Nitration of Tyrosine 247 Inhibits Protein Kinase G-1α Activity by Attenuating Cyclic Guanosine Monophosphate Binding

Aggarwal, Saurabh; Groß, Christine; Rafikov, Ruslan; Kumar, Sanjiv; Fineman, Jeffrey R.; Ludewig, Britta; Jonigk, Danny; Black, Stephen M.

doi:10.1074/jbc.m113.534313

Cited by 33 publications

(37 citation statements)

References 55 publications

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“…In another study, it has been shown that nitration of tyrosine 247 in PKG-1α results in decreased cGMP binding and thereby decreased PKG activity in pulmonary artery smooth muscle cells (12). Tyrosine nitration of PKG has also been shown to occur in ovine fetal intrapulmonary veins in a hypoxia-dependent manner that is endothelial NOS (eNOS)-independent but through increased levels of nitrite and nitrate (10).…”

Section: Molecular Mechanisms Of Nitrative Stress In the Pathogenementioning

confidence: 99%

“…Prominent tyrosine nitration, a hallmark of nitrative stress, is evident in lung tissues of severe PH patients including IPAH patients (13). Increased tyrosine nitration of PKG, for instance, is observed in lung tissues of IPAH patients (12). The activity of eNOS is markedly increased in the lungs of IPAH patients compared with healthy controls, without significant change in its protein levels (11).…”

Section: Nitrative Stress In Pulmonary Hypertension Patientsmentioning

confidence: 99%

“…In general, when superoxide formation occurs at a threefold greater rate than NO synthesis, NO is being quantitatively converted to peroxynitrite, which leads to decreased NO bioavailability, and induces posttranslational modifications (e.g., nitrates tyrosine residues) of proteins and resultant dysregulation of protein functions (9). Nitrative stress-induced dysregulation of molecular signaling pathways have been implicated in the pathogenesis of PH in both animal models and patients (10–12). …”

Section: Introductionmentioning

confidence: 99%

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Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension

Evans¹,

Zhao²

2017

Advances in Experimental Medicine and Biology

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Pulmonary hypertension (PH) is a lung vascular disease with marked increases in pulmonary vascular resistance and pulmonary artery pressure (>25 mmHg at rest). In PH patients, increases in pulmonary vascular resistance lead to impaired cardiac output and reduced exercise tolerance. If untreated, PH progresses to right heart failure and premature lethality. The mechanisms that control the pathogenesis of PH are incompletely understood, but evidence from human and animal studies implicate nitrative stress in the development of PH. Increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) result in nitrative stress, which in turn induces posttranslational modification of key proteins important for maintaining pulmonary vascular homeostasis. This affects their functions and thereby contributes to the pathogenesis of PH. In this chapter, molecular mechanisms underlying nitrative stress-induced PH are reviewed, molecular sources of ROS and RNS are delineated, and evidence of nitrative stress in PH patients is described. A better understanding of such mechanisms could lead to the development of novel treatments for PH.

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Section: Molecular Mechanisms Of Nitrative Stress In the Pathogenementioning

confidence: 99%

Section: Nitrative Stress In Pulmonary Hypertension Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension

Evans¹,

Zhao²

2017

Advances in Experimental Medicine and Biology

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“…Studies also show that nitration at tyrosine 247 attenuates PKG-Ia activity. An antibody against 3-NT-Y247 identifies increased levels of nitrated PKG-Ia in humans with PH (57,58). Interestingly, although cGMP is considered the sole vasoactive molecule generated by sGC, a recent study reveals that hypoxia may promote sGC to synthesize a vasoconstrictor inosine 39, 59-cyclic monophosphate.…”

