© 1997 American Heart Association, Inc.
Articles |
Nitric Oxide Synthases and Cardiac Muscle
Autocrine and Paracrine Influences
From the Department of Medicine, Pharmacology Unit, FATH 53.49, University of Louvain Medical School, Brussels, Belgium (J.-L.B.), and the Department of Medicine, Division of Cardiology, Columbia University College of Physicians and Surgeons, New York, NY (P.J.C.)
Correspondence to Paul J. Cannon, the Department of Medicine, Division of Cardiology, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032. E-mail pjc4{at}columbia.edu
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Abstract |
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 Top Abstract IntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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Abstract The different cell types comprising cardiac muscle express one or more of the three isoforms (neuronal NOS, or nNOS; inducible NOS, or iNOS; and endothelial NOS, or eNOS) of nitric oxide synthase (NOS). nNOS is expressed in orthosympathetic nerve terminals and regulates the release of catecholamines in the heart. eNOS constitutively expressed in endothelial cells inhibits contractile tone and the proliferation of underlying vascular smooth muscle cells, inhibits platelet aggregation and monocyte adhesion, promotes diastolic relaxation, and decreases O2 consumption in cardiac muscle through paracrinally produced NO. eNOS is also constitutively expressed in cardiac myocytes from rodent and human species, where it autocrinally opposes the inotropic action of catecholamines after muscarinic cholinergic and ß-adrenergic receptor stimulation. iNOS gene transcription and protein expression are induced in all cell types after exposure to a variety of inflammatory cytokines. Aside from participating in the immune defense against intracellular microorganisms and viruses, the large amounts of NO produced autocrinally or paracrinally mediate the vasoplegia and myocardial depression characteristic of systemic immune stimulation and promote cell death through apoptosis. In cardiac myocytes, NO may regulate L-type calcium current and contraction through activation of cGMP-dependent protein kinase and cGMP-modulated phosphodiesterases. Other mechanisms independent of cGMP elevations may operate through interaction of NO with heme proteins, non-heme iron, or free thiol residues on target signaling proteins, enzymes, or ion channels. Given the multiplicity of NOS isoforms expressed in cardiac muscle and of the potential molecular targets for the NO produced, tight molecular regulation of NOS expression and activity at the transcriptional and posttranscriptional level appear to be needed to coordinate the many roles of NO in heart function in health and disease.
Key Words: nitric oxide synthases • cardiac muscle • cytokines • heart failure
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Introduction |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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The nomination of nitric oxide (NO) as Science's "Molecule of the Year 1992" was a consecration for a seemingly common gas otherwise known as a component of cigarette smoke and an atmospheric pollutant. It was justified, however, by the discovery of the key signaling roles of NO in as diverse physiological functions as neurotransmission in the peripheral and central nervous systems, immune defense against microorganisms, and modulation of vascular tone.1 2 3 4
Aside from the well defined role of NO (and its derivatives) as an endothelium-derived relaxant of underlying vascular smooth muscle, much interest has recently been focused on the role of endogenous NO pathways as paracrine or autocrine regulators of cardiac muscle function. After a brief description of the biochemistry and molecular regulation of the three isoforms of nitric oxide synthase (NOS) and the general features of NO reactivity relevant to its physiological effects, we review the evidence on the role of NO produced by endothelial NOS (eNOS) or inducible NOS (iNOS) in regulating cardiac muscle function. We end with a brief review of the mechanisms by which NO regulates cardiac cell contraction.
