Progression Of PAH Research Articles

Investigation into the role of H2-Ab1 in vascular remodeling in pulmonary arterial hypertension via Bioinformatics

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease of vascular remodeling characterized by persistent pulmonary arterial pressure elevation, which can lead to right heart failure and premature death. Given the complex pathogenesis and poor prognosis of PAH, the identification and investigation of biomarkers become increasingly critical for advancing further understanding of the disease.MethodsPAH-related datasets, GSE49114, GSE180169 and GSE154959, were downloaded from the publicly available GEO database. By performing WGCNA on the GSE49114 dataset, a total of 906 PAH-related key module genes were screened out. By carrying out differential analysis on the GSE180169 dataset, a total of 576 differentially expressed genes were identified. Additionally, the GSE154959 single-cell sequencing dataset was also subjected to differential analysis, leading to the identification of 34 DEGs within endothelial cells. By taking intersection of the above three groups of DEGs, five PAH-related hub genes were screened out, namely Plvap, Cyp4b1, Foxf1, H2-Ab1, and H2-Eb1, among which H2-Ab1 was selected for subsequent experiments.ResultsA SuHx mouse model was prepared using the SU5416/hypoxia method, and the successful construction of the model was evaluated through Hematoxylin-Eosin staining, hemodynamic detection, fulton index, and Western Blot (WB). The results of WB and qRT-PCR demonstrated a significant upregulation of H2-Ab1 expression in SuHx mice. Consistent with the results of bioinformatics analysis, a time-dependent increase was observed in H2-Ab1 expression in hypoxia-treated mouse pulmonary artery endothelial cells (PAECs). To investigate whether H2-Ab1 affects the development and progression of PAH, we knocked down H2-Ab1 expression in PAECs, and found that its knockdown inhibited the viability, adhesion, migration, and angiogenesis, while concurrently promoted the apoptosis of PAECs.ConclusionH2-Ab1 could regulate the proliferation, apoptosis, adhesion, migration, and angiogenesis of PAECs.

The influence of anxiety and depressive disorders on the development of resistant arterial hypertension

The problem of comorbidity of cardiovascular diseases (CVD) and anxiety-depressive disorders is actively discussed in modern scientific literature. Taking into account the widespread prevalence of anxiety and depressive disorders in the population, their negative impact on the quality of life and functioning of patients, prerequisites are accumulating for the diagnosis and treatment of these conditions by non-psychiatric doctors. The review presents current data on risk factors, relationships and principles for diagnosing resistant arterial hypertension (RAH) and anxiety-depressive disorders. The prevalence of resistant arterial hypertension is about 10–20 %, with a significant proportion of cases accounting for secondary arterial hypertension and pseudoresistance. The incidence of anxiety and depressive disorders in patients with arterial hypertension is 42 % and 52 %, respectively. The prevalence of anxiety and depressive disorders in RAH is 36.8 %. Such comorbidity contributes to the progression of PAH, worsens the patient’s prognosis, and reduces adherence to therapy. Given the close relationship between psychoemotional factors and CVD, patients with RAH are advised to undergo screening for anxiety and depression.

Identification of MACC1 as a potential biomarker for pulmonary arterial hypertension based on bioinformatics and machine learning

BackgroundPulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormal early activation of pulmonary arterial smooth muscle cells (PASMCs), yet the underlying mechanisms remain to be elucidated. MethodsNormal and PAH gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database and analyzed using gene set enrichment analysis (GSEA) to uncover the underlying mechanisms. Weighted gene co-expression network analysis (WGCNA) and machine learning methods were deployed to further filter hub genes. A number of immune infiltration analysis methods were applied to explore the immune landscape of PAH. Enzyme-linked immunosorbent assay (ELISA) was employed to compare MACC1 levels between PAH and normal subjects. The important role of MACC1 in the progression of PAH was verified through Western blot and real-time qPCR, among others. Results39 up-regulated and 7 down-regulated genes were identified by ‘limma’ and ‘RRA’ packages. WGCNA and machine learning further narrowed down the list to 4 hub genes, with MACC1 showing strong diagnostic capacity. In vivo and in vitro experiments revealed that MACC1 was highsly associated with malignant features of PASMCs in PAH. ConclusionsThese findings suggest that targeting MACC1 may offer a promising therapeutic strategy for treating PAH, and further clinical studies are warranted to evaluate its efficacy.

