Specific beta1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia.
OBJECTIVE
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.
Arnold
Anne-Sophie
AS
Children's Research Institute, Department of Pediatrics, University of South Florida, Saint Petersburg, FL 33701, USA.
Tang
Yao Liang
YL
Qian
Keping
K
Shen
Leping
L
Valencia
Valery
V
Phillips
Michael Ian
MI
Zhang
Yuan Clare
YC
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis; D001794:Blood Pressure; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000473:pathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D016277:Ventricular Function, Left
D000959:Antihypertensive Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018342:Receptors, Adrenergic, beta-1