Role In Pulmonary Hypertension Research Articles

Dysfunctional Mitochondria and Hemolysis are Linked by Impaired Maturation of Reticulocytes: Possible Role in Pulmonary Hypertension

IntroductionWe previously demonstrated that significantly elevated levels of circulating free heme (CFH) is associated with preclinical (Sugen/Hypoxia in rats) pulmonary hypertension (PH) and clinical pulmonary arterial hypertension (PAH). However, the pathogenic mechanisms of free heme release in PAH patients and animal models in the absence of hemolytic disease are yet to be elucidated.HypothesisThe mitochondria play a crucial role in reticulocyte maturation (precursors to red blood cells). Our hypothesis tests if mitochondrial dysfunction (MD) impaired reticulocyte maturation increases its fragility and causes rupture, elevating CFH levels that promote PAH.MethodsRecently reported genetic PH rat models carrying the NFU1G206C mutation spontaneously develop PH with severe MD. Erythropoiesis activation, reticulocyte counts, and CFH levels were monitored in this model. ChemiDoc imaging system was used to visualize FITC‐dextran extravasation in fresh transversely cut pulmonary slices 24 hours after FITC‐dextran injection (60 mg/kg. i.v.). Changes in right ventricle (RV) hemodynamics were used to determine the level of disease severity. Pulmonary artery smooth muscle cells (PASMCs) isolated from wild‐type (WT) and NFU1G206C rats were used to evaluate effects of free heme in vitro. Matrigel assay was used to evaluate the tube formation potential of endothelial cells (EC’s).ResultsThe NFU1G206C rats showed significantly higher erythropoietin levels and immature reticulocyte counts compared to WTs. Correspondingly, significantly elevated plasma free heme and extravasation of FITC‐dextran into lung parenchyma were observed, indicating pulmonary endothelial barrier dysfunction, previously demonstrated as an essential contributor to PH pathobiology. Notably, treatment of human pulmonary artery EC’s with 50µM heme completely abolished EC tube formation, indicating that CFH could trigger a cellular environment leading to PH. Additionally, exposing isolated PASMC from NFU1G206C to 50µM heme increased the proliferation rate by ~1.5 and ~2.9 folds compared to untreated NFU1G206C or WT PASMC. Chronic lipoic acid (LA) supplementation to restore mitochondrial function (1.7mM orally), normalized total/immature reticulocyte counts in NFU1G206C rats (WT/NFU1G206C/NFU1G206C+LA for total and immature reticulocyte, p<0.002 and p<0.001) and fully reversed the PAH phenotype. Alternatively, the RV systolic pressure of NFU1G206C rats was significantly (p<0.0001) attenuated by blocking the heme transporter (HCP1) with sulfasalazine (SL, 20mg/ml/kg, i.p.).ConclusionWe show that mitochondrial dysfunction impaired reticulocyte maturation promotes hemolysis resulting in increased CFH. Elevated CFH can trigger pathogenic pathways leading to PH/PAH via EC barrier dysfunction and increased PASMC proliferation. Treatment approaches that improve mitochondrial metabolism (LA) or inhibit free heme entrance to the cell (SL) abrogate the PH phenotype, highlighting the critical role of free heme‐induced signaling in disease pathobiology.

FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19.

Long non‐coding RNAs (lncRNAs) play a significant role in pulmonary hypertension (PH). Our preliminary data showed that hypoxia‐induced PH is attenuated by fibroblast growth factor 21 (FGF21) administration. Therefore, we further investigated the regulatory role of long non‐coding RNAs in PH treated with FGF21. RNA sequencing analysis and real‐time PCR identified a significantly up‐regulation of the H19 after FGF21 administration. Moreover, gain‐ and loss‐of‐function assays demonstrated that FGF21 suppressed hypoxia‐induced proliferation of pulmonary artery smooth muscle cells partially through upregulation of H19. In addition, FGF21 deficiency markedly exacerbated hypoxia‐induced increases of pulmonary artery pressure and pulmonary vascular remodelling. In addition, AAV‐mediated H19 overexpression reversed the malignant phenotype of FGF21 knockout mice under hypoxia expose. Further investigation uncovered that H19 also acted as an orchestra conductor that inhibited the function of mechanistic target of rapamycin complex 1 (mTORC1) by disrupting the interaction of mTORC1 with eukaryotic translation initiation factor 4E–binding protein 1 (EIF4EBP1). Our work highlights the important role of H19 in PH treated with FGF21 and suggests a mechanism involving mTORC1/EIF4EBP1 inhibition, which may provide a fundamental for clinical application of FGF21 in PH.

