ROS-Dependent Signaling Mechanisms for Hypoxic Ca<sup>2+</sup>Responses in Pulmonary Artery Myocytes

Wang, Yong-Xiao; Zheng, Yun‐Min

doi:10.1089/ars.2009.2877

Cited by 73 publications

(94 citation statements)

References 116 publications

(113 reference statements)

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“…Hypoxic inhibition of K + channels results in membrane depolarization, the activation of voltage-dependent Ca 2+ (Ca V ) channels, extracellular Ca 2+ influx and intracellular Ca 2+ release, thus resulting in an increase in [Ca 2+ ] i , followed by pulmonary vasoconstriction and proliferation of PASMCs [29] . Opening K + channels contributes to the regulation of hypoxic pulmonary vasoconstriction and vascular remodeling.…”

Section: Discussionmentioning

confidence: 99%

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

et al. 2015

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altitude diseases that are associated with significant morbidity and mortality, such as high-altitude pulmonary edema and heart diseases [3] . Echinacoside (ECH) (Figure 1) is a phenylethanoid glycoside found in a variety of Chinese herbs such as the Tibetan herb Lagotis brevituba Maxim and Cistanche tubulosa [4,5] . Lagotis brevituba Maxim is a species of Lagotis spp belonging to the Scrophulariaceae and grows widely at an altitude over 3000 meter in the Qinghai-Tibet Plateau. ECH has various desirable pharmacological characteristics, such as antioxidative, anti-inflammatory, neuroprotective, hepatoprotective, and nitric oxide (NO) radical-scavenging properties [6] . It can also elicit endothelium-dependent relaxation in rat thoracic aortic rings and cure cardiovascular diseases [7] . HowEchinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BK Ca channels and reducing intracellular Ca 2+ levels Aim: Sustained pulmonary vasoconstriction as experienced at high altitude can lead to pulmonary hypertension (PH). The main purpose of this study is to investigate the vasorelaxant effect of echinacoside (ECH), a phenylethanoid glycoside from the Tibetan herb Lagotis brevituba Maxim and Cistanche tubulosa, on the pulmonary artery and its potential mechanism. Methods: Pulmonary arterial rings obtained from male Wistar rats were suspended in organ chambers filled with Krebs-Henseleit solution, and isometric tension was measured using a force transducer. Intracellular Ca 2+ levels were measured in cultured rat pulmonary arterial smooth muscle cells (PASMCs) using Fluo 4-AM. Results: ECH (30-300 μmol/L) relaxed rat pulmonary arteries precontracted by noradrenaline (NE) in a concentration-dependent manner, and this effect could be observed in both intact endothelium and endothelium-denuded rings, but with a significantly lower maximum response and a higher EC 50 in endothelium-denuded rings. This effect was significantly blocked by L-NAME, TEA, and BaCl 2 . However, IMT, 4-AP, and Gli did not inhibit ECH-induced relaxation. Under extracellular Ca 2+ -free conditions, the maximum contraction was reduced to 24.54%±2.97% and 10.60%±2.07% in rings treated with 100 and 300 μmol/L of ECH, respectively. Under extracellular calcium influx conditions, the maximum contraction was reduced to 112.42%±7.30%, 100.29%±8.66%, and 74.74%±4.95% in rings treated with 30, 100, and 300 μmol/L of ECH, respectively. After cells were loaded with Fluo 4-AM, the mean fluorescence intensity was lower in cells treated with ECH (100 μmol/L) than with NE. Conclusion: ECH suppresses NE-induced contraction of rat pulmonary artery via reducing intracellular Ca 2+ levels, and induces its relaxation through the NO-cGMP pathway and opening of K + channels (BK Ca and K IR ).

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Section: Discussionmentioning

confidence: 99%

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

et al. 2015

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“…In addition, NFATc3 nuclear export is regulated by phosphorylation by several serine/threonine kinases, such as glycogen synthase kinase-3␤ and JNK1/2 (3,(33)(34)(35), and by the activity of the exportin CRM1 (3,33,35). The components of this signaling pathway, except for CRM1, have been shown to be differentially regulated by O 2 ·Ϫ and H 2 O 2 (4,5,14,17,18,40,49,53,64,71).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of NFATc3 activation by increased superoxide and reduced hydrogen peroxide in pulmonary arterial smooth muscle

