Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy

Cappola, Thomas P.; Cope, Leslie; Cernetich, Amy; Barouch, Lili A.; Minhas, Khalid M.; Irizarry, Rafael A.; Parmigiani, Giovanni; Durrani, Sarfraz; Lavoie, Tera; Hoffman, Eric P.; Ye, Shui Q.; Garcia, Joe G.N.; Hare, Joshua M.

doi:10.1152/physiolgenomics.00156.2002

Cited by 33 publications

(23 citation statements)

References 37 publications

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“…Interestingly, TTCCs were shown to regulate NO-cGMP-induced smooth muscle relaxation and contraction responsible for penile erection control (44). In its coupled state of activation, NOS3 signaling has been shown to be protective and anti-hypertrophic (45)(46)(47). Indeed, Nos3 -/-mice become hypertrophic with aging and show greater hypertrophy following pressure overload stimulation (45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

“…In its coupled state of activation, NOS3 signaling has been shown to be protective and anti-hypertrophic (45)(46)(47). Indeed, Nos3 -/-mice become hypertrophic with aging and show greater hypertrophy following pressure overload stimulation (45)(46)(47)(48). NOS3-overexpressing transgenic mice also showed less secondary hypertrophic remodeling after myocardial infarction (48).…”

Section: Discussionmentioning

confidence: 99%

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α1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice

Nakayama

Bódi²,

Correll³

et al. 2009

J. Clin. Invest.

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In noncontractile cells, increases in intracellular Ca 2+ concentration serve as a second messenger to signal proliferation, differentiation, metabolism, motility, and cell death. Many of these Ca 2+ -dependent regulatory processes operate in cardiomyocytes, although it remains unclear how Ca 2+ serves as a second messenger given the high Ca 2+ concentrations that control contraction. T-type Ca 2+ channels are reexpressed in adult ventricular myocytes during pathologic hypertrophy, although their physiologic function remains unknown. Here we generated cardiac-specific transgenic mice with inducible expression of α1G, which generates Ca v 3.1 current, to investigate whether this type of Ca 2+ influx mechanism regulates the cardiac hypertrophic response. Unexpectedly, α1G transgenic mice showed no cardiac pathology despite large increases in Ca 2+ influx, and they were even partially resistant to pressure overload-, isoproterenol-, and exercise-induced cardiac hypertrophy. Conversely, α1G -/-mice displayed enhanced hypertrophic responses following pressure overload or isoproterenol infusion. Enhanced hypertrophy and disease in α1G -/-mice was rescued with the α1G transgene, demonstrating a myocyte-autonomous requirement of α1G for protection. Mechanistically, α1G interacted with NOS3, which augmented cGMP-dependent protein kinase type I activity in α1G transgenic hearts after pressure overload. Further, the anti-hypertrophic effect of α1G overexpression was abrogated by a NOS3 inhibitor and by crossing the mice onto the Nos3 -/-background. Thus, cardiac α1G reexpression and its associated pool of T-type Ca 2+ antagonize cardiac hypertrophy through a NOS3-dependent signaling mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

α1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice

Nakayama

Bódi²,

Correll³

et al. 2009

J. Clin. Invest.

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“…There is substantial physiologic support obtained from studies in NOS deletion mice for the notion that NOS1 and NOS3 exert independent and, in some cases, opposite effects on cardiac contractility (22,33,34,(89)(90)(91) -actions that are well rationalized by the spatial localization of the NO-signaling module (Figure 1). Specifically, NOS3 exerts its effects on signal-transduction events occurring at the plasmalemmal membrane, inhibiting the L-type Ca 2+ channel and in turn attenuating β-adrenergic myocardial contractility (33,92,93).…”