Role of Pulmonary Hypertension in Acute Exacerbation of Chronic Obstructive Pulmonary Disease; Outcomes and Healthcare Utilization

<h3>Purpose</h3> Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). Mortality in COPD and PH has significantly improved due to advances made in the field, however, the effect of PH during acute exacerbation of COPD (AECOPD) remains unknown. We aim to analyze the outcomes, 30-day readmission rates, and healthcare resource utilization associated with PH in patients with AECOPD. <h3>Methods</h3> We used the 2016 and 2017 National Readmission Database with an inclusion criterion of AECOPD as a primary and PH as a secondary diagnosis using ICD 10-CM codes. Exclusion criteria were age under 18 years, non-elective admissions to better assess readmission rates and discharges in December. The primary outcome was in-hospital mortality during the index admission. Secondary outcomes were 30-day readmission rate, Length of stay (LOS), resource utilization, and instrument utilization including intubation, prolonged invasive mechanical ventilation >96hr (PIMV), tracheostomy, chest tube placement, and bronchoscopy during the index admission. <h3>Results</h3> A total of 627,848 patients with AECOPD were included in the study, and 68,429 (10.90 %) patients had a diagnosis of PH. PH was more common among females (61.14%) with a mean age of 71 ±11.66, Medicare recipients (79.5%), higher Charlson Comorbidity Index, and treatment in an urban teaching hospital. PH was associated with greater in-hospital mortality [Adjusted odds ratio (aOR): 1.89, p<0.001], higher 30-day readmission (aOR: 1.24, p<0.001), higher LOS [adjusted mean difference (aMD): 1.09, p<0.001], higher cost (aMD: $2785, p<0.01), and higher instrument utilization including intubation (aOR: 1.99, p<0.001), PIMV (aOR: 2.12, p<0.001), tracheostomy (aOR: 2.15, p<0.001), bronchoscopy (aOR:1.46, p=0.007) and chest tube placement (aOR: 1.39 p<0.004). <h3>Conclusion</h3> Our study indicates that PH is associated with greater in-hospital mortality, LOS, and 30-day readmission among patients with AECOPD. It is also associated with increased procedure utilization and higher healthcare resource utilization leading to increased hospital expenses. These factors lead to a detrimental effect on a patient's well-being and impact their quality of life. Prompt diagnosis and appropriate treatment of PH in patients with COPD may improve outcomes in these patients.

Endothelial cell ferroptosis mediates monocrotaline-induced pulmonary hypertension in rats by modulating NLRP3 inflammasome activation

Inflammation triggers pulmonary vascular remodelling. Ferroptosis, a nonapoptotic form of cell death that is triggered by iron-dependent lipid peroxidation and contributes to the pathogenesis of several inflammation-related diseases, but its role in pulmonary hypertension (PH) has not been studied. We examined endothelial cell ferroptosis in PH and the potential mechanisms. Pulmonary artery endothelial cells (PAECs) and lung tissues from monocrotaline (MCT)-induced PH rats were analysed for ferroptosis markers, including lipid peroxidation, the labile iron pool (LIP) and the protein expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1) and NADPH oxidase-4 (NOX4). The effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on endothelial cell ferroptosis and pulmonary vascular remodelling in MCT-induced rats were studied in vitro and in vivo. Ferroptosis was observed in PAECs from MCT-induced PH rats in vitro and in vivo and was characterized by a decline in cell viability accompanied by increases in the LIP and lipid peroxidation, the downregulation of GPX4 and FTH1 expression and the upregulation of NOX4 expression. High-mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signalling was measured by western blotting. These changes were significantly blocked by Fer-1 administration in vitro and in vivo. These results suggest that Fer-1 plays a role in inhibiting ferroptosis-mediated PAEC loss during the progression of PH. The ferroptosis-induced inflammatory response depended on the activation of HMGB1/TLR4 signalling, which activated the NLRP3 inflammasome in vivo. We are the first to suggest that pulmonary artery endothelial ferroptosis triggers inflammatory responses via the HMGB1/TLR4/NLRP3 inflammasome signalling pathway in MCT-induced rats. Treating PH with a ferroptosis inhibitor and exploring new treatments based on ferroptosis regulation might be promising therapeutic strategies for PH.

