scholarly journals PKR deficiency alleviates pulmonary hypertension via inducing inflammasome adaptor ASC inactivation

2021 ◽  
Vol 11 (4) ◽  
pp. 204589402110461
Author(s):  
Yapei Li ◽  
Ying Li ◽  
Lijun Li ◽  
Minghui Yin ◽  
Jiangang Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Interleukin 1 ◽  
High Mobility ◽  
Interleukin 1 Beta ◽  
Therapeutic Approaches ◽  
Downstream Signaling ◽  
Dependent Protein ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Pulmonary hypertension is a progressive fatal disease that currently has no specific therapeutic approaches. In this study, dsRNA-dependent protein kinase (PKR) was considered a candidate molecule in pulmonary hypertension. We demonstrated that PKR is activated in the endothelium of experimental pulmonary hypertension models. Deletion of PKR or treatment with the PKR activation inhibitor C16 inhibited the development of pulmonary hypertension. To explore the mechanism of PKR in pulmonary hypertension, we detected its downstream signaling and found that PKR knockout represses apoptosis-associated speck-like protein containing CARD (ASC) activation to inhibit high mobility group box 1 (HMGB1) and interleukin-1 beta release. To further explore whether ASC mediates the pro-pulmonary hypertension role of PKR, we used ASC deletion mice and found that ASC deletion inhibits the development of pulmonary hypertension and the release of HMGB1 and interleukin-1 beta. Furthermore, we co-cultured pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs) and found that endothelial PKR promotes PASMCs proliferation through the release of HMGB1 and interleukin-1 beta. In conclusion, these data indicate that endothelial PKR promotes the excessive proliferation of PASMCs by inducing ASC activation to release HMGB1 and interleukin-1 beta, which lead to the development of pulmonary hypertension. Our study will provide a novel insight that PKR is a potential target in the future treatment of pulmonary hypertension.

scholarly journals Reduced membrane cholesterol limits pulmonary endothelial Ca2+ entry after chronic hypoxia

2017 ◽  
Vol 312 (6) ◽  
pp. H1176-H1184 ◽  
Author(s):  
Bojun Zhang ◽  
Jay S. Naik ◽  
Nikki L. Jernigan ◽  
Benjimen R. Walker ◽  
Thomas C. Resta
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Barometric Pressure ◽  
Membrane Cholesterol ◽  
Potential Mechanism ◽  
Direct Role ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Chronic hypoxia (CH)-induced pulmonary hypertension is associated with diminished production of endothelium-derived Ca2+-dependent vasodilators such as nitric oxide. Interestingly, ATP-induced endothelial Ca2+ entry as well as membrane cholesterol (Chol) are decreased in pulmonary arteries from CH rats (4 wk, barometric pressure = 380 Torr) compared with normoxic controls. Store-operated Ca2+ entry (SOCE) and depolarization-induced Ca2+ entry are major components of the response to ATP and are similarly decreased after CH. We hypothesized that membrane Chol facilitates both SOCE and depolarization-induced pulmonary endothelial Ca2+ entry and that CH attenuates these responses by decreasing membrane Chol. To test these hypotheses, we administered Chol or epicholesterol (Epichol) to acutely isolated pulmonary arterial endothelial cells (PAECs) from control and CH rats to either supplement or replace native Chol, respectively. The efficacy of membrane Chol manipulation was confirmed by filipin staining. Epichol greatly reduced ATP-induced Ca2+ influx in PAECs from control rats. Whereas Epichol similarly blunted endothelial SOCE in PAECs from both groups, Chol supplementation restored diminished SOCE in PAECs from CH rats while having no effect in controls. Similar effects of Chol manipulation on PAEC Ca2+ influx were observed in response to a depolarizing stimulus of KCl. Furthermore, KCl-induced Ca2+ entry was inhibited by the T-type Ca2+ channel antagonist mibefradil but not the L-type Ca2+ channel inhibitor diltiazem. We conclude that PAEC membrane Chol is required for ATP-induced Ca2+ entry and its two components, SOCE and depolarization-induced Ca2+ entry, and that reduced Ca2+ entry after CH may be due to loss of this key regulator. NEW & NOTEWORTHY This research is the first to examine the direct role of membrane cholesterol in regulating pulmonary endothelial agonist-induced Ca2+ entry and its components. The results provide a potential mechanism by which chronic hypoxia impairs pulmonary endothelial Ca2+ influx, which may contribute to pulmonary hypertension.

scholarly journals EXPRESS: Pulmonary Hypertension Associated With Neurofibromatosis Type 2

2021 ◽  
pp. 204589402110295
Author(s):  
Hirohisa Taniguchi ◽  
Tomoya Takashima ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Asuka Furukawa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Neurofibromatosis Type ◽  
Pulmonary Vascular Remodeling ◽  
Life Threatening ◽  
History Of ◽  
Pulmonary Arterial ◽  
First Time

Although precapillary pulmonary hypertension (PH) is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and treated with PAH-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from IPAH patients compared to control lungs, suggesting a potential role of NF2 in PAH development. To our knowledge, this is the first time that precapillary PH has been described in a patient with NF2. The altered endothelial NF2 expression pattern in PAH lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodeling associated to these severe life-threatening conditions.

