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

作者：Fajardo G; Zhao MM; Powers J; Bernstein D^*

来源：Journal of Molecular and Cellular Cardiology, 2006, 40(3): 375-383.

DOI：10.1016/j.yjmcc.2005.12.004

• cardiomyopathy
• signal transduction
• apoptosis
• adrenergic receptors
• anthracyclines

beta-Adrenoceptor (beta-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 beta 2(-/-) mice, which is rescued by the additional deletion of the beta 1-AR. We determined whether this differential response was myocyte specific by examining the effects of doxorubicin in myocytes and Fibroblasts from WT and beta 1, beta 2 and beta 1/beta 2(-/-) mice. Cells were exposed to doxorubicin at 1-50 mu M 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 mu M after 24 h). beta 2(-/-) Myocytes showed a greater decrease in viability vs. WT (20.8% less at 6 h; 14% less at 24 h, P < 0.05);beta 1(-/-) and beta 1/beta 2-/- myocytes showed enhanced survival (beta 1-/- 11%; beta 1/beta 2-/ -18% greater than WT P < 0.05). TUNEL staining demonstrated a similar differential Susceptibility (WT 26% apoptotic nuclei, beta 2-/- 45.9%- beta 1/beta 2-/- 16.8%, P < 0.05). beta 2-/- Fibroblasts also showed enhanced toxicity. Pertussis toxin pretreatment of WT cells decreased survival similar to the beta 2-/-, Suggesting a role for Gi signaling. JNK was differentially activated in beta 2-/- myocytes after doxorubicin and its inhibition increased cardiotoxicity. In conclusion, the differential cardioprotective/cardiotoxic effects mediated by beta 1 vs. beta 2-AR subtypes in knockout mice are recapitulated in myocytes isolated from these mice. beta 2-ARs appear to play a cardioprotective role, whereas beta 1-ARs a cardiotoxic role.