Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms (original) (raw)

• Letter
• Published: 21 March 2002
• Robert W. Harrison1 na1,
• Michel W. Skaf1 na1,
• Gisele O. Rosas1,
• Thomas P. Cappola1,
• Zoulficar A. Kobeissi1,
• Ion A. Hobai1,
• Christopher A. Lemmon2,
• Arthur L. Burnett3,
• Brian O'Rourke1,
• E. Rene Rodriguez4,
• Paul L. Huang6,
• João A. C. Lima1,
• Dan E. Berkowitz2,5 na1 &
• …
• Joshua M. Hare1

Nature volume 416, pages 337–339 (2002)Cite this article

Abstract

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling1. In the heart, NO inhibits L-type Ca2+ channels2 but stimulates sarcoplasmic reticulum (SR) Ca2+ release3,4,5, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae6,7,8, where compartmentalization with β-adrenergic receptors and L-type Ca2+ channels9 allows NO to inhibit β-adrenergic-induced inotropy8,10. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR11. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro3, 4 suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both _NOS1_−/− and _NOS3_−/− mice develop age-related hypertrophy, although only _NOS3_−/− mice are hypertensive. _NOS1/3_−/− double knockout mice have suppressed β-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.

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Acknowledgements

This work was supported by grants from the NIH, the American Heart Association, and the American Federation for Aging Research.

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Author notes

1. Lili A. Barouch, Robert W. Harrison, Michel W. Skaf and Dan E. Berkowitz: These authors contributed equally to this work

Authors and Affiliations

1. Department of Medicine (Cardiology Division), The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, USA
   Lili A. Barouch, Robert W. Harrison, Michel W. Skaf, Gisele O. Rosas, Thomas P. Cappola, Zoulficar A. Kobeissi, Ion A. Hobai, Brian O'Rourke, João A. C. Lima & Joshua M. Hare
2. Department of Biomedical Engineering, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, USA
   Christopher A. Lemmon & Dan E. Berkowitz
3. Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, USA
   Arthur L. Burnett
4. Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, USA
   E. Rene Rodriguez
5. Department of Anaesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, USA
   Dan E. Berkowitz
6. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, 02129, Massachusetts, USA
   Paul L. Huang

Authors

1. Lili A. Barouch
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2. Robert W. Harrison
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3. Michel W. Skaf
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4. Gisele O. Rosas
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5. Thomas P. Cappola
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6. Zoulficar A. Kobeissi
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7. Ion A. Hobai
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8. Christopher A. Lemmon
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9. Arthur L. Burnett
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10. Brian O'Rourke
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11. E. Rene Rodriguez
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12. Paul L. Huang
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13. João A. C. Lima
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14. Dan E. Berkowitz
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15. Joshua M. Hare
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Correspondence toJoshua M. Hare.

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Barouch, L., Harrison, R., Skaf, M. et al. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms.Nature 416, 337–339 (2002). https://doi.org/10.1038/416337a

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• Received: 24 August 2001
• Accepted: 17 January 2002
• Issue Date: 21 March 2002
• DOI: https://doi.org/10.1038/416337a