Maresin-1 protects against pulmonary arterial hypertension by improving mitochondrial homeostasis through ALXR/HSP90α axis

AimsPulmonary arterial hypertension (PAH) is a progressive and lethal disease characterized by continuous proliferation of pulmonary arterial smooth muscle cell (PASMCs) and increased pulmonary vascular remodeling. Maresin-1 (MaR1) is a member of pro-resolving lipid mediators and exhibits protective effects on various inflammation-related diseases. Here we aimed to study the role of MaR1 in the development and progression of PAH and to explore the underlying mechanisms. Methods and resultsWe evaluated the effect of MaR1 treatment on PAH in both monocrotaline (MCT)-induced rat and hypoxia+SU5416 (HySu)-induced mouse models of pulmonary hypertension (PH). Plasma samples were collected from patients with PAH and rodent PH models to examine MaR1 production. Specific shRNA adenovirus or inhibitors were used to block the function of MaR1 receptors. The data showed that MaR1 significantly prevented the development and blunted the progression of PH in rodents. Blockade of the function of MaR1 receptor ALXR, but not LGR6 or RORα, with BOC-2, abolished the protective effect of MaR1 against PAH development and reduced its therapeutic potential. Mechanistically, we demonstrated that the MaR1/ALXR axis suppressed hypoxia-induced PASMCs proliferation and alleviated pulmonary vascular remodeling by inhibiting mitochondrial accumulation of heat shock protein 90α (HSP90α) and restoring mitophagy. ConclusionMaR1 protects against PAH by improving mitochondrial homeostasis through ALXR/HSP90α axis and represents a promising target for PAH prevention and treatment.

Mortality and prognostic factors in connective tissue disease-associated pulmonary arterial hypertension patients complicated with right heart failure.

To identify predictive factors associated with mortality in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) patients who were complicated with right heart failure (RHF). In this single-center retrospective study, baseline demographics, clinical features, laboratory results, and hemodynamic assessments were collected. Kaplan-Meier analysis was applied to analyze all-cause mortality. Univariate and forward stepwise multivariate Cox proportional regression analyses were performed to identify independent predictors of mortality. A total of 51 right heart catheterization-confirmed CTD-PAH patients complicated with RHF were consecutively enrolled in this study from 2012 to 2022. Forty-eight (94%) enrolled patients were female and the mean age was 36.0 ± 11.8 years. Thirty-two (61.5%) were systemic lupus erythematosus-PAH and 33%/67% showed World Health Organization functional class III/IV, respectively. Twenty-five (49%) of those patients died and Kaplan-Meier analysis showed the overall 1-, 3-, and 5-week survival rates from the time of hospitalization as 86.28%, 60.78%, and 56.86%, respectively. RHF in CTD-PAH patients mainly resulted from progression of PAH (n=19) and infection (n=5), which also contributed to the leading causes of death. Statistical analysis between survivors and non-survivors showed that death from RHF was associated with higher levels of urea (9.66 vs 6.34 mmol/L, P=0.002), lactate (cLac: 2.65 vs 1.9 mmol/L, P=0.006), total bilirubin (23.1 vs 16.9 μmol/L, P=0.018) and direct bilirubin (10.5 vs 6.5 μmol/L, P=0.004), but with lower levels of hematocrit (33.7 vs 39, P=0.004), cNa+ (131 vs 136 mmol/L, P=0.003). Univariate and forward stepwise multivariate Cox proportional regression analyses indicated that the level of cLac (hazards ratio:1.297; 95% CI: 1.076-1.564; P=0.006) was an independent risk factor for mortality. The short-term prognosis of CTD-PAH complicated with RHF was very poor, and hyperlactic acidemia (cLac > 2.85 mmoL/L) was an independent predicting factor for mortality of CTD-PAH patients complicated with RHF.