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NOS |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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The three NOS isoforms originally identified in the brain (neuronal NOS, or nNOS),5 macrophages (inducible NOS, or iNOS),6 7 and endothelial cells (endothelial NOS, or eNOS)8 9 10 share 50% to 60% homology of their amino acid sequence and are encoded by three different genes (designated NOS 1, NOS 2, and NOS 3, respectively). All three isoforms combine two functionally complementary portions, a carboxyl-terminal reductase domain homologous to cytochrome P450 reductase and an amino-terminal oxygenase domain containing binding sites for heme, L-arginine, and tetrahydrobiopterin (THB4), the two portions being connected by a calmodulin-binding domain in the middle. In addition, on activation, the three isoforms presumably function as homodimers. Within each monomer, electrons provided by NADPH are transferred from the flavins (FAD or FMN) in the carboxyl-terminal portion of the molecule to heme iron, which is activated to bind O2 and, in the presence of the substrate L-arginine, to catalyze the synthesis of NO and L-citrulline. The binding of calmodulin appears to be required to enable electron transfer from the flavin prosthetic groups to heme.11 12 13 In nNOS and eNOS, physiological concentrations of calcium regulate calmodulin binding to its specific domain and the flow of electrons to heme; in iNOS, calmodulin is tightly bound even at low concentrations of intracellular calcium.11 12 In addition to the binding of calmodulin, activation of all three NOSs requires THB4, which appears to enable electron transport by stabilizing the homodimeric conformation of the enzymes.14 15 16 17 Subunit dimerization of nNOS and the binding of THB4 also appear to be dependent on the presence of the heme prosthetic group.18 During NO synthesis, L-arginine is first hydroxylated to the intermediate N-hydroxyl-L-arginine, which then undergoes further oxidation to yield NO and L-citrulline. If the substrate L-arginine is unavailable in sufficient amounts, the electron transfer after oxidation of NADPH in nNOS and eNOS is to oxygen, leading to formation of superoxide anions and H2O2.19 20 21 22 In the nNOS and iNOS isoforms, there is evidence that NO may exert negative feedback on NO synthesis by forming ferrous nitrosyl complexes in their heme prosthetic groups, which partially self-inactivate the enzymes.23 24 25 26 In activated macrophages, NO can inhibit iNOS activity by reducing heme availability and its insertion into monomers, thus blocking the dimerization required for enzyme activity.27 A 10-kDa protein that interacts with nNOS and inhibits its activity, designated PIN, has recently been identified; it binds to nNOS and destabilizes the dimer conformation necessary for activity.28
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nNOS |
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The gene coding for nNOS, NOS 1, is located on human chromosome 12. Twenty-nine exons encode various alternatively spliced mRNAs that are differentially expressed among various tissues, which are translated into proteins of
160 kDa.5 29 The amino
acid sequences are highly conserved between species, with 93% identity
at the amino acid level between rats and humans. The use of at least
eight different exon 1's, each under the control of a distinct
5'-flanking region, contributes to the tissue and developmental stage
heterogeneity of generated cDNAs.30 In
skeletal muscle, nNOS contains 34 additional amino acids compared with
the cerebellar protein, owing to a 102-bp segment alternatively spliced
between exons 16 and 17. This isoform, termed nNOSµ, is detected only
in differentiated striated muscle.31 nNOS protein is
expressed in neurons and epithelial cells but not in isolated cardiac
myocytes (at least in the rat species). nNOS is expressed in
cholinergic and nonadrenergic, noncholinergic nerve
terminals, in specialized conduction tissue in the
heart32 33 , and in sympathetic nerve terminals, where it
has been postulated to play a role in catecholamine release
and reuptake.34 35 nNOS phosphorylation by
a variety of protein kinases
(calcium/calmodulin–dependent, cAMP-dependent, and
cGMP-dependent protein kinases and protein kinase C [PKC]) results in
diminished enzyme activity, at least in vitro.36 37
Dephosphorylation of nNOS by calcineurin produces the
opposite effect.38 |
iNOS |
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The gene encoding iNOS, NOS 2, is located on human chromosome 17 and contains 26 exons.39 The cDNA encodes a protein of 130 kDa that in the mouse (and partially in humans) tightly binds calmodulin even when intracellular calcium levels are low.39 40 41 42 NOS 2 was first cloned and characterized in macrophages,6 7 but iNOS activity has been detected in a variety of cell types, including endocardial and endothelial cells, vascular smooth muscle cells, fibroblasts, and neonatal and adult cardiac myocytes from several species.43 44 45 46 47 48 iNOS expression is induced by a wide variety of agents, including endotoxin (lipopolysaccharide [LPS]), interleukin (IL)-1ß, tumor necrosis factor (TNF)-
, interferon
(IFN)-
, and IL 6, reflecting the complexity of and differences in
the regulatory elements in the NOS 2 promoter in both murine
and human species.42 49 50 In the 5'-flanking region of
the NOS 2 gene in both mice and humans, multiple consensus
sequences for the binding of transcription factors that mediate
responsiveness to cytokines have been identified, including
those for nuclear factor (NF)-
B, IFN-, NF-1, IL-6, and interferon
regulatory factor (IRF)-1 (which appears to be critical for iNOS
expression in murine macrophages).42 49 51 52 53 Even
within the same rodent species, exposure to the same stimuli results in
differential expression of iNOS transcripts among various cell types,
reflecting the accessibility of the NOS 2 promoter to a
variety of transcription factors generated by cell-specific signaling
pathways. For example, IFN- stimulates iNOS mRNA accumulation in
cardiac myocytes but not in microvascular endothelial
cells from adult rat hearts.54 55 56 In both of the latter
two cell types, IFN-–induced signal transducer and activator of
transcription-1 (STAT-1) phosphorylation was
apparent, but induction of iNOS mRNA expression occurred in myocytes
only. In the myocytes, induction of iNOS by IFN- was blocked by
benzodiazepine peptidomimetic (BZA 5B), an agent that blocked
activation of the 44- and 42-kDa mitogen–activated protein
kinases (MAPKs; ERK1/ERK2). In microvascular
endothelial cells, treatment with the phosphatase
inhibitor okadaic acid in the absence of cytokines
activated ERK2 and induced accumulation of iNOS
transcripts.56 These results suggested that activation of
ERK1/ERK2 was required for induction of iNOS by cytokines in
both cell types and that in microvascular endothelial
cells, phosphorylation of STAT-1 is necessary, but
is not in itself sufficient for NOS 2 gene expression.
