Specific β1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia

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 beta(2)-adrenergic receptor (AR). Currently available beta-blockers are at best selective but not specific for beta(1) or beta(2)-AR. Methods To specifically inhibit the expression of the beta(1)-AR, we developed a small interfering RNA (siRNA) targeted to beta(1)-AR. Three different sequences of P, siRNA were delivered into C6-213 cells with 90% efficiency. Results One of the three sequences reduced the level of beta(1)-AR mRNA by 70%. The siRNA was highly specific for beta(1)-AR inhibition with no overlap with beta(2)-AR. To test this in vivo, systemic injection of beta(1) siRNA complexed with liposomes resulted in efficient delivery into the heart, lung, kidney and liver, and effectively reduced beta(1)-AR expression in the heart without altering beta(2)-AR. beta(1) 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 P, 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 beta(1) 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 beta(1)-AR.