Cell Biology and Anatomy, University of South Carolina-School of Medicine, Columbia, USA.
Physiol Genomics. 2012 Mar 19;44(6):362-73. doi: 10.1152/physiolgenomics.00146.2011. Epub 2012 Jan 24.
Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-α in male hearts secondary to sustained volume overload. These elevated levels of TNF-α are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats (n = 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula + Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (≥2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-α, which was downregulated by estrogen, and the TNF-α receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the β1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes.
我们的实验室之前曾报道过，男性心脏由于持续的容量超负荷会导致促炎细胞因子 TNF-α 的显著增加。这些升高的 TNF-α 水平伴随着左心室（LV）扩张和心功能障碍。相比之下，雌激素已被证明可以预防这种不利的心脏重构，无论是在雌性还是雄性大鼠中。本研究的目的是确定雌激素是否对炎症相关基因有影响，这些基因有助于这种雌激素介导的心脏保护作用。通过给 8 周龄雄性 Sprague-Dawley 大鼠施行腹主动脉-腔静脉瘘，诱导心肌容量超负荷（n = 30），并在 Sham、Fistula 和 Fistula + 雌激素处理（0.02mg/kg/天，在瘘管形成前 2 周开始）组中使用炎症 PCR 阵列来确定感兴趣的基因。在瘘管形成后 3 天，共有 55 个炎症基因发生改变（≥2 倍变化）。雌激素治疗将炎症基因的数量减少到 21 个，而在瘘管形成组中，有 13 个基因的变化相似。最显著的是 TNF-α，它被雌激素下调，而 TNF-α 受体则被雌激素差异调节。与花生四烯酸代谢有关的特定基因，包括环氧化酶-1 和 -2，也被雌激素下调。最后，雌激素处理动物的 LV 中β1-整合素细胞黏附亚基的基因表达显著上调。蛋白水平反映了基因水平观察到的变化。这些数据表明，雌激素至少部分通过对许多炎症相关基因的基因组调节来提供其心脏保护作用。
