Original article role of endogenous testosterone in TNF-induced myocardial injury in males

Meijing Wang, Hongmei Gu, Benjamin D. Brewster, Chunyan Huang

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)96-104
Number of pages9
JournalInternational Journal of Clinical and Experimental Medicine
Volume5
Issue number2
StatePublished - Apr 26 2012

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Keywords

  • Estrogen
  • Gender differences
  • Myocardial function
  • Testosterone
  • TNF

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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