Many factors appear to be involved in the complex regulation of iNOS
induction in response to cytokines.57 58 Among
these, activation of angiotensin II59 and
-adrenergic receptors,60 activation of PKC
isoforms,61 and increases in cAMP62 63 all
promote iNOS expression in cardiac myocytes, where the effects of cAMP
have been shown to involve increases in iNOS mRNA
stability.62 Conversely, when iNOS has been induced by
cytokines in cardiac myocytes, the generation of cAMP in
response to ß-adrenergic agonists is blunted in these
cells.64 Transforming growth factor (TGF)-ß, which
stimulates iNOS expression in 3T3 fibroblasts,65
diminishes iNOS expression in response to cytokines in
microvascular endothelial cells, cardiac myocytes, and
vascular smooth muscle cells.44 45 54 66 67 68 In the
latter cells, inhibition involves regions in the promoter/enhancer
region of NOS 2 other than the NF-B site.69
Salicylate or aspirin suppress iNOS induction and activity in cardiac
fibroblasts in vitro,70 and glucocorticoids suppress iNOS
induction by cytokines in microvascular
endothelial cells and cardiac myocytes, in part by
increasing expression of the matrix phosphoprotein osteopontin, which
acts to decrease iNOS expression.71
The availability of cofactors and substrate also influences iNOS expression and NO biosynthesis. Cytokine induction of iNOS in macrophages, microvascular endothelial cells, and cardiac myocytes is accompanied by coinduction of GTP cyclohydrolase, the key enzyme for de novo biosynthesis of THB4 (the induction of which can also be downregulated by dexamethasone).54 72 In addition to stabilizing iNOS mRNA,73 THB4 can limit the rate of NO synthesis, presumably through its role, along with heme and L-arginine, in stabilizing the iNOS dimers required for full enzyme activity (see above).74 In wounds it has been demonstrated that the concentration of L-arginine can also be rate limiting for NO synthesis by macrophage iNOS.75 76 Cytokine treatment of macrophages, microvascular endothelial cells, or cardiac myocytes results in the coinduction of iNOS and the cationic amino acid transporter proteins CAT1, CAT2B (both high affinity), and CAT2A (low affinity), which increase intracellular substrate availability.77 When the intracellular level of L-arginine is reduced by competitively inhibiting its transport with the amino acid L-lysine or, in macrophages, by multivalent guanylhydrazone CNI 1493, nitrite release is significantly reduced from these cells.78
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eNOS |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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The human gene encoding eNOS, NOS 3, is located on human chromosome 7.79 80 NOS 3 comprises 26 exons and its cDNA, first characterized in bovine aortic endothelial cells,8 9 10 encodes a 135-kDa enzyme protein that is activated by increases in intracellular calcium. eNOS has been shown to be constitutively expressed in endocardial cells; endothelial cells of arteries, veins, and capillaries; kidney epithelial cells; hippocampal pyramidal neurons; skeletal myocytes; and cardiac sinoatrial, atrioventricular nodal, and ventricular myocytes from rodent species.4 81 82 83 84 85 86 In addition, there is unequivocal evidence for eNOS expression in atrial and ventricular myocytes from human hearts.81 87 88 The promoter region of the NOS 3 gene contains several cis-regulatory sequences, including AP-1, AP-2, NF-1, cAMP, Sp-1, and GATA response elements, the latter two being critical for basal promoter activity in large-vessel endothelial cells.89 90 In addition, shear stress–and sterol-responsive elements are probably involved in the upregulation of eNOS in endothelial cells in response to shear stress, exercise, and estradiol.9 10 80 91 NOS 3 transcription has also been reported to increase in response to lysophosphatidylcholine and oxidized LDL.92 93 In cardiac myocytes from adult rats, treatment with cytokines such as IFN-
and IL-1ß is associated with decreased eNOS
transcripts by a mechanism that is currently undefined.81
In endothelial cells from large vessels, TNF-
destabilizes eNOS mRNA.94 In studies of rat cardiac
myocytes in vitro and in vivo, interventions that increased cAMP, such
as administration of forskolin, milrinone, or 8-bromo-cAMP, were
associated with reductions in eNOS mRNA and protein, which appeared to
involve a transcriptional mechanism because eNOS mRNA half-life was
unchanged.95 This effect of cAMP appeared to be cell type
specific, since it did not occur in microvascular
endothelial cells from the same hearts. eNOS undergoes significant posttranslational modifications. In both endothelial cells and cardiomyocytes, the enzyme is mainly associated with membrane fractions, where it is both myristoylated and palmitoylated.81 96 97 98 Mutation of the N-myristoylation site converts eNOS from a membrane-associated to a cytosolic protein.96 97 Bradykinin promoted the depalmitoylation of eNOS and its translocation to the cytosol in one study98 but not in another.99 Recombinant eNOS can also be phosphorylated by PKC, PKA, and calmodulin kinase 2.100 However, these in vitro phosphorylations differ from the phosphorylation pattern induced by bradykinin in intact endothelial cells, which accompanies translocation of the enzyme from the particulate to cytosolic fractions.100