Association of nutritional status and mortality risk in patients with primary pulmonary hypertension.

Malnutrition plays a crucial role in pulmonary hypertension (PH). The prognostic nutritional index (PNI) is a reliable indicator for nutritional status assessment. However, its relationship with mortality risk in PH patients has not yet been investigated. This study analyzed data from the Patient Registry for Primary PH. PNI was calculated through albumin and lymphocyte counts. Subjects with missing data for PNI calculation were excluded. The primary endpoint was all‐cause mortality. Cox proportional hazard model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Of the 317 patients records available in the registry, we finally included 136 patients. The average age of the included subjects was 40.56 (14.91) years and 63.24% (86/136) were female. In our analysis of Cox regression, per 1‐point increment of PNI was associated with 4% decreased risk of mortality in PH patients (age‐ and sex‐adjusted HR: 0.96, 95% CI: 0.93–0.98, p = 0.002). We further categorized these subjects by quartiles of PNI. Compared to quartile 4, the age‐ and sex‐adjusted HRs of death for quartiles 1, 2, and 3 were 2.39 (95% CI: 1.21–4.72, p = 0.01), 2.25 (95% CI: 1.15–4.39, p = 0.02), and 1.72 (95% CI: 0.84–3.52, p = 0.14). In addition, logistic regression analyses suggested a positive correlation of PNI with total lung capacity (β = 0.98, p = 0.002) and forced expiratory volume in 1 min (β = 1.53, p = 0.03). This study demonstrates that low PNI was associated with an increased risk of death in PH patients. These findings help to enlighten our understanding of the nutritional status and adverse outcomes in PH patients.

Predictive association of pulmonary hypertension with risks of adverse renal outcomes in type 2 diabetes

Abstract Background Diabetic kidney disease is a major diabetic complication which contributes to the end-stage renal disease and renal deaths in diabetic patients. The aim of our study was to investigate the role of pulmonary hypertension (PHT) in the development of adverse renal outcomes in patients with type 2 diabetes (T2DM). Methods A total of 1479 diabetic patients (mean age 67±13 years; women, 44.7%) were recruited. Pulmonary artery systolic pressure (PASP) was estimated by transthoracic echocardiography at baseline. Adverse renal outcomes were defined as a composite endpoint of a sustained 40% decline in eGFR, end-stage renal disease requiring renal replacement therapy, kidney transplantation or renal deaths. Cox regression hazard model was used to assess the association between PHT and incident adverse renal outcomes. Results Patients were divided into three groups based on their baseline PASP: no PHT (n=1204, 75.1%), mild PHT (321, 20.0%) and significant PHT (78, 4.9%). A total of 474 adverse renal outcomes occurred during a median follow-up of 53 months, Kaplan-Meier survival curve showed that patients with significant PHT had highest risk of adverse renal outcomes. Multivariate cox regression demonstrated both mild PHT (HR=1.66, 95% CI 1.33, 2.06, P&amp;lt;0.001) and significant PHT (HR=2.09, 95% CI 1.45, 3.02, P&amp;lt;0.001) were independently associated with the incident adverse renal outcomes. Conclusion The presence of PHT was associated with adverse renal outcomes in patients with T2DM. Funding Acknowledgement Type of funding sources: None.

