scholarly journals Hydrogen Sulfide Metabolism and Pulmonary Hypertension

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1477
Author(s):  
Lukas Roubenne ◽  
Roger Marthan ◽  
Bruno Le Le Grand ◽  
Christelle Guibert
Keyword(s):  
Pulmonary Hypertension ◽  
Hydrogen Sulfide ◽  
Pulmonary Circulation ◽  
Pulmonary Arteries ◽  
K Channel ◽  
Protective Effects ◽  
Pulmonary Arterial ◽  
Regulatory Functions

Pulmonary hypertension (PH) is a severe and multifactorial disease characterized by a progressive elevation of pulmonary arterial resistance and pressure due to remodeling, inflammation, oxidative stress, and vasoreactive alterations of pulmonary arteries (PAs). Currently, the etiology of these pathological features is not clearly understood and, therefore, no curative treatment is available. Since the 1990s, hydrogen sulfide (H2S) has been described as the third gasotransmitter with plethoric regulatory functions in cardiovascular tissues, especially in pulmonary circulation. Alteration in H2S biogenesis has been associated with the hallmarks of PH. H2S is also involved in pulmonary vascular cell homeostasis via the regulation of hypoxia response and mitochondrial bioenergetics, which are critical phenomena affected during the development of PH. In addition, H2S modulates ATP-sensitive K+ channel (KATP) activity, and is associated with PA relaxation. In vitro or in vivo H2S supplementation exerts antioxidative and anti-inflammatory properties, and reduces PA remodeling. Altogether, current findings suggest that H2S promotes protective effects against PH, and could be a relevant target for a new therapeutic strategy, using attractive H2S-releasing molecules. Thus, the present review discusses the involvement and dysregulation of H2S metabolism in pulmonary circulation pathophysiology.

scholarly journals Endothelial cell senescence exacerbates pulmonary hypertension through Notch-mediated juxtacrine signaling

2021 ◽  
Author(s):  
Risa Ramadhiani ◽  
Koji Ikeda ◽  
Kazuya Miyagawa ◽  
Gusty Rizky Teguh Ryanto ◽  
Naoki Tamada ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Notch Signaling ◽  
Pulmonary Arteries ◽  
Hypoxia Exposure ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
And Migration ◽  
Notch Ligands

AbstractPulmonary arterial hypertension (PAH) is a fatal disease characterized by pathological pulmonary artery remodeling. Endothelial cells (EC) injury including DNA damage is critically involved in the vascular remodeling in PAH, and persistent injury leads to cellular senescence in ECs. Here, we show that EC senescence exacerbates pulmonary hypertension through Notch-mediated juxtacrine signaling. EC-specific progeroid mice that we recently generated showed exacerbated pulmonary hypertension after chronic hypoxia exposure, accompanied by the enhanced pulmonary arterial smooth muscle cells (PASMCs) proliferation in the distal pulmonary arteries. Mechanistically, we identified that senescent ECs highly expressed Notch ligands, and thus activated Notch signaling in PASMCs, leading to enhanced PASMCs proliferation and migration capacities. Consistently, pharmacological inhibition of Notch signaling attenuated the effects of senescent ECs on SMCs functions in vitro, and on the pulmonary hypertension in EC-specific progeroid mice in vivo. These data establish EC senescence as a crucial disease-modifying facor in PAH.

scholarly journals Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 155
Author(s):  
Daniel Morales-Cano ◽  
Bianca Barreira ◽  
Beatriz De Olaiz Navarro ◽  
María Callejo ◽  
Gema Mondejar-Parreño ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Gas Exchange ◽  
Pulmonary Circulation ◽  
Pulmonary Arteries ◽  
Blood Perfusion ◽  
Mesenteric Arteries ◽  
Oxygen Sensitivity ◽  
Low Oxygen ◽  
Oxygen Selectivity

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.

Abstract 3570: A Critical and Novel Role of Nogo (Neurite Outgrowth Inhibitor) in Pulmonary Arterial Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Gopinath Sutendra ◽  
Sebastien Bonnet ◽  
Paulette Wright ◽  
Peter Dromparis ◽  
Alois Haromy ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Nuclear Translocation ◽  
Pulmonary Arteries ◽  
Over Expression ◽  
Nfat Activation ◽  
Pulmonary Arterial ◽  
Systemic Arteries

