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Cardiovascular Research 1999 44(3):543-548; doi:10.1016/S0008-6363(99)00254-0
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Chronic antisense therapy for angiotensinogen on cardiac hypertrophy in spontaneously hypertensive rats

Naoki Makino*, Masahiro Sugano, Shoji Ohtsuka, Shojiro Sawada and Tomoji Hata

Departments of Bioclimatology and Medicine, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, 874-0838 Beppu, Japan

* Corresponding author. Tel.: +81-977-27-1676; fax: +81-977-27-1607

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

KEYWORDS Blood pressure; Gene expression; Gene therapy; Hypertrophy; Remodelling


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