Abstract 15659: Development of Novel EMAP-II Neutralizing Antibody Therapy for HIV-Associated Pulmonary Hypertension via Abrogation of HIV-Nef Induced Pulmonary Endothelial Damage

Rationale: People living with HIV experience increased rates of cardiovascular co-morbidities including pulmonary hypertension (600-fold higher prevalence) despite immediate prescription of combined antiviral therapy (ART) upon HIV diagnosis. Previously, we reported that the virally encoded HIV-Nef protein persists in extracellular vesicles (EV) isolated from bronchoalveolar lavage fluid of aviremic HIV patients on ART. Interestingly, Nef-positivity correlated with increased EMAPII levels, a cellular protein which when released extracellularly specifically amplifies endothelial apoptosis. We hypothesize that Nef-EMAPII signaling axis induces endothelial apoptosis and senescence, which could give rise to apoptosis-senescence-resistant, plexiform lesion-forming endothelial cells. Methods and Results: Co-culture with Nef EV producing SupT1 T-cells induces endothelial senescence quantified using senescence associated marker-p16INK4a (p<0.001) which corresponds to increased EMAPII surface expression. Nef induced endothelial senescence as quantified by β-Galactosidase activity was blocked with EMAPII neutralizing antibody (Fig). Transgenic mice with endothelium specific Nef expression had elevated EMAP II surface expression. Two-dose injection of EMAPII neutralizing antibodies (1 mg/mouse, sc) abrogates apoptosis induction as determined by cleaved caspase 3+ pulmonary endothelial cells (p<0.001). Furthermore, Nef Tg mice derived pulmonary endothelial cells had reduced colony formation (p<0.001) which is being tested with EMAPII neutralization as a therapeutic agent. Conclusion: Nef induced apoptosis and cellular senescence can be targeted with EMAP II neutralizing antibodies both in vitro and in vivo . These data suggest that A) Nef can give rise to apoptosis-senescence-resistant plexiform lesion forming endothelial cells and B) neutralizing EMAPII antibodies can be employed to block progression of PAH.

Integrated metabolomics and mechanism to reveal the protective effect of kaempferol on pulmonary arterial hypertension

Currently, there have been breakthroughs in the study of the underlying mechanisms of pulmonary arterial hypertension, but treatment is still challenging. The aim of this study was explore the effect of kaempferol in PAH and discover the mechanism of this process. First, we assessed the effect of kaempferol in animal models of PAH. The echocardiography and pressure-volume admittance catheter data showed that kaempferol could improve right ventricular function and alleviate the progression of PAH. Moreover, morphometric analysis of the lung vasculature indicated that pulmonary vascular remodeling could be reduced by kaempferol. The expression of autophagy-related proteins and autophagic processes were evaluated by western blotting and mRFP-GFP-LC3 fluorescence microscopy, the results indicated that autophagy played an important role in the process by which kaempferol prevents PAH. Moreover, we performed untargeted and targeted plasma metabolomics analysis on rat models of PAH and used multivariate analysis to reveal multiple pathways and targets. Consequently, we identified 247 plasma biomarkers that were tightly linked to the preventive effects of kaempferol, which were mainly related to amino acid metabolism and arachidonic acid metabolism. In conclusion, kaempferol could effectively alleviate the development of PAH by regulating abnormal autophagy and metabolic disorders, providing a novel perspective on the treatment of PAH.

At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension.

