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Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes

Nature Cell Biology volume 3, pages 867–873 (2001)Cite this article

Abstract

Stretching of cardiac muscle modulates contraction through the enhancement of the Ca2+ transient, but how this occurs is still not known. We found that stretching of myocytes modulates the elementary Ca2+ release process from ryanodine-receptor Ca2+-release channels (RyRCs), Ca2+ sparks and the electrically stimulated Ca2+ transient. Stretching induces PtdIns-3-OH kinase (PI(3)K)-dependent phosphorylation of both Akt and the endothelial isoform of nitric oxide synthase (NOS), nitric oxide (NO) production, and a proportionate increase in Ca2+-spark frequency that is abolished by inhibiting NOS and PI(3)K. Exogenously generated NO reversibly increases Ca2+-spark frequency without cell stretching. We propose that myocyte NO produced by activation of the PI(3)K–Akt–endothelial NOS axis acts as a second messenger of stretch by enhancing RyRC activity, contributing to myocardial contractile activation.

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Figure 1: Stretch modulation of Ca2+ release properties and NO in cardiac myocytes.
Figure 2: The stretch-mediated increase in both spontaneous Ca2+-spark frequency and stimulated-Ca2+ transient amplitude is simulated by exposure to an NO donor, but is not mediated by changes in Ca2+ loading in SR.
Figure 3: Comparison of the stretch dependence of Ca2+ release in wild-type and eNOS-deficient cardiac myocytes.
Figure 4: Stretch increases Akt and eNOS phosphorylation and Ca2+ spark frequency in a PI(3)K-dependent fashion.

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Acknowledgements

We thank E.G. Lakatta and H. Cheng for useful discussions, M.D. Stern for critical comments on the manuscript, and M. Juhaszova, H.A. Spurgeon, K. Tarasov and B.D. Ziman for technical support. This work was supported by the Intramural Research Program, National Institute on Aging (S.J.S.), and an Action de Recherche Concertée (French Community of Belgium) and the National Fund for Scientific Research (J.L.B.).

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Authors and Affiliations

  1. Laboratory of Cardiovascular Science, Gerontology Research Center, Intramural Research Program, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, 21224-6825, Maryland, USA

    Martín G. Vila Petroff, Suhn Hee Kim, Salvatore Pepe & Steven J. Sollott

  2. Department of Medicine, University of Louvain Medical School, Unit of Pharmacology and Therapeutics, UCL-FATH 5349, Avenue E. Mounier 53, Brussels, B-1200, Belgium

    Chantal Dessy & Jean-Luc Balligand

  3. Department of Medicine, Division of Cardiology, The Johns Hopkins Medical Institutions, 720 Rutland Avenue, 844 Ross Building, Baltimore, 21205, Maryland, USA

    Eduardo Marbán

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  1. Martín G. Vila Petroff
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Correspondence to Steven J. Sollott.

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Analysis of membrane distribution of caveolae and estimation of the spatial range of NO action (PDF 125 kb)

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Petroff, M., Kim, S., Pepe, S. et al. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol 3, 867–873 (2001). https://doi.org/10.1038/ncb1001-867

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