Editors' ChoiceISCHEMIA

The Trouble with Having a Big Heart

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Science's STKE  27 Mar 2007:
Vol. 2007, Issue 379, pp. tw99
DOI: 10.1126/stke.3792007tw99

When the heart is put under stress, it adapts by increasing in size, a process known as cardiac hypertrophy. After prolonged periods, however, heart failure ensues. Sano et al. examined the contribution that angiogenesis (the growth of new blood vessels) makes to the development of hypertrophy and cardiac failure. They established a model of hypertrophy by introducing a severe transverse aorta constriction (TAC) in mice. The resultant increase in pressure caused a gradual development of hypertrophy over 14 days, with an accompanying increase in the number of blood vessels in the heart, followed by a second phase (days 14 to 28), during which the continued pressure led to systolic dysfunction. Increased amounts of messenger RNA and protein for the angiogenic factor vascular endothelial growth factor (VEGF) were present in the TAC heart, peaking on day 14 and sharply decreasing by day 28. Hypertrophy results in ischemia (insufficient oxygen) in the myocardium, and the authors found that both the production and activity of hypoxia-inducible factor (HIF)-1α (a transcription factor that induces angiogenic factors under ischemic conditions) were stimulated in the hearts of TAC mice from days 3 to 14, returning to basal levels by day 28. The tumor suppressor p53 is known to bind to and promote the degradation of HIF-1α, and elevated amounts of p53 in the myocardium were observed 14 days after TAC. Producing TAC in p53-deficient mice resulted in higher HIF-1α activity, amounts of VEGF, and numbers of blood vessels than in wild-type mice, leading to better systolic function. This study establishes p53 as an important regulator of cardiac hypertrophy by inhibiting angiogenesis.

M. Sano, T. Minamino, H. Toko, H. Miyauchi, M. Orimo, Y. Qin, H. Akazawa, K. Tateno, Y. Kayama, M. Harada, I. Shimizu, T. Asahara, H. Hamada, S. Tomita, J. D. Molkentin, Y. Zou, I. Komuro, p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446, 444-448 (2007). [PubMed]

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