针对一种新型血管紧张素原mRNA稳定蛋白的反义寡脱氧核苷酸可降低自发性高血压大鼠的血压。

Antisense oligodeoxynucleotides directed against a novel angiotensinogen mRNA-stabilizing protein reduce blood pressure in spontaneously hypertensive rats.

作者信息

Klett Christoph P R, Anderson Dock, Sholook Myssara, Granger Joey P

机构信息

Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, USA.

出版信息

Am J Physiol Regul Integr Comp Physiol. 2004 Sep;287(3):R619-26. doi: 10.1152/ajpregu.00140.2004. Epub 2004 May 20.

DOI:10.1152/ajpregu.00140.2004

PMID:15155278

Abstract

We have previously reported that hypertension in the young spontaneously hypertensive rat (SHR) is associated with an elevation in tissue angiotensinogen and a novel polysomal protein known to stabilize angiotensinogen mRNA. In our current study we determined the role of the mRNA-stabilizing protein in the regulation of tissue angiotensinogen expression and mean arterial pressure (MAP) in the SHR utilizing antisense oligodeoxynucleotide (AON) inhibition. Three AONs (RNASTAAS1, position 31-50; RNASTAAS2, position 21-40; RNASTAAS3, position 143-162 of the cDNA coding for the polysomal protein) were administered intravenously (dose 450, 900, and 1,800 microg/kg; 1 dosage/day over 3 days) in conscious, chronically instrumented male SHRs at the age of 7 wk. Control SHRs received corresponding scrambled oligodeoxynucleotide sequences (SCR1, SCR2, SCR3). Each animal received the increasing dose schedule. RNASTAAS2 resulted in a reduced expression of the polysomal protein to 21% (liver), 12% (brain), 27% (heart), 18% (renal cortex), and 22% (renal medulla) of control. Angiotensinogen expression was inhibited to 54% (liver), 41% (brain), 68% (heart), 52% (renal cortex), and 74% (renal medulla) compared with control SHRs. Decreases in plasma concentrations of angiotensinogen and plasma renin activities were associated with a significant decrease in MAP from 147 +/- 6 mmHg (after SCR2) to 106 +/- 4 mmHg after RNASTAAS2. The effects of the two other AONs on MAP were less (RNASTAAS1, -31 mmHg; RNASTAAS3, -16 mmHg) with corresponding decreases in mRNAs coding for angiotensinogen and the polysomal protein. A significant decrease in intracellular concentrations of the polysomal protein accompanied AON inhibition. The magnitude of effects (-15 to -41 mmHg) was comparable to the effects of captopril (100 mg x kg(-1) x day(-1) for 3 days: -32 mmHg) and an AT(1) receptor antagonist (L-158809, 1.5 mg x kg(-1) x day(-1) for 3 days: -36 mmHg). These data suggest an important role of the mRNA-stabilizing protein for hepatic and extrahepatic angiotensinogen expression and MAP in the SHR.

摘要

我们之前报道过，年轻的自发性高血压大鼠（SHR）中的高血压与组织血管紧张素原升高以及一种已知可稳定血管紧张素原mRNA的新型多核糖体蛋白有关。在我们当前的研究中，我们利用反义寡脱氧核苷酸（AON）抑制来确定该mRNA稳定蛋白在SHR中组织血管紧张素原表达和平均动脉压（MAP）调节中的作用。向7周龄、长期植入仪器的清醒雄性SHR静脉注射三种AON（RNASTAAS1，位于编码多核糖体蛋白的cDNA的31 - 50位；RNASTAAS2，位于21 - 40位；RNASTAAS3，位于143 - 162位）（剂量分别为450、900和1800μg/kg；连续3天，每天1次剂量）。对照SHR接受相应的乱序寡脱氧核苷酸序列（SCR1、SCR2、SCR3）。每只动物接受递增剂量方案。RNASTAAS2导致多核糖体蛋白表达降低至对照的21%（肝脏）、12%（脑）、27%（心脏）、18%（肾皮质）和22%（肾髓质）。与对照SHR相比，血管紧张素原表达被抑制至54%（肝脏）、41%（脑）、68%（心脏）、52%（肾皮质）和74%（肾髓质）。血管紧张素原血浆浓度和血浆肾素活性的降低与MAP从147±6 mmHg（SCR2后）显著降至RNASTAAS2后的106±4 mmHg相关。另外两种AON对MAP的影响较小（RNASTAAS1，-31 mmHg；RNASTAAS3，-16 mmHg），同时编码血管紧张素原和多核糖体蛋白的mRNA相应减少。AON抑制伴随着多核糖体蛋白细胞内浓度的显著降低。效应幅度（-15至-41 mmHg）与卡托普利（100 mg·kg⁻¹·天⁻¹，连续3天：-32 mmHg）和AT₁受体拮抗剂（L - 158809，1.5 mg·kg⁻¹·天⁻¹；连续3天：-36 mmHg）的效应相当。这些数据表明，mRNA稳定蛋白在SHR的肝脏和肝外血管紧张素原表达及MAP中起重要作用。