title: Effects of PPARα/PGC-1α on the energy metabolism remodeling and apoptosis in the doxorubicin induced mice cardiomyocytes in vitro.
abstract: Dilated cardiomyopathy is the most frequent form of myocardial disease. Many factors contribute to dilated cardiomyopathy, for instance, long-term use of doxorubicin, one of the anthracyclines clinically used for cancer chemotherapy, result in dilated cardiomyopathy and congestive heart failure. However, the mechanism underlining doxorubicin-induced cardiomyocyte is still not fully understood. In this study, we evaluate the effects and their mechanisms of PPARα and PGC-1α pathways in doxorubicin induced mice cardiomyocytes. In vitro, cardiomyocytes isolated from hearts of adult FVB/NJ mice were treated with doxorubicin, GW 6471 (PPARα inhibitors) and WY14643 (PPARα agonists). The expression of PPARα and PGC-1α were detected via western blotting and Quantitative Real-Time PCR methods. Changes in energy and substrate metabolism were analyzed. MTT and flow cytometry were used for cell proliferation and apoptosis analysis. We detected expression of PPARα and PGC-1α was significantly higher in control group than doxorubicin group. Mitochondrial dysfunction was found in doxorubicin group including lower content of high-energy phosphates, significantly decreased mitochondrial ANT transport activity and markedly reduced mitochondrial membrane potential compared with control group. Metabolic remodeling existed in doxorubicin group because of higher concentration of free fatty acid and glucose consumption than of control group. More accumulations of reactive oxygen species were detected in doxorubicin group. The decreased cell viability and increased cell apoptosis observed in doxorubicin group. Severe apoptosis in doxorubicin group was verified by a set of markers including Bax, Bcl-2, cytosolic cytochrome c and caspase-3 up-regulation expression. These findings indicate that the PPARα and PGC-1α are closely involved in energy metabolism remodeling and apoptosis in cardiomyocytes.
authors.affiliation: Department of Cardiology, Guizhou Provincial People's Hospital Guiyang, China.
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiology, The General Hospital of Jinan Military Region Jinan, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The General Hospital of Jinan Military Region Jinan, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Guizhou Provincial People's Hospital Guiyang, China.
authors.forename: Tianhe
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Guizhou Provincial People's Hospital Guiyang, China.
authors.forename: Qingan
authors.initials: Q
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D005230:Fatty Acids, Nonesterified; C449302:GW 6471; D010080:Oxazoles; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D014443:Tyrosine; D004317:Doxorubicin; C006253:pirinixic acid; D005947:Glucose
keywords: PGC-1α; PPARα; doxorubicin; energy metabolism; in vitro