Research ArticleCardiovascular Disease

Klf15 Deficiency Is a Molecular Link Between Heart Failure and Aortic Aneurysm Formation

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Science Translational Medicine  07 Apr 2010:
Vol. 2, Issue 26, pp. 26ra26
DOI: 10.1126/scitranslmed.3000502

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Editor's Summary

The aorta should really be considered part of the heart. The elastic walls of this huge vessel expand with each heartbeat, smoothing out the pulses of blood spurting into it from the left ventricle. Some patients with disease in one tend to have disease in the other. By studying genetically engineered mice, Haldar and Lu and colleagues have now identified a transcription factor that seems essential for proper functioning of both organs and that is deficient in patients with cardiomyopathy and aortopathy. This common underlying molecule may help define new approaches for the treatment of patients with co-occurring heart and aortic disease.

The authors first noticed that rodents treated with angiotensin II, which stresses the heart and vasculature, causing disease, had very little Kruppel-like factor 15 (KLF15), a key zinc finger transcription factor, in their heart and aorta. The same was true in patients with disease in these areas. Then, by engineering mice that were missing KLF15 from birth, the authors showed that this transcriptional regulator was necessary for proper functioning of the heart and aorta. Without KLF15, mice developed large dilated hearts that could not pump properly and aortas with aneurysms and, in some animals, hematomas. Further investigation in cells from these animals showed that these effects depended on p53 and p300 acetyltransferase likely because KLF15 directly or indirectly inhibits p300-mediated acetylation of p53. As in human diseased tissue, hearts and aorta from Klf15-deficient mice have hyperacetylated p53.

Therefore, for some individuals, stress on the heart and aorta may decrease KLF15 concentrations, which sets in motion an undesirable set of cellular signaling cascades that lead to cardiovascular disease. Having a better handle on what these signals are may help us to interfere with their nefarious work.

Footnotes

  • * These authors contributed equally to this work.

  • Citation: S. M. Haldar, Y. Lu, D. Jeyaraj, D. Kawanami, Y. Cui, S. J. Eapen, C. Hao, Y. Li, Y.-Q. Doughman, M. Watanabe, K. Shimizu, H. Kuivaniemi, J. Sadoshima, K. B. Margulies, T. P. Cappola, M. K. Jain, Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation. Sci. Transl. Med. 2, 26ra26 (2010).