Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity.
OBJECTIVE
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.
Laboratory of Physiological Studies, NIH/NIAAA, Bethesda, Maryland 20892, USA.
Partha
P
Mukhopadhyay
Sándor
S
Bátkai
Mohanraj
M
Rajesh
Nora
N
Czifra
Judith
J
Harvey-White
György
G
Haskó
Zsuzsanna
Z
Zsengeller
Norma P
NP
Gerard
Lucas
L
Liaudet
George
G
Kunos
Pál
P
Pacher
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects*; D006333:Heart Failure / Q000139:chemically induced* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects; D000077285:Rimonabant
D000903:Antibiotics, Antineoplastic; D063385:Cannabinoid Receptor Modulators; D009025:Morpholines; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D004317:Doxorubicin; D000077285:Rimonabant; C109925:AM 281