Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-Induced Cardiotoxicity

Partha Mukhopadhyay, Sándor Bátkai, Mohanraj Rajesh, Nora Czifra, Judith Harvey-White, G. Haskó, Zsuzsanna Zsengeller, Norma P. Gerard, Lucas Liaudet, George Kunos, Pál Pacher

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Abstract

Objectives: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity. Background: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists. Methods: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. Results: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists. Conclusions: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

Original languageEnglish
Pages (from-to)528-536
Number of pages9
JournalJournal of the American College of Cardiology
Volume50
Issue number6
DOIs
Publication statusPublished - Aug 7 2007

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Cannabinoid Receptors
Cannabinoids
Cannabinoid Receptor Antagonists
Doxorubicin
Pharmacology
Endocannabinoids
Cannabinoid Receptor CB2
rimonabant
Ventricular Pressure
Apoptosis
Microscopy
Flow Cytometry
Stroke
Blood Pressure
Left Ventricular Function
Liquid Chromatography
Cardiac Output
Antineoplastic Agents
Reverse Transcription
Cardiotoxicity

ASJC Scopus subject areas

  • Nursing(all)

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Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-Induced Cardiotoxicity. / Mukhopadhyay, Partha; Bátkai, Sándor; Rajesh, Mohanraj; Czifra, Nora; Harvey-White, Judith; Haskó, G.; Zsengeller, Zsuzsanna; Gerard, Norma P.; Liaudet, Lucas; Kunos, George; Pacher, Pál.

In: Journal of the American College of Cardiology, Vol. 50, No. 6, 07.08.2007, p. 528-536.

Research output: Contribution to journalArticle

Mukhopadhyay, P, Bátkai, S, Rajesh, M, Czifra, N, Harvey-White, J, Haskó, G, Zsengeller, Z, Gerard, NP, Liaudet, L, Kunos, G & Pacher, P 2007, 'Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-Induced Cardiotoxicity', Journal of the American College of Cardiology, vol. 50, no. 6, pp. 528-536. https://doi.org/10.1016/j.jacc.2007.03.057
Mukhopadhyay, Partha ; Bátkai, Sándor ; Rajesh, Mohanraj ; Czifra, Nora ; Harvey-White, Judith ; Haskó, G. ; Zsengeller, Zsuzsanna ; Gerard, Norma P. ; Liaudet, Lucas ; Kunos, George ; Pacher, Pál. / Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-Induced Cardiotoxicity. In: Journal of the American College of Cardiology. 2007 ; Vol. 50, No. 6. pp. 528-536.
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abstract = "Objectives: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity. Background: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists. Methods: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. Results: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists. Conclusions: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.",
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AU - Rajesh, Mohanraj

AU - Czifra, Nora

AU - Harvey-White, Judith

AU - Haskó, G.

AU - Zsengeller, Zsuzsanna

AU - Gerard, Norma P.

AU - Liaudet, Lucas

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N2 - Objectives: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity. Background: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists. Methods: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. Results: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists. Conclusions: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

AB - Objectives: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity. Background: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists. Methods: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. Results: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists. Conclusions: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

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