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

A study on clinical manifestations, radiological features, electrocardiographic and echocardiographic changes in various lung diseases associated with cor-pulmonale in patients attending Government General Hospital, Kakinada

Cor-pulmonale is an alteration in the structure and function of right ventricle secondary to many broncho-pulmonary vascular diseases and from different chest wall abnormalities. The development of PAH has an important prognostic role, as it significantly increases the risk of hospitalization and is associated with reduced survival.100 patients of cor-pulmonale confirmed by clinical, radiological and electrocardiographic manifestations from outpatient and inpatients in Pulmonology Department, Government General Hospital, RMC, Kakinada, over a period of November 2018-November 2019 were included in the study.Out of 100 study cases, most affected age group is 51-60 years, males were more affected than females maybe because of the fact number of smokers were male. Out of 100, seventy patients were smoker, of which 63 were male and 7 were female. Almost every patient of cor-pulmonale presented with dyspnea and cough and had features suggestive of RHF. On ECG, p-pulmonale was the most common finding followed by right axis deviation for cor-pulmonale. On ECHO, RVSP>60mmHg is found in 56%cases. Radiologically, 48% cases of cor-pulmonale were secondary to chronic bronchitis and emphysema.Echocardiographic screening of all patients with chronic lung disease especially the middle age males and the smokers will benefit in early detection of disease and initiation of treatment, thus improving their prognosis. A combined clinical, radiological, ECG andechocardiographic findings can give clue about progression of PAH and cor-pulmonale.

Upregulation of G protein‐couple receptor 68 (GPCR68) in pulmonary artery smooth muscle cells from animals and humans with pulmonary hypertension

IntroductionPulmonary arterial hypertension (PAH) is a progressive and fatal disease with no cure. It is characterized by elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in part due to pulmonary vascular remodeling and sustained pulmonary vasoconstriction. The increased pulmonary arterial smooth muscle cell (PASMC) proliferation contributes to excessive pulmonary vascular remodeling while a rise in cytosolic free Ca2+concentration ([Ca2+]cyt) in PASMC is a major trigger for pulmonary vasoconstriction and a key stimulus for PASMC proliferation. G‐protein coupled receptors (GPCR), which are attractive pharmacological targets, are important regulators of pulmonary vascular tone and PASMC phenotype. Stimulation of GPCR leads to Ca2+ influx and increased [Ca2+]cytdue to store‐operated Ca2+ entry (SOCE) via inositol 1,4,5‐trisphosphate (IP3) production and receptor‐operated Ca2+entry (ROCE) via diacylglycerol (DAG) production. GPCR68 (or OGR1) is a proton‐sensing GPCR that responds to extracellular acidity and regulates a variety of cellular functions. As a Gq/11‐coupled receptor, GPR68 activation is known to lead to Ca2+ release from the intracellular stores in IP3‐dependent manner but the role of GPCR68 in the development of PAH is still unknown.MethodsLung, heart, brain, liver, and kidney tissues were isolated from control rats. Pulmonary hypertension model was induced by a single dose of monocrotaline (MCT) in rats. PASMC isolated from control or MCT rats and healthy subjects or patients with idiopathic pulmonary arterial hypertension (IPAH) were cultured in 5% fetal bovine serum (FBS) smooth muscle growth media and incubated in a humidified 5% CO2 atmosphere at 37°C. Total RNA was isolated from tissue or cells using TRIZOL method. mRNA expression of GPCR68 was quantified by RT‐PCR and qRT‐PCR. The data was analyzed using ImageJ and statistical analysis was performed using paired or unpaired Student’s t‐test.ResultsRT‐PCR analysis revealed that GPCR68 is expressed in brain, lung, heart, liver, and kidney in normal rat tissues (n=5). GPCR68 mRNA level was significantly higher in lung tissue and PASMC isolated from MCT‐treated rats compared with controls. Moreover, our data shows that GPCR68 is expressed in both human PASMC and pulmonary arterial endothelial cells. qRT‐PCR showed that GPCR68 was upregulated in PASMC isolated from IPAH patients compared with cells isolated from healthy subjects.ConclusionOur finding suggest that GPR68 is involved in the development and progression of PAH and may play an important role in Ca2+ signaling and enhanced [Ca2+]cyt in PASMC from animals and humans with PAH.Support or Funding InformationThis work was supported, in part, by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL125208, HL135807, and HL126609).