Section: Cardiac No Signalingmentioning

confidence: 97%

NO/redox disequilibrium in the failing heart and cardiovascular system

Hare¹,

Stamler²

2005

J. Clin. Invest.

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151

155

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There is growing evidence that the altered production and/or spatiotemporal distribution of reactive oxygen and nitrogen species creates oxidative and/or nitrosative stresses in the failing heart and vascular tree, which contribute to the abnormal cardiac and vascular phenotypes that characterize the failing cardiovascular system. These derangements at the integrated system level can be interpreted at the cellular and molecular levels in terms of adverse effects on signaling elements in the heart, vasculature, and blood that subserve cardiac and vascular homeostasis. Cellular damage versus malfunction in signalingAltered cellular production of ROS and/or reactive nitrogen species (RNS) is a ubiquitous feature of human disease. Many years of study, beginning with the discovery of superoxide (1) and superoxide dismutase (2), provide a sound understanding of the diverse chemical mechanisms by which these agents damage lipids, DNA, and proteins, and a pathophysiologic context is imparted by analyses of diseased tissues, which show the chemical footprints of oxidative and nitrosative stress (3-6). Thus, it has been widely assumed that direct chemical (oxidative and nitrosative) injury is a principal factor in the damage or disruption of cellular and subcellular structure-function that typifies such pathologic situations. A major difficulty with this hypothesis, however, lies in understanding how the salient features of chemical injury, which are common across organ systems, underlie the diverse pathophysiology of chronic disease. Moreover, irreversible oxidative damage cannot be easily reconciled with the acute restoration of cardiovascular performance by certain classes of antioxidants (see ref. 7 for example). It thus remains unclear to what extent the damage caused by RNS and ROS contributes to disease pathogenesis.It was appreciated early on that NO and/or related congeners have a function in signal transduction, and over the past decade, the idea that additional redox-active species may have signaling roles has been strengthened (8-13). Although the molecular mechanisms by which RNS and ROS modulate cellular signal transduction remain incompletely understood, there is a general consensus that cysteine residues are principal sites of redox regulation (10,13,14). Crosstalk between ROS-and RNS-regulated pathways may occur at both the chemical interaction level (15, 16) and through their coordinate effects on target proteins (17, 18); this is reflected in a growing awareness that RNS and ROS may subserve conjoint signaling roles. Analysis of several such examples (17)(18)(19)(20)(21)(22) has shown that S-nitrosylation (the covalent attachment of NO to cysteine thiol) may play a primary effector role while oxygen and other ROS may control the responsivity to S-nitrosylation (much as ROS control the strength of phosphorylation signaling by inhibiting phosphatases; ref. 11). This article addresses the physiologic and pathophysiologic consequences of the interplay between ROS and RNS in the cardiovascular system (Figure...

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“…To compare the levels of XOR mRNA, we performed quantitative PCR on hearts from WT (n ϭ 3), NOS3 Ϫ/Ϫ (n ϭ 3), and NOS1 Ϫ/Ϫ (n ϭ 3) mice (2-3 months old). Total RNA was isolated, cDNA was synthesized, and each sample was run in duplicate on a GeneAmp 7900 Sequence Detection System (PE Applied Biosystems, Foster City, CA) and was analyzed by using SDS 2.0 software (Applied Biosystems) as described (14,15 Isolated Myocyte Preparation. Myocytes were isolated and prepared from 2-month-old mouse hearts as described in detail by Khan et al (13).…”

Section: Immunoprecipitation and Western Blotsmentioning

confidence: 99%

Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling

Khan

Lee

Minhas

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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215

206

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Although interactions between superoxide (O 2•؊ ) and nitric oxide underlie many physiologic and pathophysiologic processes, regulation of this crosstalk at the enzymatic level is poorly understood. Here, we demonstrate that xanthine oxidoreductase (XOR), a prototypic superoxide O 2•؊ -producing enzyme, and neuronal nitric oxide synthase (NOS1) coimmunoprecipitate and colocalize in the sarcoplasmic reticulum of cardiac myocytes. Deficiency of NOS1 (but not endothelial NOS, NOS3) leads to profound increases in XOR-mediated O 2•؊ production, which in turn depresses myocardial excitation-contraction coupling in a manner reversible by XOR inhibition with allopurinol. These data demonstrate a unique interaction between a nitric oxide and an O 2•؊ -generating enzyme that accounts for crosstalk between these signaling pathways; these findings demonstrate a direct antioxidant mechanism for NOS1 and have pathophysiologic implications for the growing number of disease states in which increased XOR activity plays a role.

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Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy

Cited by 33 publications

References 37 publications

α1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice

α1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice

NO/redox disequilibrium in the failing heart and cardiovascular system

Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling

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