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Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy

Nature Medicine volume 11, pages 214–222 (2005)Cite this article

Abstract

Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3′,5′-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.

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Figure 1: Inhibition of PDE5A with sildenafil prevents load-induced cardiac hypertrophy.
Figure 2: Inhibition of PDE5A with sildenafil reverses established cardiac hypertrophy.
Figure 3: In vivo heart function as shown by pressure-volume relations in sham controls (Con), controls treated with 3 weeks of sildenafil (3-wk Sil) or 3 weeks of TAC with or without sildenafil, and mice with hypertrophy induced by 1 week of TAC and then sildenafil added for 2 additional weeks (3 wk TAC + delay Sil 2 wk).
Figure 4: Enhanced PDE5A activity with hypertrophy amplifies the effect of sildenaRl on PKG-1 and stress-response proteins.
Figure 5: PDE5A inhibition with sildenafil prevents neonatal rat cardiomyocyte hypertrophy by means of the calcineurin-NFAT–dependent pathway.
Figure 6: Inactivation of Akt pathway by PDE5A inhibition.

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Acknowledgements

We thank A. Rosenzweig for Akt transgenic mice; J. Molkentin for the calcineurin adenoviral vector and F. Baber for the NFAT-reporter adenoviral vectors; and G. Dorn II for the oligonucleotide probes. This study was supported in part by National Institute of Health Grants PO1-HL59408, HL-47511 and AG18324, the Peter Belfer Laboratory for Heart Failure Research. (D.A.K.); a Uehara Memorial Foundation Grant; an American Heart Association (Mid-Atlantic Affiliate) Fellowship Grant (E.T.); a Shih-Chun Wang Young Investigator Award; a Giles F. Filley Award of the American Physiological Society; and the Bernard Family Foundation (H.C.C.).

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Author notes

  1. Eiki Takimoto, Hunter C Champion and Manxiang Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Ross 835, 720 Rutland Avenue, Baltimore, 21205, Maryland, USA

    Eiki Takimoto, Hunter C Champion, Manxiang Li, Diego Belardi & David A Kass

  2. Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at UCLA, Room BH 569, CHS, 650 Charles E. Young Drive, Los Angeles, 90095, California, USA

    Shuxun Ren & Yibin Wang

  3. Department of Pathology, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    E Rene Rodriguez

  4. Division of Comparative Medicine, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Djahida Bedja & Kathleen L Gabrielson

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Supplementary information

Supplementary Fig. 1

Free plasma concentration dose response curve to oral sildenafil in mice. (PDF 67 kb)

Supplementary Fig. 2

Inhibition of PDE5A by EMD360527 prevents load-induced cardiac hypertrophy, improves cardiac function, and reverses fetal gene expression changes. (PDF 153 kb)

Supplementary Fig. 3

Adenoviral transfection efficiency in neonatal myocytes. (PDF 334 kb)

Supplementary Fig. 4

NFAT activation assessed in neonatal myocytes transfected with an adenovirus coupling the NFAT promoter coupled to luciferase. (PDF 63 kb)

Supplementary Table 1

Effect of sildenafil treatment on serial echocardiographic measurements of left ventricular structure and function in conscious mice. (PDF 85 kb)

Supplementary Table 2

Effect of sildenafil treatment with and without TAC on in vivo cardiac hemodynamics obtained by pressure-volume analysis. (PDF 88 kb)

Supplementary Table 3

Hemodynamic analysis of non-transgenic controls (NTG) and transgenics with cardiac-targeted Akt overexpression (AktTG). (PDF 14 kb)

Supplementary Methods (PDF 15 kb)

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Takimoto, E., Champion, H., Li, M. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11, 214–222 (2005). https://doi.org/10.1038/nm1175

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