CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes

Partha Mukhopadhyay, Mohanraj Rajesh, Sándor Bátkai, Vivek Patel, Yoshihiro Kashiwaya, Lucas Liaudet, Oleg V. Evgenov, Ken MacKie, G. Haskó, Pál Pacher

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

AimsHere we investigated the mechanisms by which cardiovascular CB 1 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 resultsBoth 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 CB 1 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.ConclusionCB1 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.

Original languageEnglish
Pages (from-to)773-784
Number of pages12
JournalCardiovascular Research
Volume85
Issue number4
DOIs
Publication statusPublished - Mar 2010

Fingerprint

Cannabinoid Receptor CB1
Endocannabinoids
Cardiomyopathies
Cardiac Myocytes
Doxorubicin
Oxidative Stress
Cell Death
Mitogen-Activated Protein Kinases
rimonabant
p38 Mitogen-Activated Protein Kinases
Reactive Oxygen Species
Flow Cytometry
Reactive Nitrogen Species
Cannabinoid Receptors
Left Ventricular Dysfunction
Metabolic Networks and Pathways
Left Ventricular Function
Molecular Biology
Fibrosis
Cardiovascular Diseases

Keywords

  • AM281
  • CB receptor
  • Endocannabinoids
  • Heart failure
  • Rimonabant
  • SR141716

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. / Mukhopadhyay, Partha; Rajesh, Mohanraj; Bátkai, Sándor; Patel, Vivek; Kashiwaya, Yoshihiro; Liaudet, Lucas; Evgenov, Oleg V.; MacKie, Ken; Haskó, G.; Pacher, Pál.

In: Cardiovascular Research, Vol. 85, No. 4, 03.2010, p. 773-784.

Research output: Contribution to journalArticle

Mukhopadhyay, P, Rajesh, M, Bátkai, S, Patel, V, Kashiwaya, Y, Liaudet, L, Evgenov, OV, MacKie, K, Haskó, G & 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, vol. 85, no. 4, pp. 773-784. https://doi.org/10.1093/cvr/cvp369
Mukhopadhyay, Partha ; Rajesh, Mohanraj ; Bátkai, Sándor ; Patel, Vivek ; Kashiwaya, Yoshihiro ; Liaudet, Lucas ; Evgenov, Oleg V. ; MacKie, Ken ; Haskó, G. ; Pacher, Pál. / CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. In: Cardiovascular Research. 2010 ; Vol. 85, No. 4. pp. 773-784.
@article{4e096fc90ab44d68b3498d5357e6ef81,
title = "CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes",
abstract = "AimsHere we investigated the mechanisms by which cardiovascular CB 1 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 resultsBoth 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 CB 1 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.ConclusionCB1 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.",
keywords = "AM281, CB receptor, Endocannabinoids, Heart failure, Rimonabant, SR141716",
author = "Partha Mukhopadhyay and Mohanraj Rajesh and S{\'a}ndor B{\'a}tkai and Vivek Patel and Yoshihiro Kashiwaya and Lucas Liaudet and Evgenov, {Oleg V.} and Ken MacKie and G. Hask{\'o} and P{\'a}l Pacher",
year = "2010",
month = "3",
doi = "10.1093/cvr/cvp369",
language = "English",
volume = "85",
pages = "773--784",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "4",

}

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, G.

AU - Pacher, Pál

PY - 2010/3

Y1 - 2010/3

N2 - AimsHere we investigated the mechanisms by which cardiovascular CB 1 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 resultsBoth 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 CB 1 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.ConclusionCB1 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.

AB - AimsHere we investigated the mechanisms by which cardiovascular CB 1 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 resultsBoth 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 CB 1 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.ConclusionCB1 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.

KW - AM281

KW - CB receptor

KW - Endocannabinoids

KW - Heart failure

KW - Rimonabant

KW - SR141716

UR - http://www.scopus.com/inward/record.url?scp=76749118468&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76749118468&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvp369

DO - 10.1093/cvr/cvp369

M3 - Article

C2 - 19942623

AN - SCOPUS:76749118468

VL - 85

SP - 773

EP - 784

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 4

ER -