scholarly journals Cellular senescence impairs the reversibility of pulmonary arterial hypertension

2020 ◽  
Vol 12 (554) ◽  
pp. eaaw4974 ◽  
Author(s):  
Diederik E. van der Feen ◽  
Guido P. L. Bossers ◽  
Quint A. J. Hagdorn ◽  
Jan-Renier Moonen ◽  
Kondababu Kurakula ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
Human Situation ◽  
Vascular Phenotype ◽  
Pulmonary Arterial ◽  
End Stage ◽  
Irreversible Nature

Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH.

Beta3-adrenergic stimulation restores endothelial mitochondrial dynamics and prevents pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Oliver ◽  
S.F Rocha ◽  
M Spaczynska ◽  
D.V Lalama ◽  
M Gomez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Strategy ◽  
Mitochondrial Dynamics ◽  
Systolic Pressure ◽  
Funding Source ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is one of the most important hallmarks of pulmonary arterial hypertension (PAH). This leads to anomalous production of vasoactive mediators that are responsible for a higher vascular tone and a subsequent increase in pulmonary artery pressure (PAP), and to an increased vascular permeability that favors perivascular inflammation and remodeling, thus worsening the disease. Therefore, preservation of the endothelial barrier could become a relevant therapeutic strategy. Purpose In previous studies, others and we have suggested the pharmacological activation of the β3-adrenergic receptor (AR) as a potential therapeutic strategy for pulmonary hypertension (PH) due to left heart disease. However, its potential use in other forms of PH remain unclear. The aim of the present study was to elucidate whether the β3-AR agonist mirabegron could preserve pulmonary endothelium function and be a potential new therapy in PAH. Methods For this purpose, we have evaluated the effect of mirabegron (2 and 10 mg/kg·day) in different animal models, including the monocrotaline and the hypoxia-induced PAH models in rats and mice, respectively. Additionally, we have used a transgenic mouse model with endothelial overexpression of human β3-AR in a knockout background, and performed in vitro experiments with human pulmonary artery endothelial cells (HPAECs) for mechanistic experiments. Results Our results show a dose dependent effect of mirabegron in reducing mean PAP and Right Ventricular Systolic Pressure in both mice and rats. In addition, the use of transgenic mice has allowed us to determine that pulmonary endothelial cells are key mediators of the beneficial role of β3-AR pathway in ameliorating PAH. Mechanistically, we have shown in vitro that activation of β3-AR with mirabegron protects HPAECs from hypoxia-induced ROS production and mitochondrial fragmentation by restoring mitochondrial fission/fusion dynamics. Conclusions This protective effect of mirabegron would lead to endothelium integrity and preserved pulmonary endothelial function, which are necessary for a correct vasodilation, avoiding increased permeability and remodeling. Altogether, the current study demonstrates a beneficial effect of the β3-AR agonist mirabegron that could open new therapeutic avenues in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Programa de Atracciόn de Talento, Comunidad de Madrid

scholarly journals Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

2020 ◽  
pp. 1902061
Author(s):  
David Macias ◽  
Stephen Moore ◽  
Alexi Crosby ◽  
Mark Southwood ◽  
Xinlin Du ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension

2007 ◽  
Vol 293 (3) ◽  
pp. L548-L554 ◽  
Author(s):  
Fares A. Masri ◽  
Weiling Xu ◽  
Suzy A. A. Comhair ◽  
Kewal Asosingh ◽  
Michelle Koo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Janus Kinase ◽  
Vascular Lesions ◽  
Nuclear Antigen ◽  
Pulmonary Arterial

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation and Ki67 nuclear antigen expression and decreased apoptosis as determined by caspase-3 activation and TdT-mediated dUTP nick end labeling assay. IPAH cells had greater migration than control cells but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream prosurvival target, Mcl-1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.

