Document Detail


Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation.
MedLine Citation:
PMID:  20375365     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Current therapies for diseases of heart muscle (cardiomyopathy) and aorta (aortopathy) include inhibitors of the renin-angiotensin system, beta-adrenergic antagonists, and the statin class of cholesterol-lowering agents. These therapies have limited efficacy, as adverse cardiovascular events continue to occur with some frequency in patients taking these drugs. Although cardiomyopathy and aortopathy can coexist in a number of conditions (for example, Marfan's syndrome, acromegaly, pregnancy, and aging), pathogenetic molecular links between the two diseases remain poorly understood. We reasoned that identification of common molecular perturbations in these two tissues could point to therapies for both conditions. Here, we show that deficiency of the transcriptional regulator Kruppel-like factor 15 (Klf15) in mice leads to both heart failure and aortic aneurysm formation through a shared molecular mechanism. Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.
Authors:
Saptarsi M Haldar; Yuan Lu; Darwin Jeyaraj; Daiji Kawanami; Yingjie Cui; Sam J Eapen; Caili Hao; Yan Li; Yong-Qiu Doughman; Michiko Watanabe; Koichi Shimizu; Helena Kuivaniemi; Junichi Sadoshima; Kenneth B Margulies; Thomas P Cappola; Mukesh K Jain
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science translational medicine     Volume:  2     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-08     Completed Date:  2010-09-20     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  26ra26     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acetylation
Animals
Aorta / metabolism,  pathology
Aortic Aneurysm / complications*,  metabolism*,  pathology
Cardiomyopathies / complications,  metabolism,  pathology
Cell Line
DNA-Binding Proteins / deficiency*,  genetics,  metabolism
E1A-Associated p300 Protein / antagonists & inhibitors,  metabolism
Germ Cells
Heart Failure / complications*,  metabolism,  pathology*
Humans
Kruppel-Like Transcription Factors / deficiency*,  genetics,  metabolism*
Male
Mice
Mice, Inbred C57BL
Nuclear Proteins / deficiency*,  genetics,  metabolism*
Rats
Transcription Factors / deficiency*,  genetics,  metabolism
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
HL064310/HL/NHLBI NIH HHS; HL072952/HL/NHLBI NIH HHS; HL084154/HL/NHLBI NIH HHS; HL086614/HL/NHLBI NIH HHS; HL094660/HL/NHLBI NIH HHS; K08 HL086614/HL/NHLBI NIH HHS; R01 AG023039/AG/NIA NIH HHS; R01 AG023039-06/AG/NIA NIH HHS; R01 AG023039-06S1/AG/NIA NIH HHS; R01 AG023039-07/AG/NIA NIH HHS; R01 AG023039-08/AG/NIA NIH HHS; R01 HL064310/HL/NHLBI NIH HHS; R01 HL075427/HL/NHLBI NIH HHS; R01 HL075427-07/HL/NHLBI NIH HHS; R01 HL076754/HL/NHLBI NIH HHS; R01 HL076754-07/HL/NHLBI NIH HHS; R01 HL084154/HL/NHLBI NIH HHS; R01 HL084154-04/HL/NHLBI NIH HHS; R01 HL086548/HL/NHLBI NIH HHS; R01 HL086548-05/HL/NHLBI NIH HHS; R01 HL088577/HL/NHLBI NIH HHS; R01 HL091469/HL/NHLBI NIH HHS; R01 HL091469-04/HL/NHLBI NIH HHS; R01 HL097593/HL/NHLBI NIH HHS; R01 HL097593-02/HL/NHLBI NIH HHS; R01 HL102738/HL/NHLBI NIH HHS; R01 HL102738-02/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Ep300 protein, mouse; 0/KLF15 protein, human; 0/Klf15 protein, mouse; 0/Kruppel-Like Transcription Factors; 0/Nuclear Proteins; 0/Transcription Factors; 0/Tumor Suppressor Protein p53; EC 2.3.1.48/E1A-Associated p300 Protein
Comments/Corrections

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