Differential cardiotoxic/cardioprotective effects of β-adrenergic receptor subtypes in myocytes and fibroblasts in doxorubicin cardiomyopathy

β-Adrenoceptor (β-AR) subtypes act through different signaling pathways to regulate cardiac function and remodeling. Previous in vivo data show a markedly enhanced cardiotoxic response to doxorubicin in β2–/– mice, which is rescued by the additional deletion of the β1-AR. We determined whether this differential response was myocyte specific by examining the effects of doxorubicin in myocytes and fibroblasts from WT and β1, β2 and β1/β2–/– mice. Cells were exposed to doxorubicin at 1–50 μM and viability and apoptosis assessed at 6, 24 and 48 h. WT myocytes showed a time and dose-dependent decrease in viability (42% decrease at 1 μM after 24 h). β2–/– Myocytes showed a greater decrease in viability vs. WT (20.8% less at 6 h; 14% less at 24 h, P < 0.05); β1–/– and β1/β2–/– myocytes showed enhanced survival (β1–/– 11%; β1/β2–/– 18% greater than WT, P < 0.05). TUNEL staining demonstrated a similar differential susceptibility (WT 26% apoptotic nuclei, β2–/– 45.9%, β1/β2–/– 16.8%, P < 0.05). β2–/– Fibroblasts also showed enhanced toxicity. Pertussis toxin pretreatment of WT cells decreased survival similar to the β2–/–, suggesting a role for Gi signaling. JNK was differentially activated in β2–/– myocytes after doxorubicin and its inhibition increased cardiotoxicity. In conclusion, the differential cardioprotective/cardiotoxic effects mediated by β1 vs. β2-AR subtypes in knockout mice are recapitulated in myocytes isolated from these mice. β2-ARs appear to play a cardioprotective role, whereas β1-ARs a cardiotoxic role.