title: Reversal of right ventricular remodeling by dichloroacetate is related to inhibition of mitochondria-dependent apoptosis.
abstract: Most patients with pulmonary arterial hypertension die from right ventricular failure (RVF). Right ventricular (RV) myocardial apoptosis has an important role in RVF and is regulated by the mitochondria. Dichloroacetate (DCA) can improve cardiac function in RVF, but whether it can regulate myocardial apoptosis via mitochondria is still unknown. In this study, we investigated the effects of DCA on myocardial mitochondria, the mitochondrial apoptosis and other aspects of RV remodeling, including fibrosis and capillary rarefaction. RVF was induced in rats by a single s.c. injection of monocrotaline. After 4 weeks, DCA treatment was started with i.p. injection of 50, 150 or 2007 mg kg(-1) per day during 14 days. Compared with saline-treated RVF animals, treatment with DCA resulted in decreased mean pulmonary arterial pressure and total pulmonary resistance (TPR), and increased cardiac output. The expression of pyruvate dehydrogenase kinase was suppressed, while pyruvate dehydrogenase expression was upregulated with DCA application. DCA treatment was also associated with restored RV mitochondrial function and a reduction in RV hypertrophy, fibrosis, capillary rarefaction and apoptosis. Mitochondria-dependent apoptosis was involved in DCA regulation of RV. The absent correlation between TPR and main parameters in RV suggests that the effects of DCA in the two organ systems are independent. We conclude that DCA improves cardiac function in experimental RVF partly by reversing RV remodeling, restoring mitochondrial function and regulating mitochondria-dependent apoptosis. The study shows that a fear for increased RV apoptosis with DCA treatment is unnecessary and suggests a potential role of DCA in the treatment of RVF.
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Sun
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Hong-Da
authors.initials: HD
authors.lastname: Zhang
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Peking Union Medical College and Chinese Academy Medical Science, Beijing, China.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Qin-Hua
authors.initials: QH
authors.lastname: Zhao
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Pulmonary Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: Jan Bogaard
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.|State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Peking Union Medical College and Chinese Academy Medical Science, Beijing, China.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Jing
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D062186:Arterial Pressure / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016686:Monocrotaline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D016686:Monocrotaline; D003999:Dichloroacetic Acid