Abstract 15826: SCUBE1 Controls BMPR2-relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Wei Sun ◽  
Ying Tang ◽  
Yi-Yin Tai ◽  
Adam Handen ◽  
Jingsi Zhao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Heart Disease ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Diagnostic Marker ◽  
Chronic Obstructive ◽  
Sequencing Data ◽  
Ips Cell ◽  
Pulmonary Arterial

Introduction: Pulmonary arterial hypertension (PAH) is a morbid vascular disease where mutations of bone morphogenetic protein receptor 2 (BMPR2) control pulmonary endothelial pathophenotypes. Transcriptomic screening from endothelial cells (ECs) derived from hereditary BMPR2-driven disease offers an opportunity to identify novel effectors in PAH pathogenesis. Methods: Public RNA-sequencing data were analyzed from inducible pluripotent stem (iPS) cell-derived endothelial cells with and without BMPR2 mutations. Candidate genes were assessed in cultured pulmonary arterial ECs (PAECs) and in rodent and human PAH. Correlations were assessed of human plasma expression with clinical disease indices. Results: Signal Peptide CUB-EGF-Domain Containing Protein 1 (SCUBE1), a putative binding partner to BMPR2, was differentially expressed in ECs carrying BMPR2 mutations. SCUBE1 was enriched in PAECs, dependent on hypoxia inducible factor-1α, and downregulated by PAH triggers, including BMPR2 knockdown, hypoxia, and IL-1β exposure. In vitro analyses defined SCUBE1 as a pathogenic effector activating BMPR2-associated SMAD1/5/9, thus regulating endothelial angiogenic potential, proliferation, and apoptosis. SCUBE1 was decreased specifically in plasma and lungs in rodents and patients with PAH but not in those with pulmonary hypertension due to left heart disease, or in the patients of other acute and chronic cardiopulmonary pathologies, including pneumonia, acute lung injury, chronic obstructive pulmonary disease, ischemic heart disease, and cardiomyopathy. An optimal plasma SCUBE1 cut point of 5.02 ng/mL was defined to diagnose PAH from control cohort with a sensitivity of 0.65 and a specificity of 0.82. In PAH patients, plasma SCUBE1 levels negatively correlated with pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular dysfunction. Conclusions: Guided by iPSC-EC sequencing, SCUBE1 was identified as a downregulated secreted factor in PAH, controlling endothelial pathophenotypes and correlated with disease indices. Clinically, SCUBE1 is a sensitive and specific PAH diagnostic marker. It may also serve as a therapeutic target given its inherent links to controlling PAH predisposition and severity.

scholarly journals Estimation of Endostatin level in pulmonary arterial hypertension patients and its relation with some parameters

2018 ◽  
Vol 31 (4) ◽  
pp. 170-179
Author(s):  
Khama’al Hussein Abod Al-Khafaji ◽  
Mohammed Noori Al-Dujaili ◽  
Arshad Noori Al-Dujaili
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Down Regulation ◽  
Primary Tumors ◽  
Non Invasive ◽  
Collagen Xviii ◽  
Potential Biomarker ◽  
Pulmonary Arterial

Abstract Biomarkers are attractive non-invasive tools for estimating and monitoring pulmonary arterial hypertension (PAH) disease and for predicting survival in patients with PAH; therefore, many studies encouraged the investigation of new biomarkers to facilitate the diagnosis of PAH. Endostatin (ES) is an endogenous inhibitor of angiogenesis. It is produced by proteolytic cleavage of the collagen XVIII that is present in both normal and cancerous tissue. In vitro examination shows that ES can manage endothelial cells (EC) physiology in ways that could influence angiogenesis. For example, solvent ES hinders EC movement and prompts improvements of the cytoskeleton that incorporate the loss of Actin stretch strands and central grips. This effect embraces restrictions on the α5β1integrins, Tropomyosin, and putative heparan sulfate proteoglycans. Consequences for the human EC cytoskeleton include Es-induced down-regulation of Mitogen-actuated Protein Kinase (MAPK), Focal Adhesion Kinase (FAK), the Urokinase Plasminogen Activator (uPA) System, and the RhoA GTPase. Human ES has likewise been shown in a few investigations to repress EC multiplication. Moreover, ES-instigated cell cycle capture in the G1 stage is joined by Cyclin D1 down-regulation. Of note, ES blocks the proliferation and organization of endothelial cells into new blood vessels, and in animal studies, ES also inhibits angiogenesis and the growth of both primary tumors and secondary metastasis. ES was initially identified by its capacity to inhibit tumor angiogenesis in vitro and also in vivo. It can also be found in both healthy and patient’ serum, and has been detected in peripheral circulation. ES could be an attractive, non-invasive prognostic marker for some diseases, notably PAH. Therefore, the presented work is aimed at investigating the ES level in blood serum as a biomarker for detection, diagnosis and early treatment of PAH patients. In doing so, the association is ascertained between gender, age, body mass index (BMI), waist circumferences, smoking, types of PAH (primary and secondary) and this potential biomarker is assessed in PAH patients.