PLASMA LEVEL OF ANTIMONY CORRELATES WITH PULMONARY HYPERTENSION SEVERITY

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: Heavy metals are linked to cardiovascular disease, but the relationship between heavy metals and pulmonary arterial hypertension (PAH) is not clear. We hypothesized that there may be a correlation between heavy metal levels and the severity of pulmonary hypertension METHODS: A prospective, single center pilot study recruited patients from our pulmonary hypertension center over a period of 3 months. Patients with PAH who were ≥ 18 years old were eligible to participate. We obtained IRB approval and all the participated patients signed an informed consent. Blood and urine samples were collected to measure essential and non-essential metal levels in blood, plasma, and urine using an X Series II quadrupole inductively coupled plasma mass spectrometry (ICP-MS, Thermo Fisher Scientific). Also, we collected demographics, hemodynamics, last 6 minute walk distance (6MWD), last available BNP level, and REVEAL Lite 2 risk score. Statistical analysis was performed using statistical software R and p value<0.05 was considered significant. RESULTS: A total of 20 patients with PAH were included in the study. The mean age was 57.6±11.8 years, 80% were female and 6 patients had idiopathic PAH. All the patients were receiving PAH combination therapies including a prostanoid agent (13 on parenteral treprostinil, 1 on epoprostenol, 5 on inhaled treprostinil, and 1 on selexipag) with a mean parenteral treprostinil dose of 67.8±28.9 ng/kg/min. Mean last 6MWD was 312.7m±96.2 and mean last BNP level was 118.3±129.6 pg/ml. RVEAL Lite 2 risk score was low in 9 patients, intermediate in 6, and high in 4 patients. Mean hemodynamic values were mRAP 5.9±4.4 mmHg, mPAP 45.6±13.9 mmHg, PAWP 8±3.5 mmHg, CO 5.1±1.4L/min, CI 2.86±1.1 L/min/m2, and PVR 8.32±4.4 WU. There was significant correlation between plasma level of 121Sb (Antimony) and mRAP (r=0.47, p=0.036), CO (r=-0.50, p=0.026), CI (r=-0.54, p=0.014), PVR (r=0.52, p=0.019), and PA saturation (r=-0.54, p=0.016). CONCLUSIONS: We found significant correlations between plasma level of 121Sb and prognostic hemodynamic markers of disease severity in PAH patients without known prior history of occupational heavy metal exposure. CLINICAL IMPLICATIONS: Antimonial compounds are still used in treatment of Leishmaniasis with cardiac toxicity being one of the known potential side effects. Ventricular myocytes of guinea-pigs treated with trivalent antimony showed impaired contraction responses to changes in stimulus frequency, reduced calcium current, and elongated action potential. However, significant correlation between serum 121Sb levels with the prognostic hemodynamic markers of disease severity in PAH patients has not been reported. This finding may suggest that environmental 121Sb can have a potential role in pulmonary hypertension and right ventricular dysfunction. More studies are needed to further elucidate this role and its mechanism. DISCLOSURES: No relevant relationships by Ozan Akca, source=Web Response No relevant relationships by Lu Cai, source=Web Response No relevant relationships by Oscar Chen, source=Web Response Speaker/Speaker's Bureau relationship with United therapeutics Please note: $5001 - $20000 by Karim El-Kersh, source=Web Response, value=Honoraria Removed 04/21/2021 by Karim El-Kersh, source=Web Response Advisory Committee Member relationship with United therapeutics Please note: $1001 - $5000 by Karim El-Kersh, source=Web Response, value=Consulting fee Removed 04/21/2021 by Karim El-Kersh, source=Web Response Advisory Committee Member relationship with Actelion Please note: $5001 - $20000 by Karim El-Kersh, source=Web Response, value=Consulting fee Removed 04/21/2021 by Karim El-Kersh, source=Web Response Advisory Committee Member relationship with United Therapeutics Please note: Current Added 04/23/2021 by Karim El-Kersh, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Actelion Please note: 2019 and 2020 Added 04/23/2021 by Karim El-Kersh, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with United Therapeutics Please note: Current Added 04/29/2021 by Karim El-Kersh, source=Web Response, value=Honoraria Advisory Committee Member relationship with United Therapeutics Please note: Current Added 04/29/2021 by Karim El-Kersh, source=Web Response, value=Honoraria Advisory Committee Member relationship with Actelion Please note: 2019 and 2020 Added 04/29/2021 by Karim El-Kersh, source=Web Response, value=Honoraria Consultant relationship with Acceleron Pharma Please note: Current Added 04/29/2021 by Karim El-Kersh, source=Web Response, value=Consulting fee No relevant relationships by C. Danielle Hopkins, source=Web Response Consultant relationship with GE Healthcare Please note: 2019-Present Added 04/27/2021 by Jiapeng Huang, source=Web Response, value=Consulting fee Research grant relationship with Gilead Sciences Please note: 2020-2022 Added 04/27/2021 by Jiapeng Huang, source=Web Response, value=Grant/Research Support Consultant relationship with GE Healthcare Please note: 2019 to Present Added 04/27/2021 by Jiapeng Huang, source=Web Response, value=Consulting fee Research Funding relationship with Gilead Sciences Please note: 2020-2022 Added 04/27/2021 by Jiapeng Huang, source=Web Response, value=Grant/Research Support No relevant relationships by Caitlin Wessel, source=Web Response

Innovative Anti-Inflammatory and Pro-resolving Strategies for Pulmonary Hypertension: High Blood Pressure Research Council of Australia Award 2019.

