Department of General Dentistry, Augusta University, Augusta, GA 30912, USA.
Department of Physiology, Augusta University, Augusta, GA 30912, USA.
Prostaglandins Other Lipid Mediat. 2022 Aug;161:106650. doi: 10.1016/j.prostaglandins.2022.106650. Epub 2022 May 23.
Numerous studies have demonstrated a sexual dimorphism in blood pressure (BP) control in spontaneously hypertensive rats (SHR), however the mechanisms remain to be further elucidated. Based on the established role of arachidonic acid metabolites and heme oxygenase (HO) in BP control, we hypothesize that higher BP in male SHR is associated with differential expression in renal HO and arachidonic acid metabolizing enzymes vs. female SHR. Higher BP in male SHR coincided with significant increases in renal cortical superoxide production and thiobarbituric acid reactive substances (TBARs) levels as measures of oxidative stress compared to normotensive female WKY and female SHR. The elevations in BP and oxidative stress in male SHR were also associated with a decrease in cortical heme oxygenase-1 (HO-1) expression when compared to normotensive female WKY. Although there was no sex or strain differences in cortical expression of the epoxyeicosatrienoic acids (EETs) producing enzyme, cytochrome P450 epoxygenase (CYP2C23), in male and female SHR and WKY, SHR had greater expression of the EETs metabolizing enzyme, soluble epoxide hydrolase (sEH) vs. WKY. Cortical expression of the 20-hydroxyeicosatetraenoic acid (20-HETE) producing enzyme, cytochrome P450 hydroxylase (CYP4A), was less in female WKY and SHR compared to strain-matched males and cortical 20-HETE levels were also less in female SHR vs. male SHR. Cortical cyclooxygenase-2 (COX-2) expression was significantly greater in female SHR and WKY vs. males and cortical prostaglandin E2 (PGE2) levels in female SHR was significantly greater than male WKY. In conclusion, our data suggest that sex differences in renal oxidative stress, HO-1 and arachidonic acid metabolizing enzymes could contribute to sexual dimorphism in hypertension in young SHR.
许多研究表明，自发性高血压大鼠（SHR）的血压（BP）控制存在性别二态性，但机制仍有待进一步阐明。基于花生四烯酸代谢物和血红素加氧酶（HO）在 BP 控制中的既定作用，我们假设雄性 SHR 的高血压与肾 HO 和花生四烯酸代谢酶的差异表达有关，而雌性 SHR 则没有。与正常血压的雌性 WKY 和雌性 SHR 相比，雄性 SHR 的高血压与肾皮质超氧化物产生和硫代巴比妥酸反应物质（TBARs）水平的显著增加有关，这些是氧化应激的衡量标准。与正常血压的雌性 WKY 相比，雄性 SHR 的血压升高和氧化应激也与皮质血红素加氧酶-1（HO-1）表达降低有关。尽管雄性和雌性 SHR 和 WKY 皮质中环氧化物水解酶（sEH）的表达没有性别或品系差异，但产生环氧二十碳三烯酸（EETs）的酶，细胞色素 P450 环氧合酶（CYP2C23）的皮质表达没有差异。与 WKY 相比，SHR 的 EETs 代谢酶可溶性环氧化物水解酶（sEH）的表达更高。与雄性 SHR 和 WKY 相比，雌性 WKY 和 SHR 的皮质 20-羟二十碳四烯酸（20-HETE）产生酶细胞色素 P450 羟化酶（CYP4A）的表达较少，皮质 20-HETE 水平也较低。与雄性 SHR 相比，雌性 SHR 的皮质环氧化酶-2（COX-2）表达明显更高，雌性 SHR 和 WKY 的皮质前列腺素 E2（PGE2）水平明显高于雄性 WKY。总之，我们的数据表明，肾氧化应激、HO-1 和花生四烯酸代谢酶的性别差异可能导致年轻 SHR 高血压的性别二态性。