scholarly journals Peculiarities remodeling the venous bed in the testis at postresection arterial hypertension in small blood circulation

2020 ◽  
Vol 19 (1) ◽  
pp. 20-24
Author(s):  
M. S. Hnatjuk ◽  
S. O. Konovalenko ◽  
L. V. Tatarchuk
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
White Male ◽  
Cor Pulmonale ◽  
Male Rats ◽  
Outer Diameter ◽  
External Diameter ◽  
Pulmonary Arterial

Morphological methods examined the venous bad testis of 45 laboratory white male rats, which were divided into 3 groups. The 1 group included 15 intact animals, 2 – 20 rats with pulmonary arterial hypertension and compensated cor pulmonale, 3 – 10 animals with pulmonary arterial hypertension and decompensated cor pulmonale. Hypertension in the small circulatory system and cor pulmonale was modeled by performing right-sided pulmonectomy in animals. It was found that the diameter of the capillary venules of the testis with compensated cor pulmonale was statistically (p<0.01) significantly increased by 4.5 %, and the diameter of venules - by 2.3 % (p<0.05), the external diameter of the venous vessels was statistically significant (p<0.05) increased by 3.1%, and internal – by 2.8 % (p<0.05). The height of endothelial cells of the venous vessels, the diameters of their nuclei in conditions of compensated cor pulmonale did not change significantly. The nuclear-cytoplasmic relations in endothelial cells were unchanged, which testified to the stability of cellular structural homeostasis. Studies and results show that the investigated morphometric parameters of venous vessels in decompensated cor pulmonale changed more pronounced. The diameter of the capillary venules in these experimental conditions increased by 19.1 % (p<0.001), the diameter of the venules – by 22.2 % (p<0.001), the outer diameter of the venous vessels increased by 18.5 % (p<0.001), and inner diameter by 22.3 % (p<0.001). The revealed remodeling of venous vessels resulted in thinning of their walls. At decompensation of the cor pulmonale, the height of the endothelial cells of the venous vessels of the testis decreased by 5.8 % (p<0.01), the diameters of the nuclei of these cells – by 2.8 % (p<0.01). Nuclear-cytoplasmic ratios changed by 6.4 % (p<0.001), indicating a marked disruption of structural cellular homeostasis. The relative volume of damaged endothelial cells of the venous testicular vessels in decompensated cor pulmonale increased in 17.5- times (p<0.001), which could lead to endothelial dysfunction and affect the degree of remodeling venous vessels of the testis. The data obtained indicate that postresection arterial hypertension in the small circle of circulation leads to pronounced structural changes in the venous bad in the testis, which significantly impairs the drainage of venous blood from the specified organ, worsens its trophic supply and plays an important role in its pathomorphogenesis. The most pronounced degree of remodeling of venous vessels was found in decompensated of the cor pulmonale.

DESIGN DEVELOPMENT AND OPTIMIZATION OF A SUSTAINED RELEASE TABLET OF BOSENTAN MONOHYDRATE FOR PULMONARY ARTERIAL HYPERTENSION

INDIAN DRUGS ◽  
2019 ◽  
Vol 56 (03) ◽  
pp. 61-67
Author(s):  
P. P Dighe ◽  
H. M Tank ◽  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Sustained Release ◽  
Arterial Hypertension ◽  
In Vitro Release ◽  
Design Development ◽  
23 Factorial Design ◽  
Sustained Release Tablet ◽  
Pulmonary Arterial ◽  
Release Tablet

Pulmonary arterial hypertension (PAH) means high blood pressure in the lungs caused by obstruction in the small arteries of the lungs.The current study involves the fabrication of oral matrix sustained release tablet of bosentan monohydrate, a dual endothelin receptor antagonist, the optimisation of its in vitro release and characterisation. Methocel K4M PremiumDC2, a directly compressible HPMC grade, has been used as the sustained release polymer. Pregelatinised starch is used as a diluent and release modifier and sodium lauryl sulphate as a solubiliser. The influence of the above variables on drug release is measured using a 23 factorial design using design expert software. Surface response plots show significant interaction among the formulation variables, thus aiding in optimization of bilayer tablet.

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