Both endogenous and exogenous testosterone decrease myocardial STAT3 activation and SOCS3 expression after acute ischemia and reperfusion

Wang, Meijing; Wang, Yue; Abarbanell, Aaron; Tan, Jiangjing; Weil, Brent; Herrmann, Jeremy; Meldrum, Daniel R.

doi:10.1016/j.surg.2009.03.035

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Volume 146, Issue 2 , Pages 138-144, August 2009

Both endogenous and exogenous testosterone decrease myocardial STAT3 activation and SOCS3 expression after acute ischemia and reperfusion

Meijing Wang, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Yue Wang, PhD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Aaron Abarbanell, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Jiangjing Tan, MD, PhD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Brent Weil, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Jeremy Herrmann, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Daniel R. Meldrum, MD
- Clarian Cardiovascular Surgery, Indiana University School of Medicine, Indianapolis, IN
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN
- Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN
- Reprint requests: Daniel R. Meldrum, MD, 635 Barnhill Drive, MS 2017, Indianapolis, IN 46202.

Accepted 10 March 2009. published online 26 June 2009.

Background

Signal transducer and activator of transduction 3 (STAT3) pathway has been shown to be cardioprotective. We observed decreased STAT3/suppressor of cytokine signaling 3 (SOCS3) in male hearts, which was associated with worse postischemic myocardial function compared with females. However, it is unclear whether this downregulation of myocardial STAT3/SOCS3 is due to testosterone in males. We hypothesized that after ischemia/reperfusion (I/R), (1) endogenous testosterone decreases myocardial STAT3 and SOCS3 in males, and (2) administration of exogenous testosterone reduces myocardial STAT3/SOCS3 in female and castrated male hearts.

Methods

To study this, hearts from I/R injury (Langendorff) were homogenized and assessed for phosphorylated-STAT3 (p-STAT3), total-STAT3 (T-STAT3), SOCS3, and GAPDH by Western blot. We grouped age-matched adult males, females, castrated males, males with androgen receptor blocker-flutamide implantation, females, and castrated males with chronic (3-week) 5α-dihydrotestosterone (DHT) release pellet implantation or acute (5-minute) testosterone infusion (ATI) before ischemia (n = 5–9 per group).

Results

Castration or flutamide treatment significantly increased SOCS3 expression in male hearts after I/R. However, only castration increased myocardial STAT3 activation. Notably, DHT replacement or ATI decreased markedly myocardial STAT3/SOCS3 in castrated males and females subjected to I/R.

Conclusion

These results suggest that endogenous and exogenous testosterone decrease myocardial STAT3 activation and SOCS3 expression after I/R. This represents the initial demonstration of testosterone-downregulated STAT3/SOCS3 signaling in myocardium.