| Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation. | |
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MedLine Citation:
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PMID: 20375365 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Science translational medicine Volume: 2 ISSN: 1946-6242 ISO Abbreviation: Sci Transl Med Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-08 Completed Date: 2010-09-20 Revised Date: 2011-03-30 |
Medline Journal Info:
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Nlm Unique ID: 101505086 Medline TA: Sci Transl Med Country: United States |
Other Details:
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Languages: eng Pagination: 26ra26 Citation Subset: IM |
Affiliation:
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Case Cardiovascular Research Institute, Department of Medicine, Harrington-McLaughlin Heart and Vascular Institute, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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 HL086614-05/HL/NHLBI 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 HL075427-07/HL/NHLBI NIH HHS; R01 HL076754-07/HL/NHLBI NIH HHS; R01 HL084154-04/HL/NHLBI NIH HHS; R01 HL086548-05/HL/NHLBI NIH HHS; R01 HL091469-04/HL/NHLBI NIH HHS; R01 HL097593-02/HL/NHLBI NIH HHS; R01 HL102738-02/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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