Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion

• Published in: American journal of physiology. Heart and circulatory physiology 2005-01, Vol.288 (1), p.H221-H226
• Main Authors: Wang, Meijing, Tsai, Ben M, Kher, Ajay, Baker, Lauren B, Wairiuko, G. Mathenge, Meldrum, Daniel R
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Apoptosis; Caspases - metabolism; Heart - physiopathology; Male; Myocardial Ischemia - metabolism; Myocardial Ischemia - physiopathology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - physiopathology; Myocarditis - etiology; Myocardium - enzymology; Myocardium - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction; Testosterone - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00784.2004

Departments of 1 Surgery and 3 Cellular and Integrative Physiology and 2 Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana Submitted 3 August 2004 ; accepted in final form 14 September 2004 Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF- , IL-1 , and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF- , IL-1 , and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R. myocardial infarction; sex hormones; inflammation; caspase cascades Address for reprint requests and other correspondence: D. R. Meldrum, 545 Barnhill Dr., Emerson Hall 215, Indianapolis, IN 46202 (E-mail: dmeldrum{at}iupui.edu )