Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation

Saptarsi M. Haldar, Yuan Lu, Darwin Jeyaraj, Daiji Kawanami, Yingjie Cui, Sam J. Eapen, Hao Caili, Yan Li, Yong Qiu Doughman, Michiko Watanabe, Koichi Shimizu, Helena Kuivaniemi, Junichi Sadoshima, Kenneth B. Margulies, Thomas P. Cappola, Mukesh K. Jain

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Current therapies for diseases of heart muscle (cardiomyopathy) and aorta (aortopathy) include inhibitors of the renin-angiotensin system, b-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.

Original languageEnglish (US)
Pages (from-to)26ra26
JournalScience translational medicine
Volume2
Issue number26
DOIs
StatePublished - 2010

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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