Anti-enolase１antibodies from a patient with systemic lupus erythematosus accompanied by pulmonary arterial hypertension promote migration of pulmonary artery smooth muscle cells

ObjectivePulmonary arterial hypertension (PAH) is an intractable complication in connective tissue diseases, but the pathological mechanisms responsible for progression remain obscure. This study aims to test whether patient IgG possesses biological activity promoting the migration of pulmonary artery smooth muscle cells (PASMCs). MethodsCell migration was estimated by lamellipodia formation and by utilizing a Boyden chamber method. The specificity of autoantibodies was established by western blotting, ELISA, and immunocytochemistry. The target antigen was investigated by mass spectrometry. ResultsIgG obtained from a patient with systemic lupus erythematosus (SLE) accompanied by PAH was found to promote lamellipodia formation and migration of PASMCs. The IgG bound to a ∼50 kDa protein expressed on the cell membrane, and in the cytoplasm and nucleus. This molecule was identified as enolase 1. Removal of enolase 1-binding antibodies from the IgG fraction, or treatment of the cells with an enolase inhibitor, significantly suppressed the migration of PASMCs. ConclusionPatients with SLE may possess autoantibodies to enolase 1 which stimulate the migration of PASMCs and are likely to play a role in the progression of PAH.

P1938In vitro characterization of a novel PI 3-kinase inhibitor for growth factor-induced effects in pulmonary artery smooth muscle cells

Abstract Rationale Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling in pulmonary arterioles. Increased activation of receptor tyrosine kinase (RTK)-mediated signaling pathways lead to increased proliferation and chemotaxis of pulmonary arterial smooth muscle cells (PASMCs). In previous studies, we identified phosphatidylinositol-3-kinase (PI3K) as a key enzyme for these processes. Since systemic PI3K inhibition is potentially associated with undesired side effects, we here for the first time tested the efficacy of the novel PI3K inhibitor CL27c to impede growth factor-mediated cellular effects in human PASMCs. CL27c is topically applicable and as a prodrug it is intracellularly activated and thus offers optimal efficacy in target cells while at the same time minimizing undesired effects in non-target cells. Methods Using Western blotting and immunohistochemistry, activation of the central PI3K effector AKT in human and murine lung tissue was investigated. Quantification of cell proliferation was performed by 5-bromo-2-deoxyuridine (BrdU) incorporation assay. PASMCs were incubated with CL27c [0.1; 0.3; 1; 3; 10μM] and stimulated either with PDGF-BB [30ng/ml] or with a growth factor combination (GFC) [PDGF-BB 30ng/ml, FGF 2ng/ml, EGF 0.5ng/ml, insulin 0.5μg/ml, FCS 5%]. Chemotaxis was quantified using modified Boyden chambers. The signal transduction cascade was investigated by Western blotting. Results Analysis of AKT activation revealed hyperphosphorylation in both the vascular wall and complete lung homogenates from PAH patients and hypoxia-treated mice. Examination of the mitogenic signal transduction revealed a markedly reduced phosphorylation of AKT and GSK3β in CL27c pretreated PASMCs. In addition, central cell cycle events, such as expression of cyclin D1, were reduced. This was in line with a CL27c concentration-dependent significant reduction of PDGF- and GFC-induced proliferation (control: 2.53±0.26 vs. CL27c: 0.73±0.14 and control: 5.27±0.61 vs. CL27c: 2.80±0.71 both at 10μM, p<0.001). Furthermore, PDGF- and GFC-induced chemotaxis were as well significantly reduced (100% ± 19 vs. CL27c: 24.43% ± 8.58 and 100% ± 5.76 vs CL27c: 25.23% ± 10.57 at 10μM p<0.001). Conclusion These results indicate that CL27c reduces both proliferation and chemotaxis of PASMCs. As these processes play a key role in the development and progression of PAH, this approach is currently being investigated in preclinical models for its therapeutic potential. This “prodrug” approach could avoid non-specific effects and systemic side effects of Pan-PI3K inhibition, especially since the substance is suitable for topical application (inhalation). Thus, CL27c represents a promising treatment option.

Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung

BackgroundPulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents.MethodsRight ventricle systolic pressure (RVSP) was measured in female rats at baseline and up to 24 days after inhibition of mitochondrial respiratory Complex III, induced by Antimycin A (AA, 0.35 mg/kg, given three times starting at baseline and then days 3 and 6 as a bolus injection into the right atrial chamber).ResultsRodents exposed to AA demonstrated sustained increases in RVSP from days 6 through 24. AA-exposed rodents also possessed a progressive increase in RV end-diastolic pressure but not RV hypertrophy, which may be attributed to either early stages of PAH development or to reduced RV contractility due to inhibition of myocardial respiration. Protein nitration levels in plasma were positively correlated with PAH development in AA-treated rats. This finding was strongly supported by results obtained from PAH humans where plasma protein nitration levels were correlated with markers of PAH severity in female but not male PAH patients. Based on previously reported associations between increased nitric oxide production levels with female gender, we speculate that in females with PAH mitochondrial dysfunction may represent a more deleterious form, in part, due to an increased nitrosative stress development. Indeed, the histological analysis of AA treated rats revealed a strong perivascular edema, a marker of pulmonary endothelial damage. Finally, AA treatment was accompanied by a severe metabolic shift toward glycolysis, a hallmark of PAH pathology.ConclusionsChronic mitochondrial dysfunction induces the combination of vascular damage and metabolic reprogramming that may be responsible for PAH development. This mechanism may be especially important in females, perhaps due to an increased NO production and nitrosative stress development.

Baicalein attenuates monocrotaline-induced pulmonary arterial hypertension by inhibiting vascular remodeling in rats

BackgroundPulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder characterized by elevated pulmonary arterial pressure (PAP) and right ventricular hypertrophy (RVH) driven by progressive vascular remodeling. Reversing adverse vascular remodeling is an important concept in the treatment of PAH. Endothelial injury, inflammation, and oxidative stress are three main contributors to pulmonary vascular remodeling. Baicalein is a natural flavonoid that has been shown to possess anti-proliferative, anti-inflammatory, anti-oxidative, and cardioprotective properties. We hypothesized that baicalein may prevent the progression of PAH and preserve the right heart function by inhibiting pulmonary arterial remodeling. MethodsMale Sprague-Dawley rats were distributed randomly into 4 groups: control, monocrotaline (MCT)-exposed, and MCT-exposed plus baicalein treated rats (50 and 100 mg/kg/day for 2 weeks). Hemodynamic changes, RVH, and lung morphological features were examined on day 28. Apoptosis was determined by TUNEL staining, and the mRNA levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 were detected by qRT-PCR. The changes in oxidative indicators, including malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured using corresponding commercial kits. The levels of Bax, Bcl-2, and cleaved caspase-3, and the activation of mitogen-activated protein kinase (MAPK) and NF-κB were assessed by western blotting. ResultsMCT induced an increase in hemodynamic parameters and RVH, which were attenuated by baicalein treatment. Baicalein also blocked MCT-induced pulmonary arterial remodeling. The levels of apoptotic (Bax/Bcl-2 ratio and cleaved caspase-3) and inflammatory (IL-6, TNF-α, and IL-1β) biomarkers in lung tissue were lower in baicalein-treated groups. Baicalein also decreased MDA level, and increased SOD and GSH-Px activity in rat pulmonary tissue. Furthermore, baicalein inhibited MCT-induced activation of the MAPK and NF-κB pathways. ConclusionBaicalein ameliorates MCT-induced PAH by inhibiting pulmonary arterial remodeling at least partially via the MAPK and NF-κB pathways in rats.