Nogo was first identified as an inhibitor of neuronal axonal regeneration. Recently, Nogo-B was implicated in the proliferative and anti-apoptotic remodeling in systemic arteries; reduced Nogo-B expression was seen in remodeled mouse femoral arteries following injury. Pulmonary arterial hypertension (PAH) is also characterized by proliferative/anti-apoptotic remodeling in pulmonary arteries (PA), sparing systemic vessels. PAH PA smooth muscle cells (PASMC) are characterized by mitochondrial hyperpolarization (increased ΔΨm), decreased production of reactive oxygen species (ROS) (suppressing mitochondria-dependent apoptosis), down-regulation of Kv1.5 and activation of the transcription factor NFAT (promoting contraction and proliferation). We found that in contrast to systemic vessels, Nogo-B expression is significantly increased in vivo and in vitro in PAs and PASMCs from patients (n=6) and mice (n=42) with PAH, compared to normals. We hypothesized that Nogo is involved in the pathogenesis of PAH . Nogo −/− mice (n=7) had a normal phenotype and, in contrast to Nogo +/+ , did not develop chronic hypoxia (CH)-induced PAH assessed invasively (catheterization, RV/LV+Septum) and non-invasively (pulmonary artery acceleration time and treadmill performance) (n=7, Table ). CH- Nogo +/+ PASMC had the expected increase in ΔΨm (measured by TMRM), decreased ROS (MitoSOX), increased [Ca ++ ] i (FLUO3), decreased Kv1.5 (immunohistochemistry) and NFAT activation (nuclear translocation). None of these changes occurred in CH- Nogo −/− PASMC while all were induced in normoxic Nogo +/+ PASMC by adenoviral over-expression of Nogo-B . Heterozygote CH- Nogo +/− (n=7) values were between Nogo −/− and Nogo +/+ suggesting a gene dose-dependent effect. Nogo is over-expressed in human and rodent PAH and induces critical features of the PAH phenotype. Nogo targeting might represent a novel and selective therapeutic strategy for PAH. Table

scholarly journals Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension

2019 ◽  
Vol 244 (3) ◽  
pp. 252-261 ◽  
Author(s):  
Gexiang Cai ◽  
Jingjing Liu ◽  
Meibin Wang ◽  
Lihuang Su ◽  
Mengsi Cai ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mouse Lung ◽  
Fibroblast Growth Factor 21 ◽  
Arterial Remodeling ◽  
Collagen Deposition ◽  
Pparγ Agonist ◽  
Pulmonary Arterial ◽  
The Relationship

Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear transcription factor, has been reported to effectively inhibit pulmonary hypertension (PH). The purpose of this study is to investigate the role of FGF21 in hypoxia-induced PH (HPH) and explore the relationship between FGF21 and PPARγ in this disorder. Adult C57BL/6 mice were subjected to four weeks of hypoxia to establish a PH model. The effects of FGF21 and PPARγ agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPARγ in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPARγ in vivo and in vitro. In vivo, we found that hypoxia resulted in pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial remodeling, and pulmonary arterial collagen deposition. Furthermore, hypoxia decreased FGF21 and PPARγ levels. These changes were reversed by exogenous FGF21 and a PPARγ agonist and were further enhanced by a PPARγ antagonist. The hypoxia-induced decrease in β-klotho (KLB) expression was improved by the PPARγ agonist and further reduced by the PPARγ antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPARγ coactivator-1α (PGC-1α) expression in PH mouse lung homogenates. In vitro, we found that knockdown of AMPK or using an AMPK antagonist inhibited the FGF21-mediated up-regulation of PPARγ expression, and the PPARγ-mediated up-regulation of FGF21 expression was inhibited by knockdown of KLB. These results indicated that FGF21 exerts protective effects in inhibiting HPH. FGF21 and PPARγ mutually promote each other’s expression in HPH via the AMPK/PGC-1α pathway and KLB protein. Impact statement In this study, we reported for the first time that FGF21 alleviated hypoxia-induced pulmonary hypertension through attenuation of increased pulmonary arterial pressure, pulmonary arterial remodeling and collagen deposition in vivo, and we confirmed the mutual promotion of FGF21 and PPARγ in hypoxia-induced pulmonary hypertension. Additionally, we found that FGF21 and PPARγ mutually promote each other’s expression via the AMPK/PGC-1α pathway and KLB protein in vitro and in vivo. Pulmonary hypertension is a progressive and serious pathological phenomenon with a poor prognosis, and current therapies are highly limited. Our results provide novel insight into potential clinical therapies for pulmonary hypertension and establish the possibility of using this drug combination and potential dosage reductions in clinical settings.

scholarly journals Hypoxia inhibits adenylyl cyclase catalytic activity in a porcine model of persistent pulmonary hypertension of the newborn

