Document Detail


Interference with akt signaling protects against myocardial infarction and death by limiting the consequences of oxidative stress.
MedLine Citation:
PMID:  23921086     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The intricacy of multiple feedback loops in the pathways downstream of Akt allows this kinase to control multiple cellular processes in the cardiovascular system and precludes inferring consequences of its activation in specific pathological conditions. Akt1, the major Akt isoform in the heart and vasculature, has a protective role in the endothelium during atherosclerosis. However, Akt1 activation may also have detrimental consequences in the cardiovascular system. Mice lacking both the high-density lipoprotein receptor SR-BI (scavenger receptor class B type I) and ApoE (apolipoprotein E), which promotes clearance of remnant lipoproteins, are a model of severe dyslipidemia and spontaneous myocardial infarction. We found that Akt1 was activated in these mice, and this activation correlated with cardiac dysfunction, hypertrophy, and fibrosis; increased infarct area; cholesterol accumulation in macrophages and atherosclerosis; and reduced life span. Akt1 activation was associated with inflammation, oxidative stress, accumulation of oxidized lipids, and increased abundance of CD36, a major sensor of oxidative stress, and these events created a positive feedback loop that exacerbated the consequences of oxidative stress. Genetic deletion of Akt1 in this mouse model resulted in decreased mortality, alleviation of multiple complications of heart disease, and reduced occurrence of spontaneous myocardial infarction. Thus, interference with Akt1 signaling in vivo could be protective and improve survival under dyslipidemic conditions by reducing oxidative stress and responses to oxidized lipids.
Authors:
Bethany A Kerr; Lining Ma; Xiaoxia Z West; Liang Ding; Nikolay L Malinin; Malory E Weber; Mira Tischenko; Anna Goc; Payaningal R Somanath; Marc S Penn; Eugene A Podrez; Tatiana V Byzova
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Publication Detail:
Type:  Journal Article     Date:  2013-08-06
Journal Detail:
Title:  Science signaling     Volume:  6     ISSN:  1937-9145     ISO Abbreviation:  Sci Signal     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-08-07     Completed Date:  2014-03-17     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  101465400     Medline TA:  Sci Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  ra67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD36 / genetics,  metabolism
Apolipoproteins E / genetics,  metabolism
Atherosclerosis / enzymology,  genetics,  pathology
Disease Models, Animal
Enzyme Activation / genetics
Mice
Mice, Knockout
Myocardial Infarction / enzymology*,  genetics,  pathology,  prevention & control
Oxidative Stress*
Proto-Oncogene Proteins c-akt / genetics,  metabolism*
Scavenger Receptors, Class B / genetics,  metabolism
Signal Transduction*
Grant Support
ID/Acronym/Agency:
F32 CA142133/CA/NCI NIH HHS; R01 HL071625/HL/NHLBI NIH HHS; R01 HL103952/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD36; 0/Apolipoproteins E; 0/SCARB1 protein, human; 0/Scavenger Receptors, Class B; EC 2.7.11.1/Akt1 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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