Pulmonary hypertension is a rare, ostensibly incurable, and etiologically diverse disease with an unacceptably high 5-year mortality rate (≈50%), worse than many cancers. Irrespective of pathogenic origin, dysregulated immune processes underlie pulmonary hypertension pathobiology, particularly pertaining to pulmonary vascular remodeling. As such, a variety of proinflammatory pathways have been mooted as novel therapeutic targets. One such pathway involves the family of innate immune regulators known as inflammasomes. In addition, a new and emerging concept is differentiating between anti-inflammatory approaches versus those that promote pro-resolving pathways. This review will briefly introduce inflammasomes and examine recent literature concerning their role in pulmonary hypertension. Moreover, it will explore the difference between inflammation-suppressing and pro-resolution approaches and how this links to inflammasomes. Finally, we will investigate new avenues for targeting inflammation in pulmonary hypertension via more targeted anti-inflammatory or inflammation resolving strategies.

Carbohydrate Antigen 125 Is a Biomarker of the Severity and Prognosis of Pulmonary Hypertension.

Background: Emerging evidence has showed that serum carbohydrate antigen 125 (CA 125) levels are associated with the severity and prognosis of heart failure. However, its role in pulmonary hypertension remains unclear. This study aimed to investigate the clinical, echocardiographic, hemodynamic, and prognostic associations of CA 125 in pulmonary hypertension.Methods and Results: We conducted a retrospective cohort study of all idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients receiving CA 125 measurement in Fuwai Hospital (January 1, 2014–December 31, 2018). The primary end-point was cumulative 1-year clinical worsening-free survival rate. Linear regression was performed to assess the association between CA 125 and clinical, echocardiographic, and hemodynamic parameters. Cox proportional hazards models were used to assess the association between CA 125 and clinical worsening events. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive performance of CA 125. A total of 231 patients were included. After adjustment, CA 125 still positively correlated with World Health Organization functional class, NT-proBNP, right ventricular end-diastolic diameter, pericardial effusion, mean right atrial pressure and pulmonary arterial wedge pressure; negatively correlated with 6-min walk distance, left ventricular end-diastolic diameter, mixed venous oxygen saturation, and cardiac index. After adjustment, CA 125 > 35 U/ml was associated with over 2 folds increased risk of 1-year clinical worsening. Further, ROC analysis showed that CA 125 provided additional predictive value in addition to the established pulmonary hypertension biomarker NT-proBNP.Conclusion: CA 125 was associated with functional status, echocardiography, hemodynamics and prognosis of pulmonary hypertension.

Eplerenone Improves Pulmonary Vascular Remodeling and Hypertension by Inhibition of the Mineralocorticoid Receptor in Endothelial Cells.

[Figure: see text].

Chronic Inhibition of Toll-Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats.

BackgroundRecent accumulating evidence suggests that toll‐like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension.Methods and ResultsA rat model of monocrotaline‐induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline‐exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin‐6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline‐exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF‐κB activation and interleukin‐6 mRNA levels to a similar extent. In the short‐term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF‐κB activation and interleukin‐6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline‐exposed rats.ConclusionsTLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF‐κB‒IL‐6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.

