title: Mediation of dopamine D2 receptors activation in post-conditioning-attenuated cardiomyocyte apoptosis.
abstract: The physiological and pathological roles of dopamine D2 receptors (DR2) in the regulation of cardiovacular functions have been recognized. DR2 activation protects hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury and apoptosis, and ischemic post-conditioning (PC) plays a critical role in cardioprotection as well; however the involvement of the DR2 activation in the PC-induced cardioprotection is unknown. In the present study, we found that the H/R increased the expressions of DR2 mRNA and protein in cardiomyocytes, which were significantly enhanced by PC. Bromocriptine (Bro, a DR2 agonist) further increased DR2 expression, but Haloperidol (Hal, a DR2 antagonist) reversed the Bro-induced DR2 expressions. PC protected against H/R-induced apoptosis, the rise of [Ca(2+)]i, the expressions of cleaved caspase-3 and -9, release of cytochrome c, and mPTP opening. In addition, PC counteracted the reduction of cell viability caused by H/R, increased the phosphorylation of ERK1/2, PI3K, Akt, GSK-3β and mitochondrial membrane potential. PC further increased Bcl-2 expression, promoted PKC-ε translocation to cell membrane, and activated the mitochondrial ATP-sensitive K channels (mKATP). Bro further enhanced the cardioprotective roles of PC, but Hal reversed these effects of Bro. Meanwhile, we found that DR2 was expressed in cell membrane and interacted with PKC-ε in PC. In conclusion, these results suggest that PC attenuates cardiomyocyte apoptosis via inhibition of mPTP opening by DR2-mediated activation of ERK1/2, PI3K-Akt-GSK-3β and PKC-ε-mKATP. These findings provide a novel target for the treatment of ischemic cardiomyopathy.
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China. Electronic address: hongzhuli61@163.com.
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
authors.forename: Can
authors.initials: C
authors.lastname: Wei
authors.affiliation: The First Hospital of Harbin, Harbin 150010, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
authors.forename: Shuzhi
authors.initials: S
authors.lastname: Bai
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Physiology, Wenzhou Medical College, Wenzhou 325035, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: The School of Kinesiology, Lakehead University, Thunder Bay, ON, Canada P7B5E1.
authors.forename: Guangdong
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Biology, Lakehead University, Thunder Bay, ON, Canada P7B5E1.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Health Science, Lakehead University, Thunder Bay, ON, Canada P7B5E1.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin 150081, China. Electronic address: xucq45@126.com.
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001971:Bromocriptine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006220:Haloperidol / Q000494:pharmacology; D057775:Ischemic Postconditioning; D054086:KATP Channels / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D001971:Bromocriptine; D002118:Calcium; D002316:Cardiotonic Agents; D053148:Caspase 3; D053453:Caspase 9; D045304:Cytochromes c; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006220:Haloperidol; D054086:KATP Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019869:Phosphatidylinositol 3-Kinases; D051744:Protein Kinase C-epsilon; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; C000605508:Gsk3b protein, rat
keywords: Cardiomyocytes; Dopamine D(2) receptors; Mitochondrial permeability transition pore; Post-conditioning