title: Abcc6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model.
abstract: OBJECTIVE
  ABCC6 genetic deficiency underlies pseudoxanthoma elasticum (PXE) in humans, characterized by ectopic calcification, and early cardiac disease. The spectrum of PXE has been noted in Abcc6-deficient mice, including dystrophic cardiac calcification. We tested the role of Abcc6 in response to cardiac ischemia-reperfusion (I/R) injury.
  
  
  RESULTS
  To determine the role of Abcc6 in cardioprotection, we induced ischemic injury in mice in vivo by occluding the left anterior descending artery (30 minutes) followed by reperfusion (48 hours). Infarct size was increased in Abcc6-deficient mice compared with wild-type controls. Additionally, an Abcc6 transgene significantly reduced infarct size on the background of a naturally occurring Abcc6 deficiency. There were no differences in cardiac calcification following I/R, but increased cardiac apoptosis was noted in Abcc6-deficient mice. Previous studies have implicated the bone morphogenetic protein (BMP) signaling pathway in directing calcification, and here we showed that the BMP responsive transcription factors pSmad1/5/8 were increased in hearts of Abcc6 mice. Consistent with this finding, BMP4 and BMP9 were increased and activin receptor-like kinase-2 and endoglin were downregulated in cardiac extracts from Abcc6-deficient mice versus controls.
  
  
  CONCLUSIONS
  These data identify Abcc6 as a novel modulator of cardiac myocyte survival after I/R. This cardioprotective mechanism may involve inhibition of the BMP signaling pathway, which modulates apoptosis.
authors: Division of Cardiology and Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. imungrue@yahoo.com
authors: Imran N
authors: IN
authors: Mungrue
authors: Peng
authors: P
authors: Zhao
authors: Yucheng
authors: Y
authors: Yao
authors: Haijin
authors: H
authors: Meng
authors: Christoph
authors: C
authors: Rau
authors: Jocelyn V
authors: JV
authors: Havel
authors: Theo G M F
authors: TG
authors: Gorgels
authors: Arthur A B
authors: AA
authors: Bergen
authors: W Robb
authors: WR
authors: MacLellan
authors: Thomas A
authors: TA
authors: Drake
authors: Kristina I
authors: KI
authors: Boström
authors: Aldons J
authors: AJ
authors: Lusis
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D004195:Disease Models, Animal; D000071063:Endoglin; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D055427:Growth Differentiation Factor 2 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D030201:Activin Receptors, Type I; D055415:Bone Morphogenetic Protein 4; D000071063:Endoglin; D055427:Growth Differentiation Factor 2; D047908:Intracellular Signaling Peptides and Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C504743:Abcc6 protein, mouse; C525810:Bmp4 protein, mouse; C502004:Eng protein, mouse; C526108:Gdf2 protein, mouse; C498943:Acvr1 protein, mouse