Ramiro-Diaz

Giermakowska

Weaver

et al. 2014

American Journal of Physiology-Cell Physiology

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·Ϫ ) and decreased H2O2 levels in pulmonary arteries of chronic hypoxia-exposed wild-type and normoxic superoxide dismutase 1 (SOD1) knockout mice. We also showed that this reciprocal change in O 2 ·Ϫ and H2O2 is associated with elevated activity of nuclear factor of activated T cells isoform c3 (NFATc3) in pulmonary arterial smooth muscle cells (PASMC). This suggests that an imbalance in reactive oxygen species levels is required for NFATc3 activation. However, how such imbalance activates NFATc3 is unknown. This study evaluated the importance of O 2 ·Ϫ and H2O2 in the regulation of NFATc3 activity. We tested the hypothesis that an increase in O2 ·Ϫ enhances actin cytoskeleton dynamics and a decrease in H2O2 enhances intracellular Ca 2ϩ concentration, contributing to NFATc3 nuclear import and activation in PASMC. We demonstrate that, in PASMC, endothelin-1 increases O 2 ·Ϫ while decreasing H2O2 production through the decrease in SOD1 activity without affecting SOD protein levels. We further demonstrate that O 2 ·Ϫ promotes, while H2O2 inhibits, NFATc3 activation in PASMC. Additionally, increased O 2 ·Ϫ -to-H2O2 ratio activates NFATc3, even in the absence of a G q protein-coupled receptor agonist. Furthermore, O2·Ϫ -dependent actin polymerization and low intracellular H2O2 concentration-dependent increases in intracellular Ca 2ϩ concentration contribute to NFATc3 activation. Together, these studies define important and novel regulatory mechanisms of NFATc3 activation in PASMC by reactive oxygen species.superoxide; hydrogen peroxide; NFATc3; endothelin-1; actin cytoskeleton; calcium NUCLEAR FACTOR OF ACTIVATED T cells (NFAT) isoform c3 (NFATc3) belongs to a family of four transcription factors (NFATc1, NFATc2, NFATc3, and NFATc4) that share the property of Ca 2ϩ /calcineurin-dependent nuclear translocation (reviewed in Ref. 35). We previously demonstrated that NFATc3 is required for chronic hypoxia (CH)-induced pulmonary arterial remodeling and pulmonary hypertension in mice (10, 25). Pulmonary hypertension is associated with polycythemia, arterial remodeling, increased vascular contractility, augmented concentrations of circulating endothelin-1 (ET-1), and elevated reactive oxygen species (ROS) (1,9,19,24,28,32,36,55 (2): SOD1 and extracellular SOD3 (Cu,Zn-SOD) and mitochondrial SOD2 (Mn-SOD); SOD1, the predominant cytosolic isoform (4), is also present in the mitochondrial intermembrane space (42). We recently showed that SOD1 knockout (KO) mice develop NFAT-dependent spontaneous pulmonary hypertension (62). CH-exposed wild-type and normoxic SOD1 KO mice have increased O 2 ·Ϫ and decreased H 2 O 2 levels in pulmonary arteries. This O 2 ·Ϫ -H 2 O 2 imbalance is associated with elevated NFATc3 activity in pulmonary arterial smooth muscle cells (PASMC) (62). Similarly, in rats exposed to CH, we recently showed decreased pulmonary arterial SOD1 activity/expression, leading to increased O 2 ·Ϫ and decreased H 2 O 2 production (59), as previously reported in newborn piglets (26). These findings suggest that an imbala...

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“…Superoxide and hydrogen peroxide are kinds of ROS produced from endothelial nitric oxide (NO) synthase, NADPH oxidase, xanthine oxidase, and the mitochondrial respiratory chain as the major sources (27). It was previously demonstrated that endotheliumderived ROS mediates contraction by elevating the intracellular Ca 2+ concentration in pulmonary arterial smooth muscle (28), by activating thromboxane A 2 (TP) receptor in aorta from SHR (29), and by inhibiting endotheliumderived relaxing factor (NO) in rat aorta (30). It seems unlikely in the present study that the TP receptor is responsible for the increased contraction, since the TPreceptor blocker SQ29548 did not affect the MGO-induced enhancement of Ang II-induced contraction.…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal Augments Angiotensin II–Induced Contraction in Rat Isolated Carotid Artery

et al. 2010

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Abstract. Methylglyoxal (MGO), a metabolite of glucose, accumulates in vascular tissues of a hypertensive animal. In the present study, we examined the effect of MGO on angiotensin (Ang) II-induced contraction of rat carotid artery. Treatment of carotid artery with MGO (420 μM, 30 min) significantly augmented Ang II (0.1 to 30 nM)-induced concentration-dependent contraction. The effect was abolished by the removal of endothelium. BQ-123 (1, 5 μM), an endothelin Areceptor blocker, had no effect on the MGO-induced enhancement of Ang II-induced contraction. AL8810 (1 μM), a prostaglandin F 2α -receptor blocker, or SQ29548 (1 μM), a thromboxane A 2 -receptor blocker, was also ineffective. However, tempol (10 μM), a superoxide scavenger, and catalase (5000 U/mL), which metabolizes hydrogen peroxide to water, significantly prevented the effect of MGO. Combined MGO and Ang II treatment increased reactive oxygen species (ROS) production. Apocynin (10 μM) or gp91ds-tat (3 μM), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, significantly prevented the effect of MGO. Gp91ds-tat or an Ang II type 1-receptor (AT1R) blocker, losartan (10 μM), prevented the MGO-mediated increased ROS production. The present study revealed that MGO augments Ang II-induced contraction by increasing AT1R-mediated NADPH oxidase-derived superoxide and hydrogen peroxide production in endothelium of rat carotid artery.

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ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes

Cited by 73 publications

References 116 publications

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

Mechanisms of NFATc3 activation by increased superoxide and reduced hydrogen peroxide in pulmonary arterial smooth muscle

Methylglyoxal Augments Angiotensin II–Induced Contraction in Rat Isolated Carotid Artery

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ROS-Dependent Signaling Mechanisms for Hypoxic Ca2+Responses in Pulmonary Artery Myocytes

Cited by 73 publications

References 116 publications

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

Mechanisms of NFATc3 activation by increased superoxide and reduced hydrogen peroxide in pulmonary arterial smooth muscle

Methylglyoxal Augments Angiotensin II–Induced Contraction in Rat Isolated Carotid Artery

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ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes