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

Am J Physiol Regul Integr Comp Physiol. 2006 Jan;290(1):R27-33. doi: 10.1152/ajpregu.00452.2005. Epub 2005 Sep 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology*
  • Enzyme Activation
  • Estrogens / metabolism*
  • Female
  • Heart / drug effects*
  • Heart / physiology
  • Heart / physiopathology
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / pharmacology*
  • MAP Kinase Kinase 4 / metabolism
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Myocardium / pathology*
  • Ovariectomy
  • Rats
  • Rats, Sprague-Dawley
  • Salmonella typhimurium
  • Tumor Necrosis Factor-alpha / metabolism
  • Ventricular Function, Left / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cardiotonic Agents
  • Estrogens
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4