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TRANSLATIONAL PHYSIOLOGY

Endogenous estrogen mediates a higher threshold for endotoxin-induced myocardial protection in females

¹Department of Surgery, ³Department of Cellular and Integrative Physiology, and ²Center for Immunobiology, Indiana University Medical Center, Indianapolis, Indiana

Submitted 28 June 2005 ; accepted in final form 30 August 2005

ABSTRACT

Myocardial endotoxin tolerance may be induced in both males and females; however, it remains unknown whether there are mechanistic and threshold differences between the sexes. We hypothesized that endogenous estrogen mediates a higher threshold for endotoxin (ETX)-induced protection in females. Adult proestrus and ovariectomized (OVX) female rats were preconditioned (PC) with intraperitoneal injections of 125 (PC+125) or 500 (PC+500) µg/kg Salmonella typhimurium LPS (ETX) or normal saline (PC–). Twenty-four hours later, injury dose ETX (500 µg/kg) was injected. After 6 h, myocardial function was measured via Langendorff. p38 MAPK and JNK activation and TNF-, IL-1, and IL-6 expression were evaluated. ETX injury significantly decreased left ventricular developed pressure in PC– groups vs. controls. PC+500 regimen protected against ETX injury, resulting in normal cardiac function. PC+125 regimen protected OVX but not proestrus females, which had diminished myocardial function. Activated JNK and TNF- increased in PC– but were diminished in PC+500 animals. Importantly, activated JNK and TNF increased in PC+125 proestrus females, whereas PC+125 OVX females displayed decreases in these molecules. There were no differences in p38 MAPK activation or expression of IL-1 or IL-6. These results demonstrate that proestrus females require a higher stimulus (PC+500) to achieve myocardial protection against ETX injury. Removal of endogenous estrogen (OVX) lowered the preconditioning threshold (PC+125), resulting in protection after lesser injury. Additionally, myocardial JNK and TNF expression was decreased in OVX PC+125 females, which correlated with myocardial function differences. Therefore, we conclude that endogenous estrogen mediates a higher threshold for ETX tolerance in female myocardium.

tolerance; gender; acute injury

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