Recently it was discovered that palmitoylated and myristoylated eNOS in both endothelial cells and cardiac myocytes is localized to caveolae and the detergent-insoluble glycosphingolipid–rich microdomains in the plasmalemma.101 102 Caveolae and these microdomains facilitate the transport of molecules across cells and are sites where G proteins and other molecules involved in signal transduction are compartmentalized.103 104 Caveolins, the principal structural proteins of caveolae, may cycle between plasma membranes and the Golgi apparatus, where eNOS has also been localized in endothelial cells.105 106 107 Recent data indicate that eNOS is coimmunoprecipitated with caveolin 1 in extracts of microvascular endothelial cells and with the myocyte-specific isoform caveolin 3 in extracts of cardiac myocytes.108 The relationship between the intracellular compartmentalization of eNOS and its enzyme activity in both endothelial and heart muscle cells awaits further study.
NO synthesis by eNOS in endothelial cells is transiently increased by agonists such as bradykinin and substance P, which promote increases in intracellular calcium after interaction with their receptors; bradykinin may also act through increases in intracellular pH.109 110 NO synthesis by eNOS in response to shear stress is more sustained, persists independently of calcium transients, and involves tyrosine phosphorylation and interactions with other molecules in caveolae of the plasmalemmma.109 111 112 Endothelial cell calcium transients and presumably NO synthesis are also stimulated by other deformations of the cell, such as tapping, stretching, or compression.113 114 115 The complex calcium-independent molecular mechanisms responsible for sustained NO production by eNOS in response to shear stress are currently under active investigation in many laboratories. In cardiac myocytes, eNOS is also activated by increases in beating rate116 117 and hypoxia.118
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Molecular Targets of NO |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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Knowledge concerning the molecular targets of NO continues to expand rapidly (the Table). NO diffuses rapidly and isotropically through cell membranes in most tissues. The concentration of NO within a cell may be equated to the sum of the NO synthesized in that cell plus the NO synthesized by nearby cells that enters by diffusion. Biological effects of NO are likely to be modulated in different microenvironments by (1) the amount of NO produced (eg, synthesis of NO by high-output iNOS tends to be greater and more prolonged than by eNOS), (2) the number and variety of available molecular targets within diffusion distance from the source of NO synthesis, along with their relative reaction rates with NO; and (3) the net redox state that prevails. Among the predominant targets of NO are heme proteins, particularly the heme moiety of soluble guanylyl cyclase, which undergoes conformational change on interaction with NO that leads to enzyme activation and increased synthesis of cGMP.119 This cyclic nucleotide in turn mediates the activation of PKG and other kinases, followed by phosphorylation of several target regulatory proteins, modulation of ion channel function, and physiological responses.1 119 NO is trapped and inactivated by interaction with heme moieties in oxyhemoglobin and myoglobin.120 The prostaglandin- and thromboxane- forming activity of heme-containing cyclooxygenase 2 is enhanced by NO,121 122 whereas the enzymatic activity of heme-containing NOS is inhibited (see above). NO also binds to non–heme iron, particularly iron-sulfur complexes in enzymes such as cis-aconitase, NADH succinate oxidoreductase, NADH ubiquinone oxidoreductase (mitochondrial complexes I and II), and cytochrome c oxidase (complex IV).2 123 124 NO can inhibit DNA synthesis by binding the non–heme iron of ribonucleotide reductase.125 126
Other major targets of NO reactivity are reduced thiol residues on most intracellular, membrane-associated, or plasma proteins, such as albumin or tissue plasminogen activator.120 127 128 Recently, hemoglobin itself has been shown to be nitrosylated at sites protected from scavenging by heme, which would allow allosterically controlled exchange of NO to other acceptors and export of NO-related vasoactive molecules (presumably S-nitrosothiols) from erythrocytes to regulate vasomotor tone and oxygen delivery to peripheral tissues.129 Nitrosylation of other proteins may also affect their function positively or negatively, such as inactivation of the NMDA receptor120 127 130 or activation of the calcium-activated potassium channel.131 NO stimulates the auto–ADP-ribosylation of GAPDH, which in addition to interactions at the active site of the enzyme, may result in inhibition of glycolysis.132 133 134 By forming S-nitrosoglutathione, NO can deplete intracellular stores of reduced glutathione, resulting in activation of the hexose monophosphate shunt.135 NO can also directly inhibit NADPH oxidase.136
NO also interacts with oxygen radicals. Interaction with superoxide leads to formation of peroxynitrite (ONOO-), which in low concentrations can release NO but at high concentrations is a potent oxidant that can oxidize lipids, directly nitrate tyrosine residues on proteins, and decompose to toxic hydroxyl radicals.137 138 Nitration of actin and/or other cytoskeletal proteins in cardiovascular cells by peroxynitrite can alter their structure and may have deleterious effects on the function of contractile myofilaments.138 139 140 NO (or a redox-related derivative, such as peroxynitrite) interacts with proteins involved in iron metabolism, liberating iron from cytosolic aconitase141 and allowing interaction of apo-aconitase (or iron response–element binding protein [IRE-BP]) with target sequences in the 5'-untranslated region of ferritin mRNA to inhibit its translation. Binding of the IRE-BP to the 3'-end of transferrin receptor mRNA stabilizes the mRNA and results in increased synthesis of the corresponding protein.142 143 144 Peroxynitrite inactivates the mitochondrial aconitase involved in the tricarboxylic acid cycle.145 NO in large amounts can also promote DNA strand breaks, which can initiate apoptosis or activate poly-ADP ribose synthetase, leading to depletion of cell energy stores and cell death of neurons146 147 148 or suppression of contractile activity, at least in vascular smooth muscle.149
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Biological Effects of Endothelial and Endocardial eNOS |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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Paracrine and autocrine influences of NO on various cell types composing cardiac muscle are summarized in Figs 1
and 2. NO
inhibits both platelet adhesion to endothelial
cells and platelet aggregation (see Fig 1; see also References 150
and 151150 151 ). NO also reduces monocyte adhesion to the
endothelium and expression of monocyte chemoattractant
protein (MCP)-1, which has been implicated in early monocyte
recruitment during atherogenesis.152 153 154 155 NO reduces both
the activation of NF-B and the induction in
endothelial cells of the leukocyte (vascular cell)
adhesion molecule (VCAM)-1 by cytokines and by oxidized
LDL.156 157 158 159 NO also inhibits migration160 and
proliferation of vascular smooth muscle cells in vitro.161
In experiments in which eNOS cDNA was transfected into rat carotid
arteries, there were significant reductions in neointimal
hyperplasia after balloon injury.162
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NO synthesized by eNOS in endocardial163 and endothelial cells in response to bradykinin and substance P has been shown to have paracrine effects in ferret papillary muscles and in isolated guinea pig hearts; endogenous and exogenous NO accelerated diastolic ventricular relaxation without significant effects on the rate of systolic force development.164 165 Similar results were obtained in patients after intracoronary infusions of substance P to stimulate endothelial cell eNOS activity and paracrine NO production.166 Studies in isolated, perfused rat hearts equipped with a porphyrinic microsensor to measure NO in myocardial tissue indicated that NO release occurred in diastole during each cardiac contraction, was increased by increases in preload, and was stimulated by factors that increased myocardial compression, such as increases in end-diastolic volume or transmural pressure.167 Because isolated endocardial and endothelial cells can increase NO synthesis in response to external force and because cardiac NO synthesis in response to applied force declined when cardiac endothelial cells were denuded with Triton X-100, the investigators attributed the source of NO synthesis induced by mechanical forces in the hearts to intramyocardial endothelial cells.167 In settings of increased heart rate and coronary flow (such as exercise), it has been suggested that the lusitropic effect of endothelium-derived NO may benefit both subendocardial coronary perfusion and diastolic ventricular filling.168 The paracrine effect of endothelium-derived NO on cardiac myocyte function was directly demonstrated in vitro by another group of investigators who used bradykinin to stimulate NO synthesis by endothelial cells in coculture with isolated guinea pig cardiac myocytes (which lack bradykinin receptors) and observed a decrease in contractility of the myocytes in response to bradykinin that was reversed by NOS inhibitors or NO scavengers, such as hemoglobin and methylene blue.169
Additional evidence for paracrine effects of microvascular endothelial cell NO on adjacent myocardial cells was provided by investigators who measured oxygen consumption of isolated segments of canine myocardium with an oxygen electrode.170 Incubation of the segments with NO-donor drugs, bradykinin, or the muscarinic agonist carbachol was associated with significant reductions in oxygen consumption of the myocardial segments. The effects of the latter two agonists were abrogated by an inhibitor of NO synthesis. Because the investigators were unable to detect NO formation by isolated canine cardiac myocytes, they suggested that microvascular endothelial NO synthesis may exert a negative influence on mitochondrial respiration (and potentially, energy formation) in adjacent heart muscle cells.170 In myocardial segments from dogs with pacing-induced heart failure (which had higher than control rates of myocardial oxygen consumption), bradykinin and carbachol did not exert similar depressant effects on myocardial oxygen consumption.170
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Biological Effects of Myocardial eNOS |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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Aside from endocardial and endothelial cell–derived NO, evidence has been provided for a functional effect of NO produced by eNOS expressed in cardiac myocytes themselves (Fig 1
).
In studies of papillary muscles and of isolated cardiac myocytes from
rats, increases in NO production were observed at higher
electrical stimulation frequencies in association with declines in the
positive amplitude of the contraction frequency
response.116 117 The declines in amplitude of contraction
at higher frequencies were reversed by administration of NOS
inhibitors or methylene blue and could be mimicked with
NO-donor drugs or 8-bromo-cGMP.116 In early studies of isolated adult rat cardiac myocytes, it was observed that inhibition of endogenous eNOS activity did not affect baseline contractile shortening but did potentiate the contractile response to submaximal concentrations of the ß-adrenergic agonist isoproterenol.171 This suggested that the agonist-regulated production of NO could act as a physiological counterregulator to limit the positive inotropic effect of adrenergic agonists. Similar results were obtained in dogs and in humans with heart failure (where eNOS has been identified in cardiac myocytes by immunohistochemistry; see above), in which myocardial NOS inhibition resulted in potentiation of the contractile responses to isoproterenol and dobutamine.172 173
In studies of isolated ventricular myocytes from neonatal rats, the negative chronotropic effect of muscarinic cholinergic agonists was abrogated by NOS inhibition.171 By contrast, the effects of muscarinic cholinergic activation were not mediated by NO in isolated ventricular myocytes from the guinea pig174 and atrial myocytes from the frog,175 which do not appear to express any constitutive NOS activity. NOS inhibitors abolished the muscarnic cholinergic attenuation of isoproterenol-stimulated increases in L-type calcium current intensity and amplitude of contraction (the classic "accentuated antagonism") in specialized atrioventricular conduction cells and ventricular myocytes from adult rabbits and rats, respectively, all of which were shown to express eNOS.81 85 More important, experiments using intracoronary infusions of NOS inhibitors in open-chest dogs were also consistent with the interpretation that NO synthesis mediated the antagonistic effect of parasympathetic stimulation on the contractile responses elicited by dobutamine or isoproterenol.176 Additional work indicated that sustained increases in cAMP induced within rat ventricular myocytes in vitro or achieved in vivo by administration of milrinone, the type 3 phosphodiesterase inhibitor, were accompanied by downregulation of eNOS mRNA, protein, and enzyme activity; these changes were accompanied by an increase in contractile responsiveness to ß-adrenergic agonists and a reduction in responsiveness to muscarinic cholinergic agonists.95 The fact that downregulation of eNOS as mentioned above was only observed in cardiac myocytes and not in endothelial cells from the same hearts has the advantage of allowing the potentiation of adrenergic contractile responsiveness while maintaining the physiological regulation of coronary vascular tone through endothelium-derived NO. It will be of interest if future studies correlate cAMP-induced decreases in eNOS-dependent muscarinic signaling of isolated cardiac myocytes with the known alterations of the parasympathetic regulation of heart function in pathophysiological situations, such as heart failure, where the hyperadrenergic drive would be expected to increase intracellular cAMP.