Section: Edno As a Paracrine Regulatormentioning

confidence: 99%

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Gao

Chen

Raj

2016

Am J Respir Cell Mol Biol

119

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In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, other mechanisms exist by which there is cross-talk between these two cell types, including communication via the myoendothelial injunctions and information transfer via extracellular vesicles. Emerging evidence suggests that these nonparacrine mechanisms play an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension.Keywords: paracrine; myoendothelial injunction; microvesicles; vasoconstriction; vascular remodelingIn the pulmonary vasculature, endothelial cells (ECs) and smooth muscle cells (SMCs) are the key cell types involved in the regulation of vessel diameter in most of the pulmonary vascular tree and thereby they regulate pulmonary arterial pressure and total vascular resistance. ECs, which are strategically located as the innermost layer of the blood vessel and are in contact with the circulating blood, exert a delicate and constant influence on the underlying vascular smooth muscle cells (VSMCs). It is well recognized that the regulation of pulmonary vasoreactivity by the endothelium is predominantly accomplished by paracrine signaling through the release of various vasoactive agents such as nitric oxide (NO), endothelin-1 (ET-1) (1-3), and others (4-8). However, there is increasing evidence that the relationship between the EC and the SMC is not a simple one-way interaction from the endothelium to the SMC; rather, there are complicated interactions between them (9-11). Moreover, the communication patterns are not limited to paracrine signaling; cross-talk through myoendothelial gap junctions (MEJs), extracellular vesicles (EVs), and other mechanisms is critically involved (12)(13)(14)(15)(16)(17)(18)(19)(20). These mechanisms operate in a complicated but co-ordinated manner to maintain the homeostasis of the pulmonary circulation. Under pathological conditions, the interaction between ECs and VSMCs may be chronically altered so that a sustained increase in vasocontractility and abnormal vascular proliferation develops, which leads to high pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and the clinical condition, pulmonary hypertension (PH) (1,(21)(22)(23)(24). This article discusses the recent progress in our knowledge of the interactions between ECs and SMCs thr...

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“…Although in Shunt lambs increased BNP-mediated activation of particulate GC may be able to compensate [81]. In addition, although it does not appear to be chaperoned by hsp90, the target of cGMP, protein kinase G-1α (PKG-1α) is also compromised in Shunt lambs [82] through the nitration of Y247 that reduces the ability of the protein to bind cGMP [83] (Figure 3). Thus, in addition to an increase in NO generation the downstream effectors of NO are also compromised.…”

Section: Hsp90 and No Signalingmentioning

confidence: 99%

Mitochondrial Dysfunction and Congenital Heart Disease

Black

Fineman²

2014

Pediat Therapeut

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The pulmonary vasculature in infants born with congenital heart defects that cause increased Pulmonary Blood Flow (PBF) is subjected to pathologic mechanical forces, including chronically increased shear stress, resulting in early functional abnormalities of the vascular endothelium. These functional abnormalities occur prior to the development of well-described morphologic changes. However, little is known about the factors that transduce the abnormal shear forces associated with increased PBF into abnormal vascular function and reactivity. Recently the disruption of mitochondrial function has been identified as a new mechanism that leads to the development of pulmonary endothelial dysfunction. This is a complex process that involves post-translational regulation of multiple proteins and the mitochondrial redistribution of uncoupled endothelial nitric oxide synthase (eNOS) resulting in the disruption of carnitine metabolism and subsequently mitochondrial bioenergetics. As both eNOS and GTP cyclohydrolase I, the rate limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, are chaperoned by hsp90 this results in a "feed-forward" signaling cascade in which eNOS becomes progressively more uncoupled resulting in pulmonary endothelial dysfunction. This review will discuss the current knowledge in the field, the limitations in our understanding this complex process, and the potential for targeting mitochondrial function in the treatment of children born with congenital heart defects that result in increased pulmonary blood flow.

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Nitration of Tyrosine 247 Inhibits Protein Kinase G-1α Activity by Attenuating Cyclic Guanosine Monophosphate Binding

Cited by 33 publications

References 55 publications

Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension

Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Mitochondrial Dysfunction and Congenital Heart Disease

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