β-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes

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Abstract
Background—Catecholamine-induced apoptosis is mediated by activation of the β-adrenergic signaling pathway. We tested the hypothesis that β1- and β2-adrenergic receptor (AR) subtypes differentially affect apoptosis in adult rat ventricular myocytes in vitro. Methods and Results—Myocytes were first exposed to norepinephrine (NE) alone (10 μmol/L) or NE+atenolol (AT) (10 μmol/L) for 12 hours. AT, a β1-selective AR antagonist, abolished the NE-induced increase in nick end-labeling (TUNEL)–positive cells compared with control (NE, 33±3% versus control, 3±1%, Pβ1). ISO and ALB induced significantly less apoptosis than NE (β1>β2) at equimolar concentrations as assessed by TUNEL staining [1 μmol/L: NE (8±2%)≈ISO (7±1%)>ALB (2±1%); 10 μmol/L: NE (35±2%)>ISO (23±1%)>ALB (3±1%); 100 μmol/L: NE (50±2%)>ISO (29±2%)>ALB (14±1%), PP=0.62]. ALB-induced apoptosis at 100 μmol/L was abolished by AT (10 μmol/L), indicating a β1AR-mediated effect. Importantly, ICI 118551 (0.1 μmol/L), a highly selective β2AR antagonist, did not decrease the percentage of NE-, ISO-, and ALB-induced apoptosis. Reverse transcription–polymerase chain reaction studies revealed that AT completely reversed the β-adrenergic signaling–induced changes in the Bcl-2–to-Bax ratio. Conclusions—These observations provide evidence that βAR-mediated apoptotic death signaling is largely dissociated from β2ARs and selectively mediated by β1ARs in adult rat ventricular myocytes.