Naito Yoshiro, Tsujino Takeshi, Kawasaki Daizo, Okumura Takahiro, Morimoto Shinji, Masai Miho, Sakoda Tsuyoshi, Fujioka Yoshio, Ohyanagi Mitsumasa, Iwasaki Tadaaki
Department of Internal Medicine, Cardiovascular Division, Hyogo College of Medicine, Nishinomiya, Japan.
J Hypertens. 2003 Jun;21(6):1107-15. doi: 10.1097/00004872-200306000-00010.
Heart and aorta possess biologic clocks, but their involvement in genetic hypertension has been unknown. Plasminogen activator inhibitor-1 (PAI-1) expression is directly regulated by clock genes, while angiotensin II modulates both PAI-1 and clock gene expression. We therefore examined circadian expression of PAI-1 and clock genes, and effects of angiotensin type 1 (AT1) receptor antagonism, in heart and aorta of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats.
We examined cardiac and aortic mRNA expression for PAI-1 and clock genes (Per2, Bmal1, Clock, and Dbp) every 4 h throughout the day by quantitative reverse transcription-polymerase chain reaction, and intervention with the AT1 receptor antagonist candesartan and equihypotensive hydralazine.
Cardiac PAI-1 expression was high in the dark, while aortic PAI-1 expression was high in the light. Both cardiac and aortic PAI-1 expression were greater in SHR than in WKY rats. Candesartan treatment decreased cardiac PAI-1 expression only in the dark in WKY rats but throughout the day in SHR. Candesartan but not hydralazine strongly attenuated circadian fluctuation of aortic PAI-1 mRNA in SHR and WKY rats. Clock genes oscillated synchronously in heart and aorta of SHR and WKY rats. Clock gene expression was increased in heart but not aorta of SHR. Candesartan did not affect clock gene expression.
Enhanced expression of clock genes may increase PAI-1 expression in concert with activated renin-angiotensin system in SHR heart. Rather than clock genes, the renin-angiotensin system induces daily fluctuation and increased expression of aortic PAI-1 mRNA in SHR.
心脏和主动脉存在生物钟，但其在遗传性高血压中的作用尚不清楚。纤溶酶原激活物抑制剂-1（PAI-1）的表达受生物钟基因直接调控，而血管紧张素II可调节PAI-1和生物钟基因的表达。因此，我们研究了自发性高血压大鼠（SHR）和Wistar-Kyoto（WKY）大鼠心脏和主动脉中PAI-1和生物钟基因的昼夜表达，以及1型血管紧张素（AT1）受体拮抗剂的作用。
通过定量逆转录-聚合酶链反应，全天每4小时检测一次心脏和主动脉中PAI-1和生物钟基因（Per2、Bmal1、Clock和Dbp）的mRNA表达，并使用AT1受体拮抗剂坎地沙坦和具有同等降压作用的肼屈嗪进行干预。
心脏PAI-1表达在黑暗中较高，而主动脉PAI-1表达在光照下较高。SHR心脏和主动脉中的PAI-1表达均高于WKY大鼠。坎地沙坦治疗仅在黑暗中降低了WKY大鼠心脏中的PAI-1表达，但在SHR中全天降低了PAI-1表达。坎地沙坦而非肼屈嗪可强烈减弱SHR和WKY大鼠主动脉PAI-1 mRNA的昼夜波动。SHR和WKY大鼠心脏和主动脉中的生物钟基因同步振荡。SHR心脏中生物钟基因表达增加，但主动脉中未增加。坎地沙坦不影响生物钟基因表达。
在SHR心脏中，生物钟基因表达增强可能与激活肾素血管紧张素系统协同增加PAI-1表达。在SHR中，肾素血管紧张素系统而非生物钟基因诱导主动脉PAI-1 mRNA的每日波动和表达增加。
