title: Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation.
abstract: 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.affiliation: 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.
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Darwin
authors.initials: D
authors.lastname: Jeyaraj
authors.forename: Daiji
authors.initials: D
authors.lastname: Kawanami
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Cui
authors.forename: Sam J
authors.initials: SJ
authors.lastname: Eapen
authors.forename: Caili
authors.initials: C
authors.lastname: Hao
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yong-Qiu
authors.initials: YQ
authors.lastname: Doughman
authors.forename: Michiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000107:Acetylation; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D009202:Cardiomyopathies / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D005854:Germ Cells; D006333:Heart Failure / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C414172:KLF15 protein, human; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse