scholarly journals Patient-Specific Computational Analysis of Hemodynamics and Wall Mechanics and Their Interactions in Pulmonary Arterial Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Byron A. Zambrano ◽  
Nathan McLean ◽  
Xiaodan Zhao ◽  
Ju-Le Tan ◽  
Liang Zhong ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Patient Specific ◽  
Pulmonary Vasculature ◽  
Control Group ◽  
Regurgitant Flow ◽  
Wall Stiffness ◽  
Wall Deformation ◽  
Pulmonary Arterial

Vascular wall stiffness and hemodynamic parameters are potential biomechanical markers for detecting pulmonary arterial hypertension (PAH). Previous computational analyses, however, have not considered the interaction between blood flow and wall deformation. Here, we applied an established computational framework that utilizes patient-specific measurements of hemodynamics and wall deformation to analyze the coupled fluid–vessel wall interaction in the proximal pulmonary arteries (PA) of six PAH patients and five control subjects. Specifically, we quantified the linearized stiffness (E), relative area change (RAC), diastolic diameter (D), regurgitant flow, and time-averaged wall shear stress (TAWSS) of the proximal PA, as well as the total arterial resistance (Rt) and compliance (Ct) at the distal pulmonary vasculature. Results found that the average proximal PA was stiffer [median: 297 kPa, interquartile range (IQR): 202 kPa vs. median: 75 kPa, IQR: 5 kPa; P = 0.007] with a larger diameter (median: 32 mm, IQR: 5.25 mm vs. median: 25 mm, IQR: 2 mm; P = 0.015) and a reduced RAC (median: 0.22, IQR: 0.10 vs. median: 0.42, IQR: 0.04; P = 0.004) in PAH compared to our control group. Also, higher total resistance (Rt; median: 6.89 mmHg × min/l, IQR: 2.16 mmHg × min/l vs. median: 3.99 mmHg × min/l, IQR: 1.15 mmHg × min/l; P = 0.002) and lower total compliance (Ct; median: 0.13 ml/mmHg, IQR: 0.15 ml/mmHg vs. median: 0.85 ml/mmHg, IQR: 0.51 ml/mmHg; P = 0.041) were observed in the PAH group. Furthermore, lower TAWSS values were seen at the main PA arteries (MPAs) of PAH patients (median: 0.81 Pa, IQR: 0.47 Pa vs. median: 1.56 Pa, IQR: 0.89 Pa; P = 0.026) compared to controls. Correlation analysis within the PAH group found that E was directly correlated to the PA regurgitant flow (r = 0.84, P = 0.018) and inversely related to TAWSS (r = −0.72, P = 0.051). Results suggest that the estimated elastic modulus E may be closely related to PAH hemodynamic changes in pulmonary arteries.

scholarly journals Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3485-3493 ◽  
Author(s):  
Samar Farha ◽  
Kewal Asosingh ◽  
Weiling Xu ◽  
Jacqueline Sharp ◽  
Deepa George ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Disease Process ◽  
Pulmonary Vasculature ◽  
Normal Numbers ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34+CD133+ proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34+CD133+ progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process.

scholarly journals Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities

2017 ◽  
Vol 8 (2-3) ◽  
pp. 47-64 ◽  
Author(s):  
Jessica B. Badlam ◽  
Todd M. Bull
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Response To Treatment ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
Efficacy Parameters

Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more ‘personalized’ therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease.

scholarly journals Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 638
Author(s):  
Shahood Fazal ◽  
Malik Bisserier ◽  
Lahouaria Hadri
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Genetic Variants ◽  
High Throughput Sequencing ◽  
Molecular Genetic ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Common Genetic Variants ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.

scholarly journals Gender, Sex Hormones, and Pulmonary Arterial Hypertension

2011 ◽  
Vol 10 (3) ◽  
pp. 160-166 ◽  
Author(s):  
Eric D. Austin
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Animal Studies ◽  
Pulmonary Arteries ◽  
Connective Tissue Diseases ◽  
World Health ◽  
Pulmonary Vasculature ◽  
Diverse Range ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling of the distal pulmonary vasculature, ultimately leading to destruction and loss of the smallest pulmonary arteries.1 The ensuing syndrome of PAH is clinically characterized by reduced pulmonary arterial circulatory flow, resulting in increased pulmonary vascular resistance, which ultimately results in failure of the right heart.2 In both children and adults, PAH presents as a primary disease or in association with a diverse range of diseases such as connective tissue diseases, portal hypertension, and congenital heart disease.3 Nearly all forms of World Health Organization (WHO) Group 1 PAH demonstrate a skewed gender ratio with significantly more females diagnosed with PAH than males.4–6 While the mechanistic details behind the female predominance remain unclear, this gender discrepancy may represent an opportunity for advanced biologic understanding and future therapeutic development. This article will briefly discuss the intersection of human, in vitro, and animal studies of PAH, and highlight the conflicting data that others have discussed and elegantly elaborated upon as the “estrogen paradox” in PAH.7–9

