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| IJCEM Copyright © 2008-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Int J Clin Exp Med 2012;5(2):96-104
Original Article
Role of endogenous testosterone in TNF-induced myocardial injury in males
Meijing Wang, Hongmei Gu, Benjamin D Brewster, Chunyan Huang
The Departments of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
Received December 2, 2011; accepted February 22, 2012; Epub April 8, 2012; Published April 30, 2012
Abstract: Background: Gender-specific disparities have been observed in myocardium exposed to tumor necrosis factor-α (TNF). Male
myocardium demonstrates greater loss in cardiac function in the presence of a given TNF level compared to female. In addition, we
have previously demonstrated that estrogen has little influence on reducing TNF-caused myocardial dysfunction in female hearts,
suggesting that male hormone – testosterone may be responsible for gender differences in TNF-mediated myocardial damage.
Therefore, in this study, we hypothesize that endogenous testosterone plays a detrimental role in TNF-induced myocardial injury in
male hearts. Methods: Isolated mouse hearts from age-matched adult males, females, castrated males and males treated with
androgen receptor blocker-flutamide were subjected to 45 minutes of TNF infusion via a Langendorff model. Left ventricular developed
pressure (LVDP) and heart rate were continuously recorded. After TNF infusion, heart tissue was analyzed for myocardial levels of
caspase-8 and caspase-3 by Western blot assay. Results: TNF infusion significantly depressed LVDP, but not heart rate in males.
Myocardial rate pressure product (RPP, LVDP*heart rate) was markedly decreased in male hearts compared to females in exposure to
TNF, which was associated with higher levels of TNF-induced caspase-8 and caspase-3. Importantly, depletion of endogenous
testosterone by castration or blockade of androgen receptor by flutamide treatment abolished TNF-decreased RPP in male hearts.
However, castration or flutamide treatment did not affect TNF production and myocardial expression of TNFR1 and TNFR2. Conclusion:
Our study shows that testosterone is critical to the gender difference in TNF-induced detrimental effects on myocardium. Relative low
threshold for TNF-caused myocardial damage in males is likely due to the interaction of testosterone with downstream signals of
TNFR1 and/or TNFR2. (IJCEM1112002).
Keywords: Gender differences, TNF, myocardial function, testosterone, estrogen
Address all correspondence to:
Dr. Meijing Wang
635 Barnhill Drive MS 2057
Indianapolis, Indiana 46202, USA.
Tel: 317-274-0827; Fax: 317-274-1511
E-mail: meiwang@iupui.edu
Original Article
Role of endogenous testosterone in TNF-induced myocardial injury in males
Meijing Wang, Hongmei Gu, Benjamin D Brewster, Chunyan Huang
The Departments of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
Received December 2, 2011; accepted February 22, 2012; Epub April 8, 2012; Published April 30, 2012
Abstract: Background: Gender-specific disparities have been observed in myocardium exposed to tumor necrosis factor-α (TNF). Male
myocardium demonstrates greater loss in cardiac function in the presence of a given TNF level compared to female. In addition, we
have previously demonstrated that estrogen has little influence on reducing TNF-caused myocardial dysfunction in female hearts,
suggesting that male hormone – testosterone may be responsible for gender differences in TNF-mediated myocardial damage.
Therefore, in this study, we hypothesize that endogenous testosterone plays a detrimental role in TNF-induced myocardial injury in
male hearts. Methods: Isolated mouse hearts from age-matched adult males, females, castrated males and males treated with
androgen receptor blocker-flutamide were subjected to 45 minutes of TNF infusion via a Langendorff model. Left ventricular developed
pressure (LVDP) and heart rate were continuously recorded. After TNF infusion, heart tissue was analyzed for myocardial levels of
caspase-8 and caspase-3 by Western blot assay. Results: TNF infusion significantly depressed LVDP, but not heart rate in males.
Myocardial rate pressure product (RPP, LVDP*heart rate) was markedly decreased in male hearts compared to females in exposure to
TNF, which was associated with higher levels of TNF-induced caspase-8 and caspase-3. Importantly, depletion of endogenous
testosterone by castration or blockade of androgen receptor by flutamide treatment abolished TNF-decreased RPP in male hearts.
However, castration or flutamide treatment did not affect TNF production and myocardial expression of TNFR1 and TNFR2. Conclusion:
Our study shows that testosterone is critical to the gender difference in TNF-induced detrimental effects on myocardium. Relative low
threshold for TNF-caused myocardial damage in males is likely due to the interaction of testosterone with downstream signals of
TNFR1 and/or TNFR2. (IJCEM1112002).
Keywords: Gender differences, TNF, myocardial function, testosterone, estrogen
Address all correspondence to:
Dr. Meijing Wang
635 Barnhill Drive MS 2057
Indianapolis, Indiana 46202, USA.
Tel: 317-274-0827; Fax: 317-274-1511
E-mail: meiwang@iupui.edu