Endothelin-1 and peak oxygen consumption in patients with heart failure with preserved ejection fraction

BackgroundMechanisms of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) are not well understood. Pulmonary hypertension, a common accompaniment in patients with HFpEF, is associated with poor outcomes. While Endothelin -1 (ET-1) plays a mechanistic role in pulmonary hypertension, its role in exercise intolerance in HFpEF is not well established. ObjectiveTo explore the association between plasma ET-1 levels and maximal oxygen consumption (pVO2), and their changes over 24 weeks in HFpEF. MethodsThis is a post-hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. We performed linear regressions to assess the relationship between plasma ET-1 and pVO2. We also used linear regressions to determine whether ET-1 was associated with change in peak VO2 (ΔpVO2). ResultsA total of 210 patients were included. Baseline plasma ET-1 levels were associated with older age, higher NT-proBNP levels, higher serum creatinine levels, and higher prevalence of atrial fibrillation. Patients with higher ET1 levels also had higher plasma galectin-3 and CITP levels. After multiple adjustments, baseline ET1 levels were associated with lower pVO2 (β -0.927, SE 0.196, p < 0.001). Over 24 weeks, the change in ET1 levels was associated with the change in pVO2 (multivariable adjusted β -0.415, SE 0.115, p = 0.018). Baseline ET1 levels did not modify the effect of sildenafil on change in peak VO2. ConclusionsPlasma ET1 levels are significantly associated with lower exercise oxygen consumption both at baseline and longitudinally over 24 weeks. Future studies should explore Endothelin-1 antagonism to improve exercise tolerance in HFpEF.

Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders.

Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension. Pulmonary hypertension due to an exaggerated hypoxic pulmonary vasoconstriction contributes to high altitude pulmonary edema (HAPE), a life-threatening disorder, occurring at high altitudes in non-acclimatized healthy individuals. Despite a strong physiologic rationale for using vasodilators for prevention and treatment of HAPE, no systematic studies of their efficacy have been conducted to date. Calcium-channel blockers are currently recommended for drug prophylaxis in high-risk individuals with a clear history of recurrent HAPE based on the extensive clinical experience with nifedipine in HAPE prevention in susceptible individuals. Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure. Further, pulmonary hypertension along with excessive erythrocytosis may complicate chronic mountain sickness, another high altitude maladaptation disorder. Importantly, other causes than hypoxia may potentially underlie and/or contribute to pulmonary hypertension at high altitude, such as chronic heart and lung diseases, thrombotic or embolic diseases. Extensive clinical experience with drugs in patients with pulmonary arterial hypertension suggests their potential for treatment of high altitude pulmonary hypertension. Small studies have demonstrated their efficacy in reducing pulmonary artery pressure in high altitude residents. However, no drugs have been approved to date for the therapy of chronic high altitude pulmonary hypertension. This work provides a literature review on the role of pulmonary hypertension in the pathogenesis of acute and chronic high altitude maladaptation disorders and summarizes current knowledge regarding potential treatment options.

Long Noncoding RNA TYKRIL Plays a Role in Pulmonary Hypertension via the p53-mediated Regulation of PDGFRβ.

Rationale: Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored.Objectives: To elucidate the role of TYKRIL (tyrosine kinase receptor–inducing lncRNA) as a regulator of p53/ PDGFRβ (platelet-derived growth factor receptor β) signaling pathway and to investigate its role in PAH.Methods: Pericytes and pulmonary arterial smooth muscle cells exposed to hypoxia and derived from patients with idiopathic PAH were analyzed with RNA sequencing. TYKRIL knockdown was performed in above-mentioned human primary cells and in precision-cut lung slices derived from patients with PAH.Measurements and Main Results: Using RNA sequencing data, TYKRIL was identified to be consistently upregulated in pericytes and pulmonary arterial smooth muscles cells exposed to hypoxia and derived from patients with idiopathic PAH. TYKRIL knockdown reversed the proproliferative (n = 3) and antiapoptotic (n = 3) phenotype induced under hypoxic and idiopathic PAH conditions. Owing to the poor species conservation of TYKRIL, ex vivo studies were performed in precision-cut lung slices from patients with PAH. Knockdown of TYKRIL in precision-cut lung slices decreased the vascular remodeling (n = 5). The number of proliferating cell nuclear antigen–positive cells in the vessels was decreased and the number of terminal deoxynucleotide transferase–mediated dUTP nick end label–positive cells in the vessels was increased in the LNA (locked nucleic acid)-treated group compared with control. Expression of PDGFRβ, a key player in PAH, was found to strongly correlate with TYKRIL expression in the patient samples (n = 12), and TYKRIL knockdown decreased PDGFRβ expression (n = 3). From the transcription factor–screening array, it was observed that TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRβ. RNA immunoprecipitation using various p53 mutants demonstrated that TYKRIL binds to the N-terminal of p53 (an important region for p300 interaction with p53). The proximity ligation assay revealed that TYKRIL interferes with the p53–p300 interaction (n = 3) and regulates p53 nuclear translocation.Conclusions: TYKRIL plays an important role in PAH by regulating the p53/PDGFRβ axis.

