Akap5组蛋白乙酰化在孕期运动改善高血压子代血管功能中的作用

The Role of Akap5 Histone Acetylation in Improving Vascular Function in Hypertensive Offspring Induced by Exercise during Pregnancy

目的:探讨AKAP150基因(Akap5)组蛋白乙酰化在孕期运动改善高血压子代血管功能中的作用。方法:将孕期正常血压对照组大鼠(Wistar-Kyoto rat,WKY)和自发性高血压大鼠(spontaneously hypertensive rat,SHR)随机分为孕期安静组(p-WKY-SED和p-SHR-SED)和孕期运动组(p-WKY-EX和p-SHR-EX)。运动组孕鼠从妊娠期第1天(gestation day 1,GD1)至GD20进行无负重游泳训练。在子代胚胎21天(embryonic day 21,ED21)和3月龄(3 month old,3M)时取雄鼠的肠系膜动脉(mesenteric arteries,MAs),采用离体微血管、膜片钳、Western blot、qPCR和ChIP-qPCR检测血管Ca_(V)1.2通道功能、AKAP150蛋白和mRNA表达、Akap5基因启动子区组蛋白H3第9位赖氨酸乙酰化(H3K9ac)水平。结果:孕期运动显著降低p-SHR-EX组子代3M雄性大鼠的血压,抑制MAs Ca_(V)1.2通道功能上调(P<0.05)。在子代ED21和3M大鼠MAs中,孕期运动明显降低p-SHR-EX组AKAP150 mRNA和蛋白表达、Akap5基因启动子区H3K9ac水平(P<0.05)。结论:孕期运动可能通过降低子代胎鼠MAs肌细胞Akap5基因启动子区H3K9ac水平,抑制AKAP150基因转录和蛋白表达,减弱高血压子代成年大鼠血管Ca_(V)1.2通道功能上调,最终降低血压。

Objective:To investigate the role of histone acetylation of AKAP150 gene(Akap5)in improving vascular function in hypertensive offspring induced by maternal exercise during pregnancy.Methods:Pregnant Wistar-Kyoto rats(WKYs)and spontaneously hypertensive rats(SHRs)were randomly assigned to either sedentary(p-WKY-SED and p-SHR-SED)or exercise group(p-WKY-EX and p-SHR-EX),and the rats of exercise groups conducted swimming training from gestation day 1(GD1)to GD20.The mesenteric arteries(MAs)were collected at embryonic day 21(ED21)and 3 months(3M)from male offsprings.The isolated microvessels,patch clamp,Western blot,qPCR,and ChIP-qPCR were utilized to assess vascular Ca_(V)1.2 channel function,AKAP150 protein and mRNA expression,and histone H3 lysine 9 acetylation(H3K9ac)levels in the Akap5 gene promoter.Results:Prenatal exercise significantly decreased the blood pressure and inhibited the upregulation of Ca_(V)1.2 channel function in 3M male offspring from p-SHR-EX(P<0.05).In both ED21 and 3M rat MAs,maternal exercise decreased the AKAP150 mRNA and protein expression,as well as H3K9ac levels in the Akap5 gene promoter region among p-SHR-EX male offspring(P<0.05).Conclusions:Maternal exercise during pregnancy can decrease H3K9ac levels in the Akap5 gene promoter region within fetal rat MAs myocytes,and subsequently inhibit AKAP150 gene transcription and protein expression,ultimately attenuating the upregulation of vascular Ca_(V)1.2 channel function in adult rats with hypertensive backgrounds,which result in a reduction in blood pressure.