Document Detail


Abcc6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model.
MedLine Citation:
PMID:  21979437     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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:
Imran N Mungrue; Peng Zhao; Yucheng Yao; Haijin Meng; Christoph Rau; Jocelyn V Havel; Theo G M F Gorgels; Arthur A B Bergen; W Robb MacLellan; Thomas A Drake; Kristina I Boström; Aldons J Lusis
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-06
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  31     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-18     Completed Date:  2012-01-27     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2806-12     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics*,  physiology*
Activin Receptors, Type I / metabolism
Animals
Apoptosis / physiology*
Bone Morphogenetic Protein 4 / metabolism
Disease Models, Animal
Female
Gene Expression Regulation / physiology*
Growth Differentiation Factor 2 / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myocardial Infarction / metabolism,  pathology*,  physiopathology
Myocardial Reperfusion Injury / metabolism,  pathology*,  physiopathology*
Myocytes, Cardiac / pathology
Signal Transduction / physiology
Smad Proteins / metabolism
Transforming Growth Factor beta / metabolism
Grant Support
ID/Acronym/Agency:
5K99HL094709-02/HL/NHLBI NIH HHS; HL30568/HL/NHLBI NIH HHS; HL81397/HL/NHLBI NIH HHS; K99 HL094709/HL/NHLBI NIH HHS; K99 HL094709-02/HL/NHLBI NIH HHS; P01 HL030568/HL/NHLBI NIH HHS; P01 HL030568-29/HL/NHLBI NIH HHS; R01 HL081397/HL/NHLBI NIH HHS; R01 HL081397-05/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Abcc6 protein, mouse; 0/Bmp4 protein, mouse; 0/Bone Morphogenetic Protein 4; 0/Gdf2 protein, mouse; 0/Growth Differentiation Factor 2; 0/Intracellular Signaling Peptides and Proteins; 0/Smad Proteins; 0/Transforming Growth Factor beta; 0/endoglin protein, mouse; EC 2.7.11.30/Activin Receptors, Type I; EC 2.7.11.30/Acvr1 protein, mouse
Comments/Corrections

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