Effect of a central CRF antagonist on cardiovascular and thermoregulatory responses induced by stress or IL-1 beta

1993 ◽  
Vol 265 (4) ◽  
pp. R834-R839 ◽  
Author(s):  
T. Nakamori ◽  
A. Morimoto ◽  
N. Murakami
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Interleukin 1 ◽  
Corticotropin Releasing Factor ◽  
Mild Stress ◽  
Induced Responses ◽  
Interleukin 1 Beta ◽  
The Central Nervous System ◽  
Beta 2

We investigated the role of central corticotropin-releasing factor (CRF) in the development of cardiovascular and thermal responses induced by stress or by interleukin-1 beta (IL-1 beta) in free-moving rats. Intracerebroventricular (icv) injection of alpha-helical CRF9-41 (10 micrograms), a CRF receptor antagonist, significantly attenuated hypertension, tachycardia, and a rise in body temperature induced by cage-switch stress, a mild stress. However, icv injection of alpha-helical CRF9-41 (10 micrograms) had no effect on hypertension, tachycardia, or fever induced by intraperitoneal (ip) injection of IL-1 beta (2 micrograms/kg) or icv prostaglandin E2 (PGE2, 100 ng). In contrast, icv injection of alpha-helical CRF9-41 (10 micrograms) significantly attenuated hypertension, tachycardia, or fever induced by icv injection of IL-1 beta (20 ng). The present results suggest that central CRF has an important role in the development of the cage-switch stress-induced responses, but it does not seem to contribute to the hypertension, tachycardia, and fever induced by ip IL-1 beta or by central PGE2. However, it is possible that when IL-1 beta directly acts on the central nervous system, some of its actions are mediated by central CRF.

Endothelial Upregulation of Mechanosensitive Channel Piezo1 in Pulmonary Hypertension

2021 ◽  
Author(s):  
Ziyi Wang ◽  
Jiyuan Chen ◽  
Aleksandra Babicheva ◽  
Pritesh P. Jain ◽  
Marisela Rodriguez ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cyclic Stretch ◽  
Mechanosensitive Channel ◽  
Pathogenic Role ◽  
Membrane Stretch ◽  
Mrna And Protein Expression ◽  
Resultant Increase ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells ◽  
Notch Ligands

Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared to normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, while downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

Corticosterone regulates behavioral effects of lipopolysaccharide and interleukin-1 beta in mice

1995 ◽  
Vol 269 (1) ◽  
pp. R154-R159 ◽  
Author(s):  
E. Goujon ◽  
P. Parnet ◽  
A. Aubert ◽  
G. Goodall ◽  
R. Dantzer
Keyword(s):  
Interleukin 1 ◽  
Behavioral Effects ◽  
Protective Effects ◽  
Interleukin 1 Beta ◽  
Social Exploration ◽  
Inhibitory Feedback ◽  
Adrenal Response ◽  
Acute Injection ◽  
Progesterone Antagonist

The modulatory role of endogenous corticoids in the behavioral effects of lipopolysaccharide (LPS) and recombinant human interleukin-1 beta (IL-1 beta) was studied in mice. Adrenalectomy enhanced the depression of social exploration induced by subcutaneous injection of 200 ng of IL-1 beta or 2 micrograms of LPS. This effect was mimicked by an acute injection of the progesterone antagonist RU-38486 (0.25-1 mg). Chronic replacement with a 15-mg corticosterone pellet abrogated the enhanced susceptibility of adrenalectomized animals to 200 ng of IL-1 beta but had only partial protective effects on their response to 400 ng of IL-1 beta and LPS. These results suggest that the pituitary-adrenal response to cytokines exerts an inhibitory feedback on the cell targets that mediate the behavioral effects of LPS and IL-1 beta.

