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

Objective: We examined the effect of the suppression of plasma angiotensino gen (AGT) by the intravenous injection of antisense oligodeoxynucleotides ( ODNs) against AGT targeted to the liver on cardiac remodeling in spontaneou sly hypertensive rats (SHR). The ODNs against rat AGT were coupled to asial oglycoprotein (ASOR) carrier molecules, which serve as an important method for regulating liver gene expression. Methods: Male SHR(n=18), and age-matc hed 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 s ystolic blood pressure (SBP) did not significantly change among them. The c ontrol 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. T his antisense therapy did not significantly change the mRNA expression for angiotensin converting enzyme, angiotensin II type 2 receptor and AGT in th e left ventricle (LV) among all three groups. Although the plasma angiotens in II (Ang II) concentration significantly decreased to the level of WKY af ter the antisense therapy, the SEP, 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 SH R. Conclusion: The plasma AGT is considered to play a role in the developme nt of cardiac hypertrophy in SHR, but it has not a complete effects on card iac remodeling even if the plasma Ang II levels are inhibited because of an insufficient suppression of hypertension. (C) 1999 Elsevier Science B.V. A ll rights reserved.