High plasma adiponectin is associated with increased pulmonary blood flow and reduced right ventricular function in patients with pulmonary hypertension

BackgroundAdiponectin is a biomarker closely related to heart failure. However, its role in pulmonary hypertension remains unclear. In this study, we investigated the association between adiponectin and hemodynamic abnormalities, right ventricular function in patients with congenital heart disease associated pulmonary hypertension (CHD-PH).MethodsPatients with CHD-PH were enrolled in this cross-sectional study. Linear regression analysis was performed to assess the association between adiponectin, N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and different clinical parameters. Results were depicted as beta-estimates(ß) with 95%-confidence intervals (95% CI). In addition, mediation and receiver operating characteristic curve analyses were used to analyze the relationships among adiponectin, NT-proBNP and right ventricular function.ResultsA total of 86 CHD-PH patients were included. The overall mean adiponectin concentration was 7.9 ± 5.8 μg/ml. Log adiponectin was positively correlated with pulmonary circulation index (ß = 2.2, 95% CI 0.5, 4.0), log NT-proBNP (ß = 0.22, 95% CI 0.04, 0.41) and inversely with the tricuspid annular plane systolic excursion (TAPSE, ß = -4.7, 95% CI -8.6, − 0.8). The mediation analysis revealed the association between NT-proBNP and TAPSE was fully mediated by adiponectin (total effect c = − 5.4, 95% CI -9.4, − 1.5, p = 0.013; direct effect c’ = − 3.7, 95% CI -7.5, 0.1, p = 0.067). Additionally, the efficiency of adiponectin for detecting right ventricular dysfunction was not inferior to NT-proBNP (AUC = 0.84, 95% CI 0.67–1.00 vs AUC = 0.74, 95% CI 0.51–0.97, p = 0.23).ConclusionsAdiponectin is closely correlated with pulmonary blood flow and right ventricular function and may be a valuable biomarker for disease assessment in patients with pulmonary hypertension.

Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-\u03baB/cyclin D1 pathway

Ca2+ signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). However, the underlying specific ion channel mechanisms remain largely unknown. Here, we report ryanodine receptor (RyR) channel activity and Ca2+ release both are increased, and association of RyR2 by FK506 binding protein 12.6 (FKBP12.6) is decreased in PASMCs from mice with chronic hypoxia (CH)-induced PH. Smooth muscle cell (SMC)-specific RyR2 knockout (KO) or Rieske iron-sulfur protein (RISP) knockdown inhibits the altered Ca2+ signaling, increased nuclear factor (NF)-κB/cyclin D1 activation and cell proliferation, and CH-induced PH in mice. FKBP12.6 KO or FK506 treatment enhances CH-induced PH, while S107 (a specific stabilizer of RyR2/FKBP12.6 complex) produces an opposite effect. In conclusion, CH causes RISP-dependent ROS generation and FKBP12.6/RyR2 dissociation, leading to PH. RISP inhibition, RyR2/FKBP12.6 complex stabilization and Ca2+ release blockade may be potentially beneficial for the treatment of PH.

Comprehensive network analysis to identify the molecular pathogenesis of pulmonary hypertension.

Pulmonary hypertension (PAH) is a chronic progressive disease that may lead to right heart failure and eventually death. At present, great progress had been achieved in the treatment of pulmonary hypertension. However, pulmonary hypertension cannot be fundamentally cured, and its pathogenesis is still unclear. A multifactor-driven dysfunction module of pulmonary hypertension has been constructed in order to explore its potential pathogenesis. We performed differential expression analysis, coexpression analysis, enrichment analysis and hypergeometric test to calculate the potential regulatory effects of multiple factors on the module. Four modules and corresponding hub genes were identified. In addition, we also obtained a series of ncRNA (MALAT1 and miR-17-5p) and transcription factor (HIF1A). Network analysis revealed that MALAT1, NFKB1 and RELA targeting IL1B of module 4 and IL6 of module 1 to participate in the occurrence and development of pulmonary hypertension through Toll-like receptor signaling pathway. It is necessary to identify disease-related disorders by integrating multiple regulatory factors. The regulatory network may play an important role in PAH. The results not only provided new methods and ideas for follow-up research, but also helps researchers to have a deeper understanding of potential pathogenesis for PAH.

