Makino N, Sugano M, Ohtsuka S, Sawada S, Hata T
Department of Bioclimatology, Kyushu University, Beppu, Japan.
Cardiovasc Res. 1999 Dec;44(3):543-8. doi: 10.1016/s0008-6363(99)00254-0.
We examined the effect of the suppression of plasma angiotensinogen (AGT) by the intravenous injection of antisense oligodeoxynucleotides (ODNs) against AGT targeted to the liver on cardiac remodeling in spontaneously hypertensive rats (SHR). The ODNs against rat AGT were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method for regulating liver gene expression.
Male SHR (n = 18), and age-matched male Wistar-Kyoto rats (WKY, n = 6) were used for this study. At 10 weeks of age, the SHR were divided into three groups (each group n = 6), and the systolic blood pressure (SBP) did not significantly change among them. The control SHR and WKY groups received saline, the sense SHR group was injected with the sense ODNs complex and the antisense SHR group was injected with the antisense ODNs complex, from 10 to 20 weeks of age. ASOR-poly(L)lysine-ODNs complex was injected via the tail veins twice a week.
At the end of the treatment, a reduction of hepatic AGT mRNA, cardiac angiotensin II type 1 receptor mRNA and the plasma AGT concentration was only observed in the antisense-injected SHR but not in the other groups of SHR and WKY. This antisense therapy did not significantly change the mRNA expression for angiotensin converting enzyme, angiotensin II type 2 receptor and AGT in the left ventricle (LV) among all three groups. Although the plasma angiotensin II (Ang II) concentration significantly decreased to the level of WKY after the antisense therapy, the SBP, LV to body weight ratio and % collagen volume fraction also showed a reduction, however, these findings were still larger than in the WKY than in either the sense-injected SHR or control SHR.
The plasma AGT is considered to play a role in the development of cardiac hypertrophy in SHR, but it has not a complete effects on cardiac remodeling even if the plasma Ang II levels are inhibited because of an insufficient suppression of hypertension.
我们研究了通过静脉注射靶向肝脏的抗血管紧张素原（AGT）反义寡脱氧核苷酸（ODN）抑制血浆AGT对自发性高血压大鼠（SHR）心脏重塑的影响。针对大鼠AGT的ODN与去唾液酸糖蛋白（ASOR）载体分子偶联，这是调节肝脏基因表达的重要方法。
本研究使用雄性SHR（n = 18）和年龄匹配的雄性Wistar-Kyoto大鼠（WKY，n = 6）。在10周龄时，将SHR分为三组（每组n = 6），三组之间收缩压（SBP）无显著变化。从10至20周龄，对照SHR组和WKY组接受生理盐水，正义SHR组注射正义ODN复合物，反义SHR组注射反义ODN复合物。ASOR-聚（L）赖氨酸-ODN复合物每周经尾静脉注射两次。
治疗结束时，仅在注射反义ODN的SHR中观察到肝脏AGT mRNA、心脏血管紧张素II 1型受体mRNA和血浆AGT浓度降低，而在其他SHR组和WKY组中未观察到。这种反义疗法在所有三组中均未显著改变左心室（LV）中血管紧张素转换酶、血管紧张素II 2型受体和AGT的mRNA表达。尽管反义治疗后血浆血管紧张素II（Ang II）浓度显著降低至WKY水平，但SBP、LV与体重比和胶原体积百分比也有所降低，然而，这些结果在WKY中仍大于注射正义ODN的SHR或对照SHR。
血浆AGT被认为在SHR心脏肥大的发展中起作用，但即使由于高血压抑制不足导致血浆Ang II水平受到抑制，它对心脏重塑也没有完全影响。
