Neutral sphingomyelinase, NADPH oxidase and reactive oxygen species. Role in acute hypoxic pulmonary vasoconstriction

Frazziano, Giovanna; Moreno, Laura; Moral-Sanz, Javier; Menéndez, Carmen; Escolano, Lucía; González, C.; Villamor, Eduardo; Álvarez-Sala, José Luis; Cogolludo, Ángel; Pérez‐Vizcaíno, Francisco

doi:10.1002/jcp.22611

Cited by 45 publications

(60 citation statements)

References 36 publications

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“…CFTR has been implicated in the homeostasis of sphingolipids (18,49), which have been shown to trigger caveolar TRPC6 translocation in lung endothelial cells (23) and hypoxia-induced vasoconstriction in isolated rat pulmonary arteries (19,22). Consistent with the latter reports (19), we found HPV to require nSMase but not aSMase.…”

Section: Discussionsupporting

confidence: 92%

“…nSMase is activated upon oxidative stress (20), possibly via arachidonic acid liberation by phospholipase A 2 (21), which all have been linked to HPV (1). In addition, ceramide accumulates in PASMCs upon hypoxia (22), mediates caveolar TRPC6 translocation in lung endothelial cells (23), and contributes to constriction of pulmonary artery rings (19,24). Although ceramide may thus potentially act as a direct mediator of HPV, it may also serve as substrate for the formation of other, bioactive sphingolipids, most notably sphingosine-1-phosphate (S1P).…”

Section: Significancementioning

confidence: 99%

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CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Tabeling¹,

Wang

et al. 2015

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

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Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca 2+ mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxiainduced TRPC6 translocation to caveolae and Ca 2+ mobilization. Ca 2+ mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase-and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P 2/4 ). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P 2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.

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Section: Discussionsupporting

confidence: 92%

Section: Significancementioning

confidence: 99%

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Tabeling¹,

Wang

et al. 2015

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

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“…As demonstrated very early, extracellular calcium inflow could be caused by opening of L-type calcium channels that could be activated by membrane depolarisation due to K V channel inhibition [77][78][79], while intracellular calcium release may occur mainly via ryanodine receptor (RyR) channels. Hypothetically, ROS could interact directly with L-type calcium channels or activate them via membrane depolarisation by inhibition of K V channels, which was recently shown in endothelium-denuded pulmonary arteries [125]. Redox regulation of L-type calcium channels and K V channels has been recently summarised [99,142].…”

Section: Downstream Targets Of Rosmentioning

confidence: 98%

“…In this regard, it was suggested that ROS release from mitochondria activates PKCε, which in turn activates NADPH oxidase to enhance ROS production and leads to a calcium increase [121]. Recently, PKCξ-dependent NADPH oxidase activation has been suggested to be induced by increased ceramide levels due to mitochondrial-dependent activation of neutral sphingomyelinase (nSMase) [122][123][124][125]. However, inhibition of the nSMase also decreased U46619-induced vasoconstriction in pulmonary arteries [122].…”

Section: Nadph Oxidases As Ros Sourcesmentioning

confidence: 99%

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

et al. 2015

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Number 11 in the series "Physiology in respiratory medicine" Edited by R. Naeije, D. Chemla, A. Vonk-Noordegraaf and A.T. Dinh-Xuan Affiliation: Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.Correspondence: Norbert Weissmann, Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, Germany. E-mail: Norbert.Weissmann@innere.med.uni-giessen.de ABSTRACT Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV. @ERSpublications ROS originating from mitochondria and/or NADPH oxidases may initiate HPV but exact signalling mechanisms are unclear http://ow.ly/SkaGC

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“…We have previously found that neutral SMase (nSMase)-derived ceramide acts as a critical mediator in the HPV response in rats by increasing reactive oxygen species (ROS) production via NADPH oxidase (8,14). However, the possible role of ceramide in other oxygen-sensing tissues remains to be explored.…”

mentioning

confidence: 99%

Ceramide Mediates Acute Oxygen Sensing in Vascular Tissues

Moreno

Moral-Sanz

Morales‐Cano

et al. 2014

Antioxidants & Redox Signaling

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Aims: A variety of vessels, such as resistance pulmonary arteries (PA) and fetoplacental arteries and the ductus arteriosus (DA) are specialized in sensing and responding to changes in oxygen tension. Despite opposite stimuli, normoxic DA contraction and hypoxic fetoplacental and PA vasoconstriction share some mechanistic features. Activation of neutral sphingomyelinase (nSMase) and subsequent ceramide production has been involved in hypoxic pulmonary vasoconstriction (HPV). Herein we aimed to study the possible role of nSMase-derived ceramide as a common factor in the acute oxygen-sensing function of specialized vascular tissues. Results: The nSMase inhibitor GW4869 and an anticeramide antibody reduced the hypoxic vasoconstriction in chicken PA and chorioallantoic arteries (CA) and the normoxic contraction of chicken DA. Incubation with interference RNA targeted to SMPD3 also inhibited HPV. Moreover, ceramide and reactive oxygen species production were increased by hypoxia in PA and by normoxia in DA. Either bacterial sphingomyelinase or ceramide mimicked the contractile responses of hypoxia in PA and CA and those of normoxia in the DA. Furthermore, ceramide inhibited voltage-gated potassium currents present in smooth muscle cells from PA and DA. Finally, the role of nSMase in acute oxygen sensing was also observed in human PA and DA. Innovation: These data provide evidence for the proposal that nSMasederived ceramide is a critical player in acute oxygen-sensing in specialized vascular tissues. Conclusion: Our results indicate that an increase in ceramide generation is involved in the vasoconstrictor responses induced by two opposite stimuli, such as hypoxia (in PA and CA) and normoxia (in DA). Antioxid. Redox Signal. 20, 1-14.

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Neutral sphingomyelinase, NADPH oxidase and reactive oxygen species. Role in acute hypoxic pulmonary vasoconstriction

Cited by 45 publications

References 36 publications

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Ceramide Mediates Acute Oxygen Sensing in Vascular Tissues

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