Differential Cardiotoxic/Cardioprotective Effects of Beta-adrenergic Receptor Subtypes in Myocytes and Fibroblasts in Doxorubicin Cardiomyopathy.
From: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
Journal of molecular and cellular cardiology
- Publish Date: Mar 2006
- ISSN: 0022-2828
- Volume: 40
- Issue: 3
- Pages: 375-83
- Medium: Print
- Language: English
- Citation (JAMA): Fajardo Giovanni, Zhao Mingming, Powers Jennifer, et al. Differential Cardiotoxic/Cardioprotective Effects of Beta-adrenergic Receptor Subtypes in Myocytes and Fibroblasts in Doxorubicin Cardiomyopathy.. J. Mol. Cell. Cardiol. Mar 2006;40:375-83
Abstract
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 beta2-/- mice, which is rescued by the additional deletion of the beta1-AR. We determined whether this differential response was myocyte specific by examining the effects of doxorubicin in myocytes and fibroblasts from WT and beta1, beta2 and beta1/beta2-/- mice. Cells were exposed to doxorubicin at 1-50 microM 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 microM after 24 h). beta2-/- Myocytes showed a greater decrease in viability vs. WT (20.8% less at 6 h; 14% less at 24 h, P<0.05); beta1-/- and beta1/beta2-/- myocytes showed enhanced survival (beta1-/- 11%; beta1/beta2-/- 18% greater than WT, P<0.05). TUNEL staining demonstrated a similar differential susceptibility (WT 26% apoptotic nuclei, beta2-/- 45.9%, beta1/beta2-/- 16.8%, P<0.05). beta2-/- Fibroblasts also showed enhanced toxicity. Pertussis toxin pretreatment of WT cells decreased survival similar to the beta2-/-, suggesting a role for Gi signaling. JNK was differentially activated in beta2-/- myocytes after doxorubicin and its inhibition increased cardiotoxicity. In conclusion, the differential cardioprotective/cardiotoxic effects mediated by beta1 vs. beta2-AR subtypes in knockout mice are recapitulated in myocytes isolated from these mice. beta2-ARs appear to play a cardioprotective role, whereas beta1-ARs a cardiotoxic role.
Mesh Headings (Keywords): Animals, Cardiomyopathies, Cardiotonic Agents, Cell Survival, Cells, Cultured, Culture Media, Conditioned, Dose-Response Relationship, Drug, Doxorubicin, Fibroblasts, Kinetics, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred Strains, Mice, Knockout, Myocytes, Cardiac, Receptors, Adrenergic, beta-1, Receptors, Adrenergic, beta-2, Time Factors
Check for Full Text / PubMed Unique Identifier (PMID): 16458323
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