Document Detail


Specific beta1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia.
MedLine Citation:
PMID:  17143192     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES:Beta-blockers are widely used and effective for treating hypertension, acute myocardial infarction (MI) and heart failure, but they present side-effects mainly due to antagonism of beta2-adrenergic receptor (AR). Currently available beta-blockers are at best selective but not specific for beta1 or beta2-AR. METHODS: To specifically inhibit the expression of the beta1-AR, we developed a small interfering RNA (siRNA) targeted to beta1-AR. Three different sequences of beta1 siRNA were delivered into C6-2B cells with 90% efficiency. RESULTS: One of the three sequences reduced the level of beta1-AR mRNA by 70%. The siRNA was highly specific for beta1-AR inhibition with no overlap with beta2-AR. To test this in vivo, systemic injection of beta1 siRNA complexed with liposomes resulted in efficient delivery into the heart, lung, kidney and liver, and effectively reduced beta1-AR expression in the heart without altering beta2-AR. beta1 siRNA significantly lowered blood pressure of spontaneously hypertensive rats (SHR) for at least 12 days and reduced cardiac hypertrophy following a single injection. Pretreatment with beta1 siRNA 3 days before induction of MI in Wistar rats significantly improved cardiac function, as demonstrated by dP/dt and electrocardiogram following the MI. The protective mechanism involved reduction of cardiomyocyte apoptosis in the beta1 siRNA-treated hearts. CONCLUSIONS: The present study demonstrates the possibility of using siRNA for treating cardiovascular diseases and may represent a novel beta-blocker specific for beta1-AR.
Authors:
Anne-Sophie Arnold; Yao Liang Tang; Keping Qian; Leping Shen; Valery Valencia; Michael Ian Phillips; Yuan Clare Zhang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of hypertension     Volume:  25     ISSN:  0263-6352     ISO Abbreviation:  J. Hypertens.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-04     Completed Date:  2007-03-02     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  197-205     Citation Subset:  IM    
Affiliation:
Children's Research Institute, Department of Pediatrics, University of South Florida, Saint Petersburg, FL 33701, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antihypertensive Agents / metabolism*,  therapeutic use
Apoptosis
Blood Pressure*
Cell Line, Tumor
Disease Models, Animal
Heart Ventricles / pathology
Hypertension / genetics,  metabolism*,  pathology,  physiopathology
Male
Mice
Myocardial Ischemia / genetics,  metabolism*,  pathology,  physiopathology
Myocardium / metabolism
RNA Interference*
RNA, Messenger / metabolism
RNA, Small Interfering / genetics,  metabolism*,  therapeutic use
Rats
Rats, Inbred SHR
Rats, Wistar
Receptors, Adrenergic, beta-1 / genetics,  metabolism*
Time Factors
Transfection
Ventricular Function, Left
Grant Support
ID/Acronym/Agency:
R01 HL67248/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Receptors, Adrenergic, beta-1

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