Sex differences in endothelial STAT3 mediate sex differences in myocardial inflammation

Meijing Wang, Wenjun Zhang, Paul Crisostomo, Troy Markel, Kirstan K. Meldrum, Xin Y. Fu, Daniel R. Meldrum

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Recent studies have shown that females have improved myocardial functional recovery, TNF receptor 1 (TNFR1) signaling resistance, and increased STAT3 phosphorylation following acute ischemia/reperfusion (I/R) compared with males. We hypothesized that 1) STAT3 deficiency in endothelial cells (EC) impairs myocardial functional recovery in both sexes, 2) EC STAT3 deficiency equalizes sex differences in functional recovery, and 3) knockout of EC STAT3 decreases activation of myocardial STAT3 and increases p38 MAPK activation following acute I/R. Isolated male and female mouse hearts from WT and EC STAT3 knockout (STAT3KO) were subjected to 20-min ischemia/60-min reperfusion, and ± dP/dt were continuously recorded. Heart tissue was analyzed for the active forms of STAT3 and p38 MAPK as well as expression of caspase-8 (Western blot) following I/R. EC STATKO had significantly decreased myocardial functional recovery in both sexes (%recovered +dP/dt: male 51.6 ± 3.1 vs. 32.1 ± 13.1%, female 79.1 ± 3.6 vs. 43.6 ± 9.1%; -dP/dt: male 52.2 ± 3.3 vs. 28.9 ± 12%, female 75.2 ± 4.1 vs. 38.6 ± 10%). In addition, EC STAT3KO neutralized sex differences in myocardial function, which existed in WT mice. Interestingly, EC STAT3 deficiency decreased myocardial STAT3 activation but increased myocardial p38 MAPK activation in both sexes; however, this was seen to a greater degree in females. We conclude that EC STAT3 deficiency resulted in decreased recovery of myocardial function in both sexes and neutralized sex differences in myocardial functional recovery following I/R. This observation was associated with decreased activation of myocardial STAT3 and increased activation of p38 MAPK in EC STAT3KO heart after I/R.

Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume293
Issue number3
DOIs
StatePublished - Sep 2007

Fingerprint

Endothelial cells
Sex Characteristics
Endothelial Cells
Inflammation
Chemical activation
p38 Mitogen-Activated Protein Kinases
Recovery
Reperfusion
Ischemia
Phosphorylation
Caspase 8
Tumor Necrosis Factor Receptors
Recovery of Function
Western Blotting
Tissue

Keywords

  • Ischemia/reperfusion
  • Myocardial function
  • Signal transducer and activator of transcription 3

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry

Cite this

Sex differences in endothelial STAT3 mediate sex differences in myocardial inflammation. / Wang, Meijing; Zhang, Wenjun; Crisostomo, Paul; Markel, Troy; Meldrum, Kirstan K.; Fu, Xin Y.; Meldrum, Daniel R.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 293, No. 3, 09.2007.

Research output: Contribution to journalArticle

Wang, Meijing ; Zhang, Wenjun ; Crisostomo, Paul ; Markel, Troy ; Meldrum, Kirstan K. ; Fu, Xin Y. ; Meldrum, Daniel R. / Sex differences in endothelial STAT3 mediate sex differences in myocardial inflammation. In: American Journal of Physiology - Endocrinology and Metabolism. 2007 ; Vol. 293, No. 3.
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abstract = "Recent studies have shown that females have improved myocardial functional recovery, TNF receptor 1 (TNFR1) signaling resistance, and increased STAT3 phosphorylation following acute ischemia/reperfusion (I/R) compared with males. We hypothesized that 1) STAT3 deficiency in endothelial cells (EC) impairs myocardial functional recovery in both sexes, 2) EC STAT3 deficiency equalizes sex differences in functional recovery, and 3) knockout of EC STAT3 decreases activation of myocardial STAT3 and increases p38 MAPK activation following acute I/R. Isolated male and female mouse hearts from WT and EC STAT3 knockout (STAT3KO) were subjected to 20-min ischemia/60-min reperfusion, and ± dP/dt were continuously recorded. Heart tissue was analyzed for the active forms of STAT3 and p38 MAPK as well as expression of caspase-8 (Western blot) following I/R. EC STATKO had significantly decreased myocardial functional recovery in both sexes ({\%}recovered +dP/dt: male 51.6 ± 3.1 vs. 32.1 ± 13.1{\%}, female 79.1 ± 3.6 vs. 43.6 ± 9.1{\%}; -dP/dt: male 52.2 ± 3.3 vs. 28.9 ± 12{\%}, female 75.2 ± 4.1 vs. 38.6 ± 10{\%}). In addition, EC STAT3KO neutralized sex differences in myocardial function, which existed in WT mice. Interestingly, EC STAT3 deficiency decreased myocardial STAT3 activation but increased myocardial p38 MAPK activation in both sexes; however, this was seen to a greater degree in females. We conclude that EC STAT3 deficiency resulted in decreased recovery of myocardial function in both sexes and neutralized sex differences in myocardial functional recovery following I/R. This observation was associated with decreased activation of myocardial STAT3 and increased activation of p38 MAPK in EC STAT3KO heart after I/R.",
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AB - Recent studies have shown that females have improved myocardial functional recovery, TNF receptor 1 (TNFR1) signaling resistance, and increased STAT3 phosphorylation following acute ischemia/reperfusion (I/R) compared with males. We hypothesized that 1) STAT3 deficiency in endothelial cells (EC) impairs myocardial functional recovery in both sexes, 2) EC STAT3 deficiency equalizes sex differences in functional recovery, and 3) knockout of EC STAT3 decreases activation of myocardial STAT3 and increases p38 MAPK activation following acute I/R. Isolated male and female mouse hearts from WT and EC STAT3 knockout (STAT3KO) were subjected to 20-min ischemia/60-min reperfusion, and ± dP/dt were continuously recorded. Heart tissue was analyzed for the active forms of STAT3 and p38 MAPK as well as expression of caspase-8 (Western blot) following I/R. EC STATKO had significantly decreased myocardial functional recovery in both sexes (%recovered +dP/dt: male 51.6 ± 3.1 vs. 32.1 ± 13.1%, female 79.1 ± 3.6 vs. 43.6 ± 9.1%; -dP/dt: male 52.2 ± 3.3 vs. 28.9 ± 12%, female 75.2 ± 4.1 vs. 38.6 ± 10%). In addition, EC STAT3KO neutralized sex differences in myocardial function, which existed in WT mice. Interestingly, EC STAT3 deficiency decreased myocardial STAT3 activation but increased myocardial p38 MAPK activation in both sexes; however, this was seen to a greater degree in females. We conclude that EC STAT3 deficiency resulted in decreased recovery of myocardial function in both sexes and neutralized sex differences in myocardial functional recovery following I/R. This observation was associated with decreased activation of myocardial STAT3 and increased activation of p38 MAPK in EC STAT3KO heart after I/R.

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