Objectives

β-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 β 2-adrenergic receptor (AR). Currently available β-blockers are at best selective but not specific for β 1 or β 2-AR.

Methods

To specifically inhibit the expression of the β 1-AR, we developed a small interfering RNA (siRNA) targeted to β 1-AR. Three different sequences of β 1 siRNA were delivered into C6-2B cells with 90% efficiency.

Results

One of the three sequences reduced the level of β 1-AR mRNA by 70%. The siRNA was highly specific for β 1-AR inhibition with no overlap with β 2-AR. To test this in vivo, systemic injection of β 1 siRNA complexed with liposomes resulted in efficient delivery into the heart, lung, kidney and liver, and effectively reduced β 1-AR expression in the heart without altering β 2-AR. β 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 β 1 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 β 1 siRNA-treated hearts.

Conclusions

The present study demonstrates the possibility of using siRNA for treating cardiovascular diseases and may represent a novel β-blocker specific for β 1-AR.