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CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes.
Cardiovasc Res 2010; 85(4):773-84CR

Abstract

AIMS

Here we investigated the mechanisms by which cardiovascular CB1 cannabinoid receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX).

METHODS AND RESULTS

Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure-volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1(+/+)), and these effects were markedly attenuated in CB1 knockouts (CB1(-/-)). In human primary cardiomyocytes expressing CB1 receptors (demonstrated by RT-PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endocannabinoid anandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX +/- AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation.

CONCLUSION

CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular diseases.

Authors+Show Affiliations

Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, NIH/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19942623

Citation

Mukhopadhyay, Partha, et al. "CB1 Cannabinoid Receptors Promote Oxidative Stress and Cell Death in Murine Models of Doxorubicin-induced Cardiomyopathy and in Human Cardiomyocytes." Cardiovascular Research, vol. 85, no. 4, 2010, pp. 773-84.
Mukhopadhyay P, Rajesh M, Bátkai S, et al. CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc Res. 2010;85(4):773-84.
Mukhopadhyay, P., Rajesh, M., Bátkai, S., Patel, V., Kashiwaya, Y., Liaudet, L., ... Pacher, P. (2010). CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovascular Research, 85(4), pp. 773-84. doi:10.1093/cvr/cvp369.
Mukhopadhyay P, et al. CB1 Cannabinoid Receptors Promote Oxidative Stress and Cell Death in Murine Models of Doxorubicin-induced Cardiomyopathy and in Human Cardiomyocytes. Cardiovasc Res. 2010 Mar 1;85(4):773-84. PubMed PMID: 19942623.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. AU - Mukhopadhyay,Partha, AU - Rajesh,Mohanraj, AU - Bátkai,Sándor, AU - Patel,Vivek, AU - Kashiwaya,Yoshihiro, AU - Liaudet,Lucas, AU - Evgenov,Oleg V, AU - Mackie,Ken, AU - Haskó,György, AU - Pacher,Pál, Y1 - 2009/11/26/ PY - 2009/11/28/entrez PY - 2009/11/28/pubmed PY - 2010/4/27/medline SP - 773 EP - 84 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 85 IS - 4 N2 - AIMS: Here we investigated the mechanisms by which cardiovascular CB1 cannabinoid receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX). METHODS AND RESULTS: Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure-volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1(+/+)), and these effects were markedly attenuated in CB1 knockouts (CB1(-/-)). In human primary cardiomyocytes expressing CB1 receptors (demonstrated by RT-PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endocannabinoid anandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX +/- AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation. CONCLUSION: CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular diseases. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/19942623/CB1_cannabinoid_receptors_promote_oxidative_stress_and_cell_death_in_murine_models_of_doxorubicin_induced_cardiomyopathy_and_in_human_cardiomyocytes_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvp369 DB - PRIME DP - Unbound Medicine ER -