Hw. Wang et al., Angiotensin I-converting enzyme antisense gene therapy causes permanent antihypertensive effects in the SHR, HYPERTENSIO, 35(1), 2000, pp. 202-208
Citations number
29
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
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.