As discussed previously, cytokines can also induce
NO-independent177 and NO-dependent178 effects
on myocardial contractility that are unrelated to iNOS
gene expression. In studies of papillary muscles, one group of
investigators observed negative inotropic effects of recombinant
TNF-, IL-2, and IL-6, which occurred within minutes (before possible
induction of iNOS) and were reversed by
L-N-monomethyl-arginine (L-NMMA), an
NOS inhibitor.178 The mechanism of these
apparently NO-mediated effects is not known but may involve activation
by cytokines of a constitutively expressed NOS (probably eNOS)
within cardiac muscle.178 NO-independent effects of
TNF- to activate the neutral sphingomyelinase pathway may
also contribute to its negative inotropic effects.179
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Biological Roles of NO Produced by iNOS: Paracrine and Autocrine Effects |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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In cardiac inflammation such as viral myocarditis, myocardial infarction, and cardiac allograft rejection, iNOS has been identified in endothelial cells, vascular smooth muscle cells, infiltrating macrophages and lymphocytes, and cardiac myocytes180 181 182 (Fig 2
). When rat coronary
microvascular endothelial cells were treated with
IL-1ß, iNOS mRNA, protein, and enzyme activity were
induced.55 67 When freshly isolated rat cardiac myocytes
were added to cultured IL-1ß–treated microvascular
endothelial cells and studied by videomicroscopy, the
basal contractile function of the myocytes was not affected; however,
the contractile response to isoproterenol was reduced, and this
reduction was reversed by NOS inhibition.67 Thus,
activation of endothelial cell iNOS by
cytokines can depress contractile responsiveness of adjacent
cardiac myocytes. Depressed contractile responses of heart muscle have
also been observed in pathological settings such as myocardial
infarction and allograft rejection, when there is abundant expression
of iNOS in macrophages infiltrating the myocardium
and, to a lesser extent, in cardiac myocytes.180 182 183
In addition, exposure of isolated paced adult rat cardiac myocytes to
media from LPS-conditioned activated macrophages
produced attenuation of the inotropic response to isoproterenol, which
was abrogated by an NOS inhibitor.46
Subsequent studies indicated that this effect of the conditioned media
was due to induction of iNOS in the cardiac myocytes
themselves.54
Impaired cardiac contraction is a known complication of the hypotensive
syndrome associated with Gram-negative sepsis and can be observed in
the absence of significant myocyte necrosis (for a review, see
Reference 184184 ). LPS was shown to induce iNOS activity and impair
contraction in guinea pig hearts, an effect that was confirmed in
isolated myocytes from the same animals.185 Several other
groups of investigators found that treatment with LPS or
cytokines such as TNF-, IFN-, and IL-1ß induced iNOS
mRNA, protein, and NO synthesis in rat cardiac
myocytes44 45 54 180 and that induction of NOS
2 was associated with diminished inotropic responsiveness to
ß-adrenergic agonists.46 54 In isolated, perfused,
working rat hearts, administration of IL-1ß and TNF- was
associated with a decline in contractile function that was partially
ameliorated by treatment with an NOS
inhibitor.186 A similar improvement of left
ventricular contractile function187 or overall
survival188 has been observed after NOS inhibition in
endotoxemia.
The induction by cytokines of high-output NO synthesis by iNOS
in macrophages and other cells and the constitutive expression
of iNOS in bronchial and intestinal mucosa are observations that are
consistent with a role for this enzyme in natural immunity to
infection by viral, mycobacterial, and parasitic
pathogens.2 3 Evidence for such a protective role for iNOS
in the heart has been provided by studies of NOS 2–knockout
mice that succumbed more rapidly to infection or
endotoxin.189 190 However, in some pathologic settings
such as myocardial infarction or cardiac allograft rejection, NO
production by iNOS may be deleterious and associated with
contractile dysfunction and death of cardiac
myocytes.140 180 182 191 192 Electron paramagnetic spin
resonance (EPR) spectra that were consistent with NO
interaction with iron-sulfur clusters in heart cells were observed in
rejecting rat cardiac allografts.193 Treatment of rat
cardiac allografts with the partially selective inhibitor
of iNOS, aminoguanidine, was associated with improved contractile
performance of papillary muscles, prolonged allograft survival,
and milder histopathology.183 Induction of iNOS by LPS and
IFN- in macrophages cocultured with adult rat cardiac
myocytes was associated with increased myocyte death (assessed by
creatine kinase release and trypan blue exclusion) that was partially
reversed by NOS inhibition.194 Similarly, induction of
iNOS by TNF-, IL-1ß, and IFN- in isolated, purified, adult rat
cardiac myocytes was associated with an NO-dependent increase in cell
death.194
Other studies have indicated that NO donors can trigger
apoptosis in macrophages, vascular smooth muscle cells,
and in preliminary experiments, in cardiac
myocytes.195 196 197 198 199 Studies in vivo have shown that
apoptosis of macrophages and cardiac myocytes occurs in
parallel with iNOS induction in experimental models of cardiac
allograft rejection and myocardial infarction and in
endomyocardial biopsies from rejecting human
hearts.140 182 200 The available data are
consistent with the concept that in some settings, NO produced
by iNOS may diminish cardiac function by increasing cell death,
possibly by triggering apoptosis. Immunohistochemical evidence
for nitrated tyrosine residues on cardiac myocyte cell membranes in
these settings suggests that peroxynitrite formed from the interaction
of NO and superoxide, along with hydroxyl breakdown products, may
also contribute to cell damage in these settings.138 140
Of interest, high circulating levels of cytokines such as
TNF- 201 have been observed in patients with heart
failure, and iNOS activity202 203 as well as iNOS and
TNF- proteins localized by
immunohistochemistry190 191 204 have been demonstrated in
sections of myocardium from patients with dilated
cardiomyopathy. These associations and the
observation of apoptotic myocytes in the human failing
myocardium205 all concur to suggest but do not
prove a role for iNOS in the pathogenesis of these clinical
syndromes.
