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PRECLINICAL STUDY

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

Partha Mukhopadhyay, PhD^_*,1, Sándor Bátkai, MD, PhD^_*,1, Mohanraj Rajesh, PhD^_*, Nora Czifra^_*, Judith Harvey-White, MSc^_*, György Haskó, MD, PhD, Zsuzsanna Zsengeller, MD, PhD, Norma P. Gerard, MD, Lucas Liaudet, MD, George Kunos, MD, PhD, FAHA^_* and Pál Pacher, MD, PhD, FAPS, FAHA^_*,_*

^_* Laboratory of Physiological Studies, NIH/NIAAA, Bethesda, Maryland
Department of Surgery, UMDNJ-New Jersey Medical School, Newark, New Jersey
Pulmonary Division, Department of Pediatrics, Children’s Hospital, Harvard Medical School, Boston, Massachusetts
Department of Intensive Care Medicine, University Hospital, Lausanne, Switzerland.

Manuscript received December 20, 2006; revised manuscript received February 23, 2007, accepted March 6, 2007.

^_* Reprint requests and correspondence: Dr. Pál Pacher, Section on Oxidative Stress Tissue Injury, Laboratory of Physiologic Studies, NIH/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, Maryland 20892. (Email: pacher{at}mail.nih.gov).

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.

Abbreviations and Acronyms   AEA = anandamide   AG = arachidonoylglycerol   CB1/CB2 = cannabinoid-1/-2   DOX = doxorubicin/adriamycin   I/R = ischemia/reperfusion   TUNEL = terminal deoxynucleotidyltransferase-mediated nick-end labeling

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