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, Joshua M. Hare

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Abstract

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, 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 caveolae, where compartmentalization with β-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit β-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro 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.

Original languageEnglish (US)
Pages (from-to)337-340
Number of pages4
JournalNature
Volume416
Issue number6878
StatePublished - Mar 21 2002

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ASJC Scopus subject areas

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Cite this

Barouch, L. A., Harrison, R. W., Skaf, M. W., Rosas, G. O., Cappola, T. P., Kobeissi, Z. A., Hobai, I. A., Lemmon, C. A., Burnett, A. L., O'Rourke, B., Rodriguez, E. R., Huang, P. L., Lima, J. A. C., Berkowitz, D. E., & Hare, J. M. (2002). Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature, 416(6878), 337-340.