Mechanisms of sex differences in TNFR2-mediated cardioprotection.
Mechanisms of sex differences in TNFR2-mediated cardioprotection.
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DOI：
10.1161/circulationaha.107.756890
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发表时间：
2008-09-30
期刊：
影响因子：
37.8
通讯作者：
Meldrum DR
中科院分区：
文献类型：
--
作者：
Wang M;Crisostomo PR;Markel TA;Wang Y;Meldrum DR
TNFR1/TNFR2 信号传导可能介导不同的细胞和分子反应（损伤与保护），并且平衡可能受到性激素的影响。先前的研究表明，与男性相比，女性在急性缺血再灌注后的心肌功能恢复、TNFR1 信号传导抵抗和 SOCS3 表达增加均有所改善。然而，尚不清楚 TNFR2 通路是否能保护心肌免受 I/R 损伤，如果是的话，TNFR2 介导的心脏保护作用是否存在性别差异。因此，我们假设：1）TNFR2通过STAT3、SOCS3和VEGF介导男女心肌对I/R的保护作用； 2) 与男性相比，TNFR2 在女性中引发更强的保护信号。对来自 TNFR2 敲除 (TNFR2 KO)、TNFR1/2KO 和野生型 (WT: C57BL/6J 或 B6129SF2/J) 的分离的雄性和雌性小鼠心脏（n=5-6/组）进行 20 分钟缺血，然后再灌注 60 分钟。 TNFR2 缺乏会降低男女缺血后心肌的恢复，但对女性的影响更大。 TNFR2 消除的有害影响与 SOCS3、STAT3 和 VEGF 的 mRNA 和蛋白质水平降低以及女性心脏中心肌 IL-1β 产生的增加有关。然而，在 I/R 后，雄性 TNFR2KO 心脏中 JNK 激活和 IL-1β 蛋白水平显着增加。此外，TNFR1/2 KO 会降低女性心脏的心肌功能，但不会降低男性心脏的心肌功能。这一观察结果与女性中 SOCS3、STAT3 和 VEGF mRNA 水平的降低以及心肌 p38 MAPK 激活的增加有关。 TNFR2 介导的心脏保护机制中的性别差异是通过增加女性中的 STAT3、SOCS3、VEGF 和减少男性中的 JNK 来实现的。
TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury vs. protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression following acute I/R when compared to males. However, it is unknown whether the TNFR2 pathway protects the myocardium from I/R injury, and if so, whether sex differences exist in TNFR2-mediated cardioprotection. Therefore, we hypothesized that: 1) TNFR2 mediates myocardial protection from I/R through STAT3, SOCS3 and VEGF in both genders; and 2) TNFR2 elicits greater protective signaling in females compared to males. Isolated male and female mouse hearts from TNFR2 knockout (TNFR2 KO), TNFR1/2KO and wild type (WT: C57BL/6J or B6129SF2/J) (n=5-6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased post-ischemic myocardial recovery in both genders, but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and VEGF, as well as an increase in myocardial IL-1beta production in female hearts. However, a significant increase in JNK activation and IL-1beta protein levels were noted in male TNFR2KO hearts following I/R. Additionally, TNFR1/2 KO decreased myocardial function in female hearts, but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3 and VEGF, and an increase in myocardial p38 MAPK activation in females. Sex differences in the mechanisms of TNFR2 mediated cardioprotection occur by increasing STAT3, SOCS3, VEGF in females and by decreasing JNK in males.