title: Angiotensin I-converting enzyme antisense gene therapy causes permanent antihypertensive effects in the SHR.
abstract: 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 therapies targeted toward the inhibition of the renin-angiotensin system are effective in the control of this disease, they pose significant limitations. We used 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 hypertension in the spontaneously hypertensive rat (SHR), an animal model of primary human 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 hypertension and (2) whether the antihypertensive phenotype is transmitted to the offspring from the antisense-treated parents. Administration of a retroviral vector containing ACE antisense (LNSV-ACE-AS) caused a modest yet significant attenuation of high BP ( approximately 15+/-2 mm Hg) exclusively in the SHR. This was associated with a complete prevention of cardiac and renovascular pathophysiological alterations that are characteristic of hypertension. Like their parents, the F(1) generation offspring of the LNSV-ACE-AS-treated SHR 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 endothelial dysfunction commonly observed in the SHR renal arterioles was significantly prevented in both parents and offspring of the LNSV-ACE-AS-treated SHR. Polymerase chain reaction followed by Southern analysis revealed that the ACE-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 for the transference of normotensive phenotypes in the SHR offspring.
authors.affiliation: Department of Physiology, College of Medicine, University of Florida, and the University of Florida Brain Institute, Gainesville, FL 32610-0274, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: P Y
authors.initials: PY
authors.lastname: Reaves
authors.forename: M L
authors.initials: ML
authors.lastname: Gardon
authors.forename: K
authors.initials: K
authors.lastname: Keene
authors.forename: D S
authors.initials: DS
authors.lastname: Goldberg
authors.forename: C H
authors.initials: CH
authors.lastname: Gelband
authors.forename: M J
authors.initials: MJ
authors.lastname: Katovich
authors.forename: M K
authors.initials: MK
authors.lastname: Raizada
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000809:Angiotensins / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000097:blood; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D003326:Coronary Circulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D006973:Hypertension / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010641:Phenotype; D010656:Phenylephrine / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation; D012190:Retroviridae / Q000235:genetics; D019076:Transgenes; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000809:Angiotensins; D016376:Oligonucleotides, Antisense; D014665:Vasodilator Agents; D010656:Phenylephrine; D007703:Peptidyl-Dipeptidase A; D000109:Acetylcholine; D001920:Bradykinin