Sympathetic Nerve Activity and Baroreflex Dysfunction Paralleled the Progression of Pulmonary Arterial Hypertension in Monocrotaline Induced Rat Model

BackgroundPulmonary arterial hypertension (PAH) is a fatal disease characterized by progressive pulmonary vascular remodeling and extremely high pulmonary artery (PA) resistance. Although patients with advanced PAH are known to have excessive sympathoexcitation and baroreflex dysfunction, the relationship between autonomic dysfunction and the progression of PAH remains unknown. Thus, we investigated how the progression of PAH alters sympathetic nerve activity (SNA) and baroreflex function in monocrotaline (MCT) induced PAH rats.MethodsIn 7 weeks‐old Sprague‐Dawley rats (220–260g), we subcutaneously injected MCT (60 mg/kg) or saline for control (CTL). One, 3 and 3.5 weeks after MCT injection (MCT1W, MCT3W and MCT3.5W, respectively), we assessed right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) (,‐the weight ratio of right to left ventricular) to evaluate the severity of PAH. We estimated SNA by 24 hours urine norepinephrine (U‐NE) and plasma norepinephrine (P‐NE). To measure open loop baroreflex function, we isolated bilateral carotid sinus regions and changed carotid sinus pressure (CSP) while measuring splanchnic SNA and arterial pressure (AP).ResultsRVSP significantly increased 3 and 3.5 week after MCT injection (CTL: 39±6, MCT3W: 73±6, MCT3.5W: 96±9 mmHg, p<0.05). RVH markedly increased in MCT3.5W (CTL: 0.29±0.04, MCT3.5W: 0.49±0.08, p<0.05). Both U‐NE and P‐NE paralleled RVSP (Fig. 1). In the baroreflex open loop analysis, increasing in CSP sigmoidally decreased SNA (neural arc), whereas SNA lineally increased AP (peripheral arc). The relationship between CSP and AP (i.e., baroreflex total loop function) was sigmoidal in both CTL and MCT3W, while the baroreflex induced maximum AP was lower in MCT3W than in CTL (Fig. 2). PAH lowered the baroreflex total loop gain at the operating point (CTL: −1.22±0.22, MCT3W:−0.35±0.14, p<0.05) (Fig. 3).ConclusionSympathetic activation paralleled the progression of PAH. RVH and excessive SNA may deteriorate the baroreflex function in rats with advanced PAH.

MicroRNA-9 is a regulator of PDGFRβ expression in pulmonary arterial hypertension

In several diseases, proteins are differentially expressed compared to healthy conditions due to microRNAs which serve as translational repressors. Therefore, we aim to define the role of microRNAs in the de-regulation of PDGFRβ expression and their impact on the onset and progression of PAH.

Macitentan approved by FDA to delay progression of PAH

FDA on October 18 approved the marketing of macitentan, or Opsumit, as a treatment to delay the progression of pulmonary arterial hypertension, a debilitating disease. The agency said clinical studies of the drug found that it could postpone some consequences of the disease, such as a decline in

Wall shear stress measured by phase contrast cardiovascular magnetic resonance in children and adolescents with pulmonary arterial hypertension.

BackgroundPulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. At the macroscopic level, disease progression is observed as a complex interplay between mean pulmonary artery pressure, pulmonary vascular resistance, pulmonary vascular stiffness, arterial size, and flow. Wall shear stress (WSS) is known to mediate or be dependent on a number of these factors. Given that WSS is known to promote architectural vessel remodeling, it is imperative that the changes of this factor be quantified in the presence of PAH.MethodsIn this study, we analyzed phase contrast imaging of the right pulmonary artery derived from cardiovascular magnetic resonance to quantify the local, temporal and circumferentially averaged WSS of a PAH population and a pediatric control population. In addition, information about flow and relative area change were derived.ResultsAlthough the normotensive and PAH shear waveform exhibited a WSS profile which is uniform in magnitude and direction along the vessel circumference at systole, time-averaged WSS (2.2 ± 1.6 vs. 6.6 ± 3.4 dynes/cm2, P = 0.018) and systolic WSS (8.2 ± 5.0 v. 20.0 ± 9.1 dynes/cm2, P = 0.018) was significantly depressed in the PAH population as compared to the controls. BSA-indexed PA diameter was significantly larger in the PAH population (1.5 ± 0.4 vs. 0.7 ± 0.1 cm/m2, P = 0.003).ConclusionsIn the presence of preserved flow rates through a large PAH pulmonary artery, WSS is significantly decreased. This may have implications for proximal pulmonary artery remodeling and cellular function in the progression of PAH.