Expression of Kv11.1 Channels in Lungs and Role in Pulmonary Hypertension

BackgroundWhile Kv11.1 potassium selective channels are well known for their contribution to the heart repolarization little is known about their importance for the lung function. Here we show that Kv11.1 channels are abundantly expressed in the human and rat lung tissues.Methods &amp; ResultsWe found that, in the lungs of healthy humans and rats, Kv11.1 channel expression was limited to the large pulmonary arteries (PAs). In the lungs of human patients with chronic obstructive pulmonary disease (COPD) and of rats with pulmonary arterial hypertension (PAH), Kv11.1 channels were expressed not only in the large PAs, but also in the small PAs with the diameter &lt;100 micrometers. The increase in the Kv11.1 channel expression followed the time course of the development of pulmonary vascular remodeling in PAH rats. Administration of dofetilide, a Kv11.1 blocker, to rats with PAH inhibited PAH‐associated pulmonary vascular remodeling.ConclusionsOur study indicates that Kv11.11 channels are expressed in the lung and that these channels mediate the development of pulmonary vascular remodeling. Dofetilide is an FDA approved drug used for treatment of atrial fibrillation. Thus, our findings raise a possibility of repurposing this antiarrhythmic drug for the treatment of pulmonary hypertension.Support or Funding InformationSupported by NIH

G Protein Coupled Receptor 75 and Its Role in Pulmonary Hypertension

Pulmonary Hypertension (PH) is a multifactorial disease with poor prognosis and inadequate treatment. Recent studies have shown that the orphan G Protein Coupled Receptor 75 (GPR75) is upregulated in the pulmonary vessels of PH patients, especially in females. Therefore, we hypothesized that GPR75 knock out (GPR75KO) mice will be protected from developing PH. We placed 3‐month‐old female GPR75KO (n=6) and control C57BL/C mice (n=10) in a hypoxic chamber with 10% Oxygen or at atmospheric oxygen for 5 weeks. At the end of 5 weeks, we performed echocardiograms and right heart catheterizations. GPR75KO mice were protected from developing PH (Right Ventricle Systolic Pressure (RVSP) of 26mmHg and Right Ventricle Diastolic Pressure (RVDP) of 2 mmHg), while C57BL/C mice developed PH under hypoxia (RSVP and RDVP of 56mmHg and 12mmHg, respectively). Wire myography was performed on isolated intra‐lobar pulmonary arteries from GPR75KO mice (n=3) and WT mice (n=31). Hypoxic pulmonary vasoconstriction (HPV) was abolished in GPR75KO as compared to WT. HPV response in WT was blocked (P&lt;0.05) by antibody against RANTES (CCL5), a putative GPR75 ligand. These results suggest GPR75 plays a major role in the development of HPV and PH.Support or Funding InformationThis study was supported by NIH grant 1RO1HL139793 (MLS).

Protective role of myelocytic nitric oxide synthases in pulmonary hypertension due to lung diseases and/or hypoxia

Nitric oxide (NO), formed from NO synthases (NOSs), plays a pathogenetic role in pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remains to be clarified. We addressed this point in clinical and basic studies. We demonstrated that, in 36 consecutive patients with idiopathic pulmonary fibrosis, pulmonary artery systolic pressure is inversely correlated with NOx levels in the bronchoalveolar lavage fluid, suggesting reduced pulmonary NO production in group III PH. We then revealed that transplantation of BM cells from mice lacking all NOSs aggravates hypoxia-induced PH in wild-type (WT) mice, and transplantation of BM cells from the WT mice ameliorates hypoxia-induced PH in the NOSs-/- mice, indicating a protective role of myelocytic NOSs in the pathogenesis of PH. Immune and inflammatory mechanisms appeared to be involved in the aggravation of hypoxia-induced PH caused by transplantation of BM cells from the NOSs-/- mice. Our findings provide novel insights into the cellular and molecular basis of group III PH.