2018 ◽  
Vol 315 (6) ◽  
pp. L933-L944 ◽  
Author(s):  
A. S. Sikarwar ◽  
M. Hinton ◽  
K. T. Santhosh ◽  
P. Dhanaraj ◽  
M. Talabis ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Catalytic Activity ◽  
Adenylyl Cyclase ◽  
Specific Activity ◽  
Pulmonary Arteries ◽  
Persistent Pulmonary Hypertension ◽  
Receptor Agonists ◽  
Pulmonary Arterial ◽  
Fraction Of Inspired Oxygen

Persistent pulmonary hypertension of the newborn (PPHN) features hypoxemia, pulmonary vasoconstriction, and impaired cardiac inotropy. We previously reported low basal and stimulated cAMP in hypoxic pulmonary artery smooth muscle cells (PASMCs). We now examine pulmonary arterial adenylyl cyclase (AC) activity and regulation in hypoxic PPHN. PPHN was induced in newborn swine by normobaric hypoxia (fraction of inspired oxygen 0.10) for 72 h and compared with age-matched normoxic controls. We studied relaxation of pulmonary arterial (PA) rings to AC activator forskolin and cGMP activator sodium nitroprusside (SNP) by isometric myography, ATP content, phosphodiesterase activity, AC content, isoform expression, and catalytic activity in presence or absence of Gαs-coupled receptor agonists, forskolin, or transnitrosylating agents in human and neonatal porcine PASMCs and HEK293T stably expressing AC isoform 6, after 72 h hypoxia (10% O2) or normoxia (21% O2). Relaxation to forskolin and SNP were equally impaired in PPHN PA. AC-specific activity decreased in hypoxia. PASMC from PPHN swine had reduced AC activity despite exposure to normoxia in culture; transient hypoxia in vitro further decreased AC activity. Prostacyclin receptor ligand affinity decreased, but its association with Gαs increased in hypoxia. Total AC content was unchanged by hypoxia, but AC6 increased in hypoxic cells and PPHN pulmonary arteries. Impairment of AC6 activity in hypoxia was associated with nitrosylation. PPHN PA relaxation is impaired because of loss of AC activity. Hypoxic AC is inhibited because of S-nitrosylation; inhibition persists after removal from hypoxia. Downregulation of AC-mediated relaxation in hypoxic PA has implications for utility of Gαs-coupled receptor agonists in PPHN treatment.

scholarly journals The Protective Effects of Κ-Opioid Receptor Stimulation in Hypoxic Pulmonary Hypertension Involve Inhibition of Autophagy Through the AMPK-MTOR Pathway

2017 ◽  
Vol 44 (5) ◽  
pp. 1965-1979 ◽  
Author(s):  
Yaguang Zhou ◽  
Yuanbo Wang ◽  
Xu Wang ◽  
Xin Tian ◽  
Shumiao Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Western Blot ◽  
Opioid Receptor ◽  
Mtor Pathway ◽  
Cell Counting ◽  
Protective Effects ◽  
Receptor Stimulation ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Arterial

Background/Aims: In a previous study, we showed that κ-opioid receptor stimulation with the selective agonist U50,488H ameliorated hypoxic pulmonary hypertension (HPH). However, the roles that pulmonary arterial smooth muscle cell (PASMC) proliferation, apoptosis, and autophagy play in κ-opioid receptor-mediated protection against HPH are still unknown. The goal of the present study was to investigate the role of autophagy in U50,488H-induced HPH protection and the underlying mechanisms. Methods: Rats were exposed to 10% oxygen for three weeks to induce HPH. After hypoxia, the mean pulmonary arterial pressure (mPAP) and the right ventricular pressure (RVP) were measured. Cell viability was monitored using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was detected by flow cytometry and Western blot. Autophagy was assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay and by Western blot. Results: Inhibition of autophagy by the administration of chloroquine prevented the development of HPH in the rat model, as evidenced by significantly reduced mPAP and RVP, as well as decreased autophagy. U50,488H mimicked the effects of chloroquine, and the effects of U50,488H were blocked by nor-BNI, a selective κ-opioid receptor antagonist. In vitro experiments showed that the inhibition of autophagy by chloroquine was associated with decreased proliferation and increased apoptosis of PASMCs. Under hypoxia, U50,488H also significantly inhibited autophagy, reduced proliferation and increased apoptosis of PASMCs. These effects of U50,488H were blocked by nor-BNI. Moreover, exposure to hypoxic conditions significantly increased AMPK phosphorylation and reduced mTOR phosphorylation, and these effects were abrogated by U50,488H. The effects of U50,488H on PASMC autophagy were inhibited by AICAR, a selective AMPK agonist, or by rapamycin, a selective mTOR inhibitor. Conclusion: Our data provide evidence for the first time that κ-opioid receptor stimulation protects against HPH by inhibiting PASMCs autophagy via the AMPK-mTOR pathway.

Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies

2020 ◽  
Vol 34 (10) ◽  
pp. 2730-2744
Author(s):  
Zhi Chang ◽  
Jia‐ling Wang ◽  
Zhi‐cheng Jing ◽  
Ping Ma ◽  
Qing‐bing Xu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
In Vitro Studies ◽  
Protective Effects ◽  
Pulmonary Arterial

scholarly journals Pulmonary vascular resistance and compliance relationship in pulmonary hypertension

2015 ◽  
Vol 46 (4) ◽  
pp. 1178-1189 ◽  
Author(s):  
Denis Chemla ◽  
Edmund M.T. Lau ◽  
Yves Papelier ◽  
Pierre Attal ◽  
Philippe Hervé
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Arterial Compliance ◽  
Pulmonary Arteries ◽  
Transpulmonary Pressure ◽  
Total Arterial Compliance ◽  
Arterial Load ◽  
Pulmonary Arterial

Right ventricular adaptation to the increased pulmonary arterial load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) and total arterial compliance (C) quantify resistive and elastic properties of pulmonary arteries that modulate the steady and pulsatile components of pulmonary arterial load, respectively. PVR is commonly calculated as transpulmonary pressure gradient over pulmonary flow and total arterial compliance as stroke volume over pulmonary arterial pulse pressure (SV/PApp). Assuming that there is an inverse, hyperbolic relationship between PVR and C, recent studies have popularised the concept that their product (RC-time of the pulmonary circulation, in seconds) is “constant” in health and diseases. However, emerging evidence suggests that this concept should be challenged, with shortened RC-times documented in post-capillary PH and normotensive subjects. Furthermore, reported RC-times in the literature have consistently demonstrated significant scatter around the mean. In precapillary PH, the true PVR can be overestimated if one uses the standard PVR equation because the zero-flow pressure may be significantly higher than pulmonary arterial wedge pressure. Furthermore, SV/PApp may also overestimate true C. Further studies are needed to clarify some of the inconsistencies of pulmonary RC-time, as this has major implications for our understanding of the arterial load in diseases of the pulmonary circulation.

scholarly journals Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide

2014 ◽  
Vol 307 (4) ◽  
pp. R426-R433 ◽  
Author(s):  
Dhara Patel ◽  
Raed Alhawaj ◽  
Michael S. Wolin
Keyword(s):  
Hydrogen Peroxide ◽  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Soluble Guanylate Cyclase ◽  
Aminolevulinic Acid ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Protoporphyrin Ix

Exposing mice to a chronic hypoxic treatment (10% oxygen, 21 days) that promotes pulmonary hypertension was observed to attenuate the pulmonary vasoconstriction response to acute hypoxia (HPV) both in vivo and in isolated pulmonary arteries. Since catalase restored the HPV response in isolated arteries, it appeared to be attenuated by extracellular hydrogen peroxide. Chronic hypoxia promoted the detection of elevated lung superoxide, extracellular peroxide, extracellular SOD expression, and protein kinase G (PKG) activation [based on PKG dimerization and vasodilator-stimulated phosphoprotein (VASP) phosphorylation], suggesting increased generation of extracellular peroxide and PKG activation may contribute to the suppression of HPV. Aorta from mice exposed to 21 days of hypoxia also showed evidence for extracellular hydrogen peroxide, suppressing the relaxation response to acute hypoxia. Peroxide appeared to partially suppress contractions to phenylephrine used in the study of in vitro hypoxic responses. Treatment of mice with the heme precursor δ-aminolevulinic acid (ALA; 50 mg·kg−1·day−1) during exposure to chronic hypoxia was examined as a pulmonary hypertension therapy because it could potentially activate beneficial cGMP-mediated effects through promoting a prolonged protoporphyrin IX (PpIX)-elicited activation of soluble guanylate cyclase. ALA attenuated pulmonary hypertension, increases in both superoxide and peroxide, and the suppression of in vitro and in vivo HPV responses. ALA generated prolonged detectible increases in PpIX and PKG-associated phosphorylation of VASP, suggesting PKG activation may contribute to suppression of pulmonary hypertension and prevention of alterations in extracellular peroxide that appear to be attenuating HPV responses caused by chronic hypoxia.

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