Endogenous estrogen mediates a higher threshold for endotoxin-induced myocardial protection in females.
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.
Pitcher
Jeffrey M
JM
545 Barnhill Dr., Emerson 215, Indiana University Medical Center, Indianapolis, IN 46202, USA.
Wang
Meijing
M
Tsai
Ben M
BM
Kher
Ajay
A
Nelson
Nicholas T
NT
Meldrum
Daniel R
DR
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004789:Enzyme Activation; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002316:Cardiotonic Agents; D004967:Estrogens; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4