Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms

Lili A. Barouch, Robert W. Harrison, Michel W. Skaf, Gisele O. Rosas, Thomas P. Cappola, Zoulficar A. Kobeissi, Ion A. Hobai, Christopher A. Lemmon, Arthur L. Burnett, Brian O'Rourke, E. Rene Rodriguez, Paul L. Huang, João A. C. Lima, Dan E. Berkowitz and Joshua M. Hare ()
Additional contact information
Lili A. Barouch: The Johns Hopkins Medical Institutions
Robert W. Harrison: The Johns Hopkins Medical Institutions
Michel W. Skaf: The Johns Hopkins Medical Institutions
Gisele O. Rosas: The Johns Hopkins Medical Institutions
Thomas P. Cappola: The Johns Hopkins Medical Institutions
Zoulficar A. Kobeissi: The Johns Hopkins Medical Institutions
Ion A. Hobai: The Johns Hopkins Medical Institutions
Christopher A. Lemmon: The Johns Hopkins Medical Institutions
Arthur L. Burnett: The Johns Hopkins Medical Institutions
Brian O'Rourke: The Johns Hopkins Medical Institutions
E. Rene Rodriguez: The Johns Hopkins Medical Institutions
Paul L. Huang: Massachusetts General Hospital
João A. C. Lima: The Johns Hopkins Medical Institutions
Dan E. Berkowitz: The Johns Hopkins Medical Institutions
Joshua M. Hare: The Johns Hopkins Medical Institutions

Nature, 2002, vol. 416, issue 6878, 337-339

Abstract: 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.

Date: 2002
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DOI: 10.1038/416337a

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