Angiotensin I-converting enzyme antisense gene therapy causes permanent antihypertensive effects in the SHR

The renin-angiotensin system plays a critical role in the control of blood pressure (BP), and its hyperactivity is associated with the development and maintenance of hypertension. Although traditional pharmacological therapie s targeted toward the inhibition of the renin-angiotensin system are effect ive in the control of this disease, they pose significant limitations. We u sed an antisense gene delivery strategy to circumvent these limitations and established that a single intracardiac administration of angiotensin type 1 receptor antisense (AT(1)R-AS) causes permanent prevention of hypertensio n in the spontaneously hypertensive rat (SHR), an animal model of primary h uman hypertension. Our objectives in this study were 2-fold: to determine ( 1) whether the targeting of angiotensin I-converting enzyme (ACE) mRNA by a similar antisense strategy would prevent the SHR from developing hypertens ion and (2) whether the antihypertensive phenotype is transmitted to the of fspring from the antisense-treated parents, Administration of a retroviral vector containing ACE antisense (LNSV-ACE-AS) caused a modest yet significa nt attenuation of high BP (approximate to 15+/-2 mm Hg) exclusively in the SHR. This was associated with a complete prevention of cardiac and renovasc ular pathophysiological alterations that are characteristic of hypertension . Like their parents, the F-1 generation offspring of the LNSV-ACE-AS-treat ed SWR expressed lower BP, decreased cardiac hypertrophy, and normalization of renal arterial excitation-coupling compared with offspring derived from the LNSV-ACE-tS (truncated sense)-treated SHR. In addition, the endothelia l dysfunction commonly observed in the SHR renal arterioles was significant ly prevented in both parents and offspring of the LNSV-ACE-AS-treated SNR. Polymerase chain reaction followed by Southern analysis revealed that the A CE-AS was integrated into the SHR genome and transmitted to the offspring. These observations suggest that transmission of ACE-AS by retroviral vector may be responsible fur the transference of normotensive phenotypes in the SHR offspring.