p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload

Abstract

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function1. However, prolonged cardiac hypertrophy causes heart failure2, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.

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Figure 1: Cardiac hypertrophy, function and angiogenesis after TAC.
Figure 2: Cardiac angiogenesis in TAC-induced hypertrophy.
Figure 3: Role of Hif-1 in adaptive hypertrophy.
Figure 4: Role of p53 accumulation in maladaptive hypertrophy.

References

  1. 1

    Frey, N. & Olson, E. N. Cardiac hypertrophy: the good, the bad, and the ugly. Annu. Rev. Physiol. 65, 45–79 (2003)

    CAS  Article  Google Scholar 

  2. 2

    Levy, D. et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med. 322, 1561–1566 (1990)

    CAS  Article  Google Scholar 

  3. 3

    Marcus, M. L. et al. Abnormalities in the coronary circulation that occur as a consequence of cardiac hypertrophy. Am. J. Med. 75, 62–66 (1983)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Tomanek, R. J. Response of the coronary vasculature to myocardial hypertrophy. J. Am. Coll. Cardiol. 15, 528–533 (1990)

    CAS  Article  Google Scholar 

  5. 5

    Giordano, F. J. et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc. Natl Acad. Sci. USA 98, 5780–5785 (2001)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Shyu, K. G. et al. Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1α and vascular endothelial growth factor in pressure-overloaded rat heart. J. Biomed. Sci. 12, 409–420 (2005)

    CAS  Article  Google Scholar 

  7. 7

    Yoon, Y. S. et al. Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation 111, 2073–2085 (2005)

    CAS  Article  Google Scholar 

  8. 8

    Ingber, D. et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348, 555–557 (1990)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Goldman, C. K. et al. Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate. Proc. Natl Acad. Sci. USA 95, 8795–8800 (1998)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Morani, A. et al. Lung dysfunction causes systemic hypoxia in estrogen receptor β knockout (ERβ-/-) mice. Proc. Natl Acad. Sci. USA 103, 7165–7169 (2006)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003)

    CAS  Article  Google Scholar 

  12. 12

    Pugh, C. W. & Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med. 9, 677–684 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Blagosklonny, M. V. et al. p53 inhibits hypoxia-inducible factor-stimulated transcription. J. Biol. Chem. 273, 11995–11998 (1998)

    CAS  Article  Google Scholar 

  14. 14

    Ravi, R. et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 14, 34–44 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Gurova, K. V. et al. Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-κB-dependent mechanism of p53 suppression in tumors. Proc. Natl Acad. Sci. USA 102, 17448–17453 (2005)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Fei, P. et al. Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. Cancer Cell 6, 597–609 (2004)

    CAS  Article  Google Scholar 

  17. 17

    Kubasiak, L. A., Hernandez, O. M., Bishopric, N. H. & Webster, K. A. Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proc. Natl Acad. Sci. USA 99, 12825–12830 (2002)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Kelly, B. D. et al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ. Res. 93, 1074–1081 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Patel, T. H. et al. Constitutively active HIF-1α improves perfusion and arterial remodeling in an endovascular model of limb ischemia. Cardiovasc. Res. 68, 144–154 (2005)

    CAS  Article  Google Scholar 

  20. 20

    Shizukuda, Y. et al. Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice. Mol. Cell. Biochem. 273, 25–32 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Takimoto, E. et al. Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload. FASEB J. 16, 373–378 (2002)

    CAS  Article  Google Scholar 

  22. 22

    Harada, M. et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nature Med. 11, 305–311 (2005)

    CAS  Article  Google Scholar 

  23. 23

    Sohal, D. S. et al. Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ. Res. 89, 20–25 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Tomita, S. et al. Defective brain development in mice lacking the Hif-1α gene in neural cells. Mol. Cell. Biol. 23, 6739–6749 (2003)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank E. Fujita, R. Kobayashi and M. Ikeda for technical support. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas and for Exploratory Research, Ministry of Education, Culture, Sports, Science and Technology; Health and Labour Sciences Research Grants; Research on Measures for Intractable Diseases; Grants from Goho Life Sciences International Fund; an Academic Award of the Mochida Memorial Foundation and Uehara Memorial Foundation (to I.K.); and grants from the Suzuken Memorial Foundation, the NOVARTIS Foundation and the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T.M.).

Author Contributions M.S., T.M., H.T., H.M., M.O., Y.Q., H.A., K.T., Y.K., M.H., I.S. and Y.Z. performed the experiments. T.A., H.H., S.T. and J.D.M. provided reagents or mice. M.S., T.M. and I.K. designed and prepared the manuscript. I.K. planned and supervised the project.

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Correspondence to Issei Komuro.

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This file contains Supplementary Figures 1–11 with Legends, Supplementary Methods describing all reagents used as well as detailed protocols and additional references. (PDF 1083 kb)

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Sano, M., Minamino, T., Toko, H. et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446, 444–448 (2007). https://doi.org/10.1038/nature05602

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