Novel peptide for attenuation of hypoxia-induced pulmonary hypertension via modulation of nitric oxide release and phosphodiesterase -5 activity

Pulmonary vascular endothelial nitric oxide (NO) synthase (eNOS)-derived NO is the major stimulant of cyclic guanosine 5′-monophosphate (cGMP) production and NO/cGMP-dependent vasorelaxation in the pulmonary circulation. We recently synthesized multiple peptides and reported that an eleven amino acid (SSWRRKRKESS) peptide (P1) but not scrambled P1 stimulated the catalytic activity but not expression of eNOS and causes NO/cGMP-dependent sustained vasorelaxation in isolated pulmonary artery (PA) segments and in lung perfusion models. Since cGMP levels can also be elevated by inhibition of phosphodiesterase type 5 (PDE-5), this study was designed to test the hypothesis that P1-mediated vesorelaxation is due to its unique dual action as NO-releasing PDE-5 inhibitor in the pulmonary circulation. Treatment of porcine PA endothelial cells (PAEC) with P1 caused time-dependent increase in intracellular NO release and inhibition of the catalytic activity of cGMP-specific PDE-5 but not PDE-5 protein expression leading to increased levels of cGMP. Acute hypoxia-induced PA vasoconstriction ex vivo and continuous telemetry monitoring of hypoxia (10% oxygen)-induced elevated PA pressure in freely moving rats were significantly restored by administration of P1. Chronic hypoxia (10% oxygen for 4 weeks)-induced alterations in PA perfusion pressure, right ventricular hypertrophy, and vascular remodeling were attenuated by P1 treatment. These results demonstrate the potential therapeutic effects of P1 to prevent and/or arrest the progression of hypoxia-induced PAH via NO/cGMP-dependent modulation of hemodynamic and vascular remodeling in the pulmonary circulation.

Attenuation of leukocyte recruitment via CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II

AbstractPrevious studies from our group have demonstrated that bone morphogenetic protein receptor-II (BMPR-II), expressed on pulmonary artery endothelial cells, imparts profound anti-inflammatory effects by regulating the release of proinflammatory cytokines and promoting barrier function by suppressing the transmigration of leukocytes into the pulmonary vessel wall. Here we demonstrate that, in mice with endothelial-specific loss of BMPR-II expression (L1Cre(+);Bmpr2f/f), reduction in barrier function and the resultant pulmonary hypertension observed in vivo are the result of increased leukocyte recruitment through increased CXCR1/2 signaling. Loss of endothelial expressed BMPR-II leads to elevated plasma levels of a wide range of soluble mediators important in regulating leukocyte migration and extravasation, including the CXCR1/2 ligand, KC. Treatment of L1Cre(+);Bmpr2f/f mice with the CXCR1/2 antagonist SCH527123 inhibits leukocyte transmigration into lung and subsequently reverses the pulmonary hypertension. Our data have uncovered a previously unrecognized regulatory function of BMPR-II, which acts to regulate the expression of CXCR2 on endothelial cells, suggesting that increased CXCR2 signaling may also be a feature of the human pathology and that CXCR1/2 pathway antagonists may represent a novel therapeutic approach for treating pulmonary hypertension because of defects in BMPR-II expression.