title: Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms.
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 beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-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 beta-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.
authors.affiliation: Department of Medicine (Cardiology Division), The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
authors.forename: Robert W
authors.initials: RW
authors.lastname: Harrison
authors.forename: Michel W
authors.initials: MW
authors.lastname: Skaf
authors.forename: Gisele O
authors.initials: GO
authors.lastname: Rosas
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Zoulficar A
authors.initials: ZA
authors.lastname: Kobeissi
authors.forename: Ion A
authors.initials: IA
authors.lastname: Hobai
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lemmon
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Burnett
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.forename: E Rene
authors.initials: ER
authors.lastname: Rodriguez
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.forename: João A C
authors.initials: JA
authors.lastname: Lima
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D051244:Caveolin 3; D022461:Caveolins / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D016133:Polymerase Chain Reaction; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000318:Adrenergic beta-Agonists; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D007527:Isoenzymes; D018342:Receptors, Adrenergic, beta-1; D019837:Ryanodine Receptor Calcium Release Channel; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D007545:Isoproterenol; D002118:Calcium