised form 19 April 2009; accepted 8 May 2009. published online 18 May 2009.

Abstract

The purpose of this study was to investigate the role of Rac1 and estrogen in sex difference of cardiac tumor necrosis factor-alpha (TNF-α) expression during endotoxemia. Endotoxemia was induced in male and female mice by peritoneal injection of lipopolysaccharide (LPS, 4 mg/kg). Compared with female mice, male mice produced more TNF-α in the heart 4 h after LPS treatment, which were correlated with higher Rac1 and NADPH oxidase activity, more phosphorylation of ERK1/2 and p38 MAPK, and up-regulation of toll-like receptor-4 (TLR-4) expression in male mice. Cardiac specific Rac1 knockout or administration of 17β-estradiol down-regulated Rac1 expression, attenuated gp91^phox-NADPH oxidase expression and activity, decreased phosphorylation of ERK1/2/p38 MAPK and inhibited cardiac TNF-α expression induced by LPS, suggesting an important role of Rac1 and estrogen in LPS-stimulated TNF-α expression in the heart. More importantly, the sex difference in TNF-α expression was abrogated by Rac1 knockout or gp91^phox knockout and by administration of apocynin or N-acetylcysteine in LPS-stimulated mice. To investigate the functional significance of sex difference in endotoxemia, heart function was measured in isolated hearts with a Langendorff system. Male mice exhibited worse myocardial dysfunction compared with female in endotoxemia. Treatment of male mice with 17β-estradiol attenuated myocardial dysfunction during endotoxemia. In conclusion, LPS induces Rac1 activation, which contributes to NADPH oxidase activity and phosphorylation of ERK1/2/p38 MAPK, leading to TNF-α expression in the heart. The sex difference in TNF-α expression is estrogen-dependent and mediated via Rac1 dependent NADPH oxidase/ERK1/2 and p38 MAPK pathway in LPS-stimulated hearts.

Keywords: Sex difference, Estrogen, Tumor necrosis factor-alpha, Rac1, NADPH oxidase, MAPK, Lipopolysaccharide, Signal transduction