title: Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice.
abstract: Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
authors.forename: Mahdieh
authors.initials: M
authors.lastname: Rahmatollahi
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
authors.forename: Somayeh Mahmoodi
authors.initials: SM
authors.lastname: Baram
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Rahimian
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.|Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.|Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran.
authors.forename: Seyed Soheil
authors.initials: SS
authors.lastname: Saeedi Saravi
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. dehpour@yahoo.com.|Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. dehpour@yahoo.com.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity; D019610:Cytoprotection; D004195:Disease Models, Animal; D004317:Doxorubicin; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002316:Cardiotonic Agents; C449302:GW 6471; D009025:Morpholines; D009281:Naphthalenes; D010080:Oxazoles; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D008315:Malondialdehyde; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D004317:Doxorubicin
keywords: Cannabinoids; Cardiotoxicity; Doxorubicin; Peroxisome proliferator-activated receptor-α