Role of Ambrisentan in the Management of Pulmonary Hypertension

2008 ◽  
Vol 42 (11) ◽  
pp. 1653-1659 ◽  
Author(s):  
Sandra L Hrometz ◽  
Kelly M Shields
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
English Language ◽  
Data Extraction ◽  
Information Service ◽  
Study Selection ◽  
Pulmonary Arterial ◽  
Improve Exercise Capacity

Objective: To review the role of ambrisentan in the treatment of pulmonary arterial hypertension (PAH). Data Sources: Literature was accessed through MEDLINE (1950-June 2008), Iowa Drug Information Service (1966–March 2008), EMBASE (1966-June 2008), bibliographies of pertinent articles, and unpublished data provided by the manufacturer and the Food and Drug Administration (FDA). Search terms included ambrisentan, endothelin antagonist, pulmonary hypertension, and pulmonary arterial hypertension. Due to limited literature available, additional criteria to limit searches were not used. Study Selection and Data Extraction: Abstracts and original preclinical and clinical research reports available in the English language were Identified for review. All manufacturer-provided data were also evaluated. Literature related to ambrisentan, endothelin antagonists, pulmonary hypertension, and pulmonary arterial hypertension were included. Four clinical trials evaluated the efficacy of ambrisentan in adults with symptomatic PAH. Data Synthesis: Ambrisentan is the latest endothelin-receptor antagonist (ERA) to obtain FDA approval for the treatment of PAH. It joins the first FDA-approved ERA, bosentan. Like bosentan, ambrisentan is available orally (with once-daily dosing compared with bosentan's twice-daily dosing) and has been shown to improve exercise capacity and delay clinical worsening. As with bosentan, the most significant safety concerns with ambrisentan relate to potential liver injury and a contraindication in pregnancy. Although ambrisentan has higher affinity for the endothelin type A receptor than for the endothelin type B receptor, specific advantages of this selectivity, in terms of efficacy compared with bosentan, a nonselective agent, have not been demonstrated. Conclusions: Ambrisentan has been shown to be an effective ERA in patients with PAH. A significant advantage of ambrisentan is the lack of any clinically important drug interactions with warfarin and sildenafil, which are frequently used by patients being treated for PAH.

scholarly journals Right heart catheterisation: best practice and pitfalls in pulmonary hypertension

2015 ◽  
Vol 24 (138) ◽  
pp. 642-652 ◽  
Author(s):  
Stephan Rosenkranz ◽  
Ioana R. Preston
Keyword(s):  
Pulmonary Hypertension ◽  
Clinical Practice ◽  
Best Practice ◽  
Data Interpretation ◽  
Volume Measurement ◽  
Right Heart ◽  
Heart Catheterisation ◽  
Right Heart Catheterisation ◽  
Pulmonary Arterial

Right heart catheterisation (RHC) plays a central role in identifying pulmonary hypertension (PH) disorders, and is required to definitively diagnose pulmonary arterial hypertension (PAH). Despite widespread acceptance, there is a lack of guidance regarding the best practice for performing RHC in clinical practice. In order to ensure the correct evaluation of haemodynamic parameters directly measured or calculated from RHC, attention should be drawn to standardising procedures such as the position of the pressure transducer and catheter balloon inflation volume. Measurement of pulmonary arterial wedge pressure, in particular, is vulnerable to over- or under-wedging, which can give rise to false readings. In turn, errors in RHC measurement and data interpretation can complicate the differentiation of PAH from other PH disorders and lead to misdiagnosis. In addition to diagnosis, the role of RHC in conjunction with noninvasive tests is widening rapidly to encompass monitoring of treatment response and establishing prognosis of patients diagnosed with PAH. However, further standardisation of RHC is warranted to ensure optimal use in routine clinical practice.

scholarly journals Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension

2012 ◽  
Vol 303 (12) ◽  
pp. C1229-C1243 ◽  
Author(s):  
Abigail S. Forrest ◽  
Talia C. Joyce ◽  
Marissa L. Huebner ◽  
Ramon J. Ayon ◽  
Michael Wiwchar ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Electromechanical Coupling ◽  
Pulmonary Arteries ◽  
Doppler Imaging ◽  
Heart Weight ◽  
Channel Activity ◽  
Cl Channels ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca2+ levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca2+-activated Cl− channels (ClCa), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of ClCa channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA)-sensitive Ca2+-activated Cl− current [ ICl(Ca)] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged-matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in ICl(Ca) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for ClCa channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 μM), an l-type Ca2+ channel blocker, and NFA (30 or 100 μM, with or without 10 μM indomethacin to inhibit cyclooxygenases) or T16AInh-A01 (10 μM), TMEM16A/ClCa channel inhibitors, than that of control animals. In conclusion, augmented ClCa/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease.

Matrix Stiffening Induces a Pathogenic QKI-miR-7-SRSF1 Signaling Axis in Pulmonary Arterial Endothelial Cells

2021 ◽  
Author(s):  
Chen-Shan Chen Woodcock ◽  
Neha Hafeez ◽  
Adam Handen ◽  
Ying Tang ◽  
Lloyd D Harvey ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Rna Binding ◽  
Vascular Diseases ◽  
Vascular Stiffness ◽  
Artery Stiffness ◽  
Signaling Axis ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells ◽  
Splicing Factor 1

Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA binding protein Quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness up-regulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally up-regulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from PAH patients and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, while forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

Sign in / Sign up

Export Citation Format

Share Document