Cinaciguat, a soluble guanylate cyclase activator, augments cGMP after oxidative stress and causes pulmonary vasodilation in neonatal pulmonary hypertension

Chester, Marc; Seedorf, Gregory J.; Tourneux, P.; Gien, Jason; Tseng, Nancy; Grover, Theresa R.; Wright, Jason T.; Stasch, Johannes‐Peter; Abman, Steven H.

doi:10.1152/ajplung.00138.2010

Cited by 80 publications

(64 citation statements)

References 48 publications

(69 reference statements)

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“…Although sGC is recognized to exist mainly as the reduced (NO-sensitive) form under physiological conditions, the ratio of oxidized and/or heme-free forms has been proposed to rise in some cardiovascular diseases (12,15). It has been already revealed that a crucial factor for the maintenance of this equilibrium is reactive oxygen and nitrogen species such as superoxide and peroxynitrite, respectively (13,14).…”

Section: Discussionmentioning

confidence: 99%

“…This sGC redox equilibrium can be shifted to the NO-insensitive heme-oxidized/ heme-free form by reactive oxygen and nitrogen species such as superoxide and peroxynitrite, which are generated under conditions of oxidative stress (13,14). Actually, an altered redox state of sGC under substantial oxidative stress contributes to impairing the relaxation mediated by (12,15). Two different types of compounds that act directly on sGC (sGC stimulators and sGC activators) have been recently developed (13,16).…”

Section: Introductionmentioning

confidence: 99%

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Soluble Guanylate Cyclase Redox State Under Hypoxia or Hypoxia/Reoxygenation in Isolated Monkey Coronary Arteries

et al. 2014

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Abstract. Hypoxia or hypoxia/reoxygenation impairs nitric oxide (NO)-mediated relaxation through the increase in superoxide generation in monkey coronary arteries. Soluble guanylate cyclase (sGC), the target enzyme of NO, has been shown to change from the NO-sensitive reduced form to the NO-insensitive oxidized/heme-free form under substantial oxidative stress, so the present study investigated whether hypoxia or hypoxia/reoxygenation influences sGC redox equilibrium. In isolated monkey coronary arteries without endothelium, the relaxation caused by the sGC stimulator BAY 41-2272 (E max : 93.3% ± 2.2%) was somewhat impaired under hypoxia (E max : 86.3% ± 2.6%) or hypoxia/reoxygenation (E max : 86.1% ± 3.2%), whereas that by the sGC activator BAY 60-2770 (E max : 86.0% ± 3.2%) was significantly augmented under hypoxia (E max : 94.4% ± 1.3%) or hypoxia/reoxygenation (E max : 95.5% ± 1.1%). In addition, cGMP formation in response to BAY 41-2272 and BAY 60-2770 was inhibited and stimulated, respectively, under hypoxia or hypoxia/reoxygenation. The effects of hypoxia or hypoxia/reoxygenation on BAY 41-2272-and BAY 60-2770-induced vasorelaxation were completely canceled by the treatment with the superoxide dismutase mimetic tempol. These findings suggest that sGC redox equilibrium in the coronary artery is shifted towards the NO-insensitive form under hypoxia or hypoxia/reoxygenation and that superoxide seems to play an important role in this shift.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Soluble Guanylate Cyclase Redox State Under Hypoxia or Hypoxia/Reoxygenation in Isolated Monkey Coronary Arteries

et al. 2014

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“…Pulmonary arterial generation of nitric oxide (NO) is normally thought to oppose this process of vasoconstriction and remodeling through promoting cGMP signaling (12). Regulation of soluble guanylate cyclase (sGC) by NO is one of the systems impaired by pulmonary hypertension as a result of processes including decreased biosynthesis of NO, increased inactivation of NO by superoxide, and oxidation of the Fe 2ϩ heme of sGC that binds NO (11,12,23,37). Oxidation of the sGC heme in pulmonary hypertension appears to enhance the pulmonary vasodilator activity of direct activators of sGC which bind its heme site (11, 37).…”

mentioning

confidence: 99%

“…Regulation of soluble guanylate cyclase (sGC) by NO is one of the systems impaired by pulmonary hypertension as a result of processes including decreased biosynthesis of NO, increased inactivation of NO by superoxide, and oxidation of the Fe 2ϩ heme of sGC that binds NO (11,12,23,37). Oxidation of the sGC heme in pulmonary hypertension appears to enhance the pulmonary vasodilator activity of direct activators of sGC which bind its heme site (11,37). The iron-free precursor of heme, protoporphyrin IX (PPIX), can activate sGC by directly binding its heme site (40), and treatment of pulmonary arteries with ␦-aminolevulinic acid (ALA) promotes sGC activation as a result of the accumulation of PPIX (29).…”

mentioning

confidence: 99%

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

Alhawaj

Patel

Kelly

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alhawaj R, Patel D, Kelly MR, Sun D, Wolin MS. Heme biosynthesis modulation via ␦-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308: L719 -L728, 2015. First published February 6, 2015 doi:10.1152/ajplung.00155.2014.-This study examines how heme biosynthesis modulation with ␦-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. endothelin; ferrochelatase; guanylate cyclase; micro-RNA 204; superoxide CHRONIC HYPOXIA IS AN IMPORTANT factor in the development of pulmonary hypertension in diseases such as chronic obstructive pulmonary disease (COPD), sleep apnea, and mountain sickness (10,20). It is thought to promote pulmonary hypertension development through persistent pulmonary vasoconstriction and vascular remodeling (31). There is substantial evidence for increases in the generation of reactive oxygen species from sources including Nox oxidases and mitochondria having important roles in the development and/or progression of pulmonary hypertension caused by chronic hypoxia and other stimuli of this disease process (7,15,18,27,30). Pulmonary arterial generation of nitric oxide (NO) is normally thought to oppose this process of vasoconstriction ...

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“…In this persistent PH of the newborn animal model, pulmonary vasodilatation caused by acetylcholine is reduced but that caused by cinaciguat is increased. Vasodilatation caused by acetylcholine depends on the release of EDNO and activation of sGC associated with heme in a reduced state, whereas cinaciguat activates sGC in a heme-independent manner (55). PKG is the primary effector in mediating cGMP actions.…”

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

109

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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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Cinaciguat, a soluble guanylate cyclase activator, augments cGMP after oxidative stress and causes pulmonary vasodilation in neonatal pulmonary hypertension

Cited by 80 publications

References 48 publications

Soluble Guanylate Cyclase Redox State Under Hypoxia or Hypoxia/Reoxygenation in Isolated Monkey Coronary Arteries

Soluble Guanylate Cyclase Redox State Under Hypoxia or Hypoxia/Reoxygenation in Isolated Monkey Coronary Arteries

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

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

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