Document Detail


Permanent cardiovascular protection from hypertension by the AT(1) receptor antisense gene therapy in hypertensive rat offspring.
MedLine Citation:
PMID:  10559146     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Our previous studies have demonstrated that the introduction of angiotensin II type I receptor antisense (AT(1)R-AS) cDNA by a retrovirally mediated delivery system prevents the development of hypertension in the spontaneously hypertensive rat (SHR), an animal model for primary hypertension in humans. These results have led us to propose the hypothesis that an interruption of the renin-angiotensin system (RAS) activity at a genetic level would prevent hypertension on a permanent basis. F(1) and F(2) generations of offspring from a retroviral vector, LNSV- and LNSV-AT(1)R-AS-treated SHR, were generated, and various physiological parameters indicative of hypertension were studied and compared with those of their parents to investigate this hypothesis. Both F(1) and F(2) generations of LNSV-AT(1)R-AS-treated SHR expressed a persistently lower blood pressure, decreased cardiac hypertrophy and fibrosis, decreased medial thickness, and normalization of renal artery excitation-contraction coupling, Ca(2+) current, and [Ca(2+)](i) when compared with offspring derived from the LNSV-treated SHR. In fact, the magnitude of the prevention of these pathophysiological alterations was similar to that observed in the LNSV-AT(1)R-AS-treated SHR parent. The prevention of cardiovascular pathophysiology and expression of normotensive phenotypes are, at least in part, a result of integration and subsequent transmission of AT(1)R-AS from the SHR parents to offspring. These data demonstrate that a single intracardiac injection of LNSV-AT(1)R-AS causes a permanent cardiovascular protection against hypertension as a result of a genomic integration and germ line transmission of the AT(1)R-AS in the SHR offspring.
Authors:
P Y Reaves; C H Gelband; H Wang; H Yang; D Lu; K H Berecek; M J Katovich; M K Raizada
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.; Retracted Publication    
Journal Detail:
Title:  Circulation research     Volume:  85     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  1999 Nov 
Date Detail:
Created Date:  1999-11-23     Completed Date:  1999-11-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  e44-50     Citation Subset:  IM    
Affiliation:
Department of Physiology, College of Medicine, Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Antihypertensive Agents / pharmacology
Aorta / pathology
Blood Pressure / drug effects,  genetics
DNA, Antisense / therapeutic use*
Fibrosis / genetics
Gene Therapy
Hypertension / genetics*,  prevention & control*
Kidney / blood supply,  physiopathology
Losartan / pharmacology
Myocardium / pathology
Organ Size / genetics
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
Receptors, Angiotensin / genetics*
Transfection
Grant Support
ID/Acronym/Agency:
HL52189/HL/NHLBI NIH HHS; HL56921/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/DNA, Antisense; 0/Receptor, Angiotensin, Type 1; 0/Receptor, Angiotensin, Type 2; 0/Receptors, Angiotensin; 114798-26-4/Losartan
Comments/Corrections
Comment In:
NIH Guide Grants Contracts. 2003 Nov 14;:NOT-OD-04-005   [PMID:  14619946 ]
Retraction In:
Circ Res. 2004 Jan 9;94(1):e14   [PMID:  14715533 ]

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