Abstract 148: Blockade of the Serotonin 2B Receptor Prevents Pulmonary Vascular Stiffening and Remodeling in a Mouse Model of Familial Pulmonary Arterial Hypertension

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Nathaniel Bloodworth ◽  
Erica Carrier ◽  
James West ◽  
W. David Merryman
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Mouse Model ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Collagen Gel ◽  
Pulmonary Vasculature ◽  
Ventricular Systolic Pressure ◽  
Wall Stiffness ◽  
Vascular Stiffening ◽  
Pulmonary Arterial

Objective: Pulmonary arterial hypertension (PAH) is a fatal disease of the pulmonary vasculature. In humans, familial PAH is caused by mutations in the bone morphogenetic protein receptor 2 gene (BMPR2). Serotonin signaling through the 2B receptor (5HT2BR) is also important in the pathogenesis of PAH, making 5HT2BR antagonism a potential target for PAH therapeutics. This study evaluates the hypothesis that antagonism of 5HT2BR will prevent PAH in a genetic mouse model and the pulmonary vascular stiffening and remodeling that is considered the underlying cause. Methods: Rosa26-Bmpr2 R899X mice on an FVB/N background express the patient-derived R899X mutation in BMPR2 in all tissues when induced with doxycycline. 10-14 week old BMPR2 mutant mice were fed doxycycline in a high-fat diet for 6 weeks. After 2 weeks, osmotic pumps containing either the 5HT2BR antagonist SB204741 (1 mg/kg/day) or DMSO/water vehicle were implanted. Right ventricular systolic pressure (RVSP) was measured via a venous jugular catheter under anesthesia, and the mice euthanized. Lungs were collected and prepared for histology, gene expression analysis, and atomic force microscopy (AFM, Bioscope Catalyst). Immortalized pulmonary microvascular smooth muscle cells (SMCs) with a BMPR2 mutation were assessed for long-term changes in cytoskeletal contractility using a free floating collagen gel assay. Data: BMPR2 R899X mice treated with SB204741 failed to develop elevated RVSP. Histologic analysis revealed that SB204741 reduced both the total number of inflammatory cells in the lung as well as the muscularization of peripheral pulmonary arterioles. Microarray analysis revealed that 5HT2BR antagonism primarily changed the expression contractility-associated genes. Measurements of pulmonary arteriole elastic modulus with AFM show significantly increased vessel wall stiffness in BMPR2 R899X arterioles that is also normalized with SB204741 treatment. Taken together, these data suggest that 5HT2BR antagonism prevents the vascular stiffening and remodeling that causes PAH.

scholarly journals Single-cell transcriptomic profile of human pulmonary artery endothelial cells in health and pulmonary arterial hypertension

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kewal Asosingh ◽  
Suzy Comhair ◽  
Lori Mavrakis ◽  
Weiling Xu ◽  
Dean Horton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Single Cell ◽  
Pulmonary Arteries ◽  
Cellular Heterogeneity ◽  
Pulmonary Vasculature ◽  
Cell Functions ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is an insidious disease characterized by severe remodeling of the pulmonary vasculature caused in part by pathologic changes of endothelial cell functions. Although heterogeneity of endothelial cells across various vascular beds is well known, the diversity among endothelial cells in the healthy pulmonary vascular bed and the pathologic diversity among pulmonary arterial endothelial cells (PAEC) in PAH is unknown and previously unexplored. Here single-cell RNA sequencing technology was used to decipher the cellular heterogeneity among PAEC in the human pulmonary arteries isolated from explanted lungs from three patients with PAH undergoing lung transplantation and three healthy donor lungs not utilized for transplantation. Datasets of 36,368 PAH individual endothelial cells and 36,086 healthy cells were analyzed using the SeqGeq bioinformatics program. Total population differential gene expression analyses identified 629 differentially expressed genes between PAH and controls. Gene Ontology and Canonical Ingenuity analysis revealed pathways that are known to be involved in pathogenesis, as well as unique new pathways. At the individual cell level, dimensionality reduction followed by density based