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Mechanisms by Which NO Regulates Cardiac Function |
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TopAbstractIntroductionNOSnNOSiNOSeNOSMolecular Targets of NOBiological Effects of...Biological Effects of Myocardial...Biological Roles of NO...Mechanisms by Which NO...References |
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The molecular mechanisms by which NO influences myocardial performance are the subject of much investigation but remain largely unexplored (Fig 3
). Given the
well known action of NO to stimulate soluble guanylyl cyclase, much
attention has been paid to cGMP-activated
pathways.119 NO and cGMP can decrease cardiac myocyte
L-type calcium current and contraction through activation of
cGMP-stimulated cAMP phosphodiesterase (type 2 PDE). This would
decrease intracellular cAMP levels and the activity of PKA which in
turn would alter the phosphorylation state of several
target proteins, including the -subunit of the L-type calcium
channel. Evidence for NO's effect mediated through activation of the
cGMP-stimulated cAMP type 2 PDE to decrease myocyte contraction and/or
L-type calcium current was provided in sinoatrial and
atrioventricular myocytes from the
rabbit,85 206 207 ventricular myocytes from
the rat208 (all via muscarinic cholinergic activation of
endogenous eNOS), and atrial myocytes from the
frog209 (the latter via perfusion with micromolar
concentrations of the NO donor 3-morpholino syndnonamine [SIN-1]). In
all these experiments, the effect of NO was mainly to antagonize the
actions of previously elevated cAMP; there was little, if any, effect
of NO on the basal contractile state. The involvement of PDE 2 was
inferred from the lack of efficacy of NO to antagonize the effects of
the phosphodiesterase inhibitor isobutyl methylxanthine or
nonhydrolyzable 8-bromo-cAMP.
|
Conversely, in some species, NO may potentiate the stimulatory effect of adrenergic stimulation or cAMP on cardiac myocyte contraction and L-type calcium current through inhibition of another cGMP-inhibited cAMP phosphodiesterase (type 3 PDE). This has been observed in frog atrial209 and adult rat ventricular210 myocytes with low concentrations of the NO donors SIN-1 (<100 nmol/L) and S-nitroso-acetyl-penicillamine (SNAP) (<100 µmol/L), respectively. Similar concentrations of SIN-1 had no effect on basal calcium current in frog cells209 but increased it in human atrial myocytes, where basal cAMP levels might be higher.211
Higher concentrations of NO donors or cGMP analogues also activate PKG, which decreases calcium current intensity and contraction, especially after their initial stimulation after increases in cAMP.208 210 212 213 214 The same pathway is operative after muscarinic cholinergic stimulation in guinea pig215 and rat ventricular208 myocytes. PKG activation may also decrease cardiac myocyte contraction through a desensitization of cardiac myofilaments for calcium187 that is possibly related to phosphorylation of troponin I.
Some or all of the cGMP-dependent pathways mentioned above probably coexist in some cells,208 210 216 and the predominance of any one to produce the observed effect may vary according to the species or the region of the heart, as well as the stimulus and the experimental conditions used.
NO or its redox-related derivatives may also regulate channel function and cardiac contraction through mechanisms independent from cGMP (the Table). Peroxynitrite has been demonstrated to inhibit enzymes involved in the citric acid cycle, such as the interaction between cis-aconitase and iron-sulfur clusters.217 In many systems NO and its derivatives, such as the nitrosonium ion (NO+), interact with sulfhydryl groups to produce biologically active S-nitrosoproteins,120 which can then support additional transnitrosation reactions with other target sulfhydryl-containing proteins, the activity of which can be enhanced or impaired. By S-nitrosylating the glycolytic enzyme GAPDH, NO increases its auto-ADP-ribosylation and decreases its activity, thereby impeding glycolysis.132 218 NO has also been shown to reduce oxygen consumption in muscle slices, presumably by inhibiting mitochondrial electron transfer,219 220 an effect that was reproduced in neonatal rat ventricular myocytes treated with IL-1ß.221 This effect could involve inactivation of the heme moiety of cytochrome c oxidase by NO.222 Finally, studies of isolated, perfused hearts by nuclear magnetic resonance spectroscopy have suggested that NO released from S-nitrosoacetylcysteine, an NO donor, impaired augmentation of contractile performance in response to increased calcium, possibly by nitrosylating creatine kinase and impeding phosphoryl transfer from creatine phosphate to ATP.223 Further elucidation of the molecular signaling mechanisms that modify expression of the NOS isoforms and that determine the actions of NO will undoubtedly enhance understanding of the roles of endothelial cell and myocardial cell NO in the modification of cardiac function and in diseases of the heart.
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Footnotes |
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Received February 20, 1997; accepted May 28, 1997.
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References |
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