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) microg/kg Salmonella typhimurium LPS (ETX) or normal saline (PC-). Twenty-four hours later, injury dose ETX (500 microg/kg) was injected. After 6 h, myocardial function was measured via Langendorff. p38 MAPK and JNK activation and TNF-alpha, 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-alpha 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.
Subject(s)
Cardiotonic Agents/pharmacology , Estrogens/metabolism , Heart/drug effects , Lipopolysaccharides/pharmacology , Myocardium/metabolism , Myocardium/pathology , Animals , Enzyme Activation , Female , Heart/physiology , Heart/physiopathology , Interleukin-1/metabolism , Interleukin-6/metabolism , MAP Kinase Kinase 4/metabolism , Myocardium/enzymology , Ovariectomy , Rats , Rats, Sprague-Dawley , Salmonella typhimurium , Tumor Necrosis Factor-alpha/metabolism , Ventricular Function, Left/drug effects , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
BACKGROUND: Preconditioning is injury-induced protection from subsequent insult. Recent data indicates that males have lower preconditioning thresholds compared to females. Therefore, we hypothesized that testosterone may mediate the lower preconditioning threshold observed in males. MATERIALS AND METHODS: Adult normal and castrated male Sprague-Dawley rats (n = 4-5) were given intraperitoneal (i.p.) injections of 125 or 500 microg/kg Salmonella typhimurium lipopolysaccharide (ETX) or 0.4 ml normal saline (NS). Another i.p. injection of 500 microg/kg ETX (injury dose) was given 24 h later. After 6 h, myocardial function was evaluated via the Langendorff perfusion model. Shams received only NS, while non-preconditioned rats (PC-) received NS followed by the 500 microg/kg ETX injury dose. Preconditioned rats received injections of 125 mug/kg ETX (PC +125) or 500 microg/kg ETX (PC +500), followed by the 500 microg/kg ETX injury dose. RESULTS: Normal PC +125 and PC +500 males were preconditioned and maintained cardiac function similar to shams (P > 0.05). Castrated PC +125 and PC +500 males were also preconditioned and maintained cardiac function similar to castrated shams (P > 0.05). Conversely, both normal and castrated PC-males showed significantly decreased cardiac function compared to shams (P < 0.05). CONCLUSIONS: Endogenous testosterone does not mediate the lower preconditioning threshold in males.
