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.
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.
Authors: Jeffrey M Pitcher; Meijing Wang; Ben M Tsai; Ajay Kher; Nicholas T Nelson; Daniel R Meldrum Journal: Am J Physiol Regul Integr Comp Physiol Date: 2005-09-08 Impact factor: 3.619
Authors: N G Frangogiannis; M L Lindsey; L H Michael; K A Youker; R B Bressler; L H Mendoza; R N Spengler; C W Smith; M L Entman Journal: Circulation Date: 1998-08-18 Impact factor: 29.690
Authors: Ryan M Samuel; Homa Majd; Mikayla N Richter; Zaniar Ghazizadeh; Seyedeh Maryam Zekavat; Albertas Navickas; Jonathan T Ramirez; Hosseinali Asgharian; Camille R Simoneau; Luke R Bonser; Kyung Duk Koh; Miguel Garcia-Knight; Michel Tassetto; Sara Sunshine; Sina Farahvashi; Ali Kalantari; Wei Liu; Raul Andino; Hongyu Zhao; Pradeep Natarajan; David J Erle; Melanie Ott; Hani Goodarzi; Faranak Fattahi Journal: Cell Stem Cell Date: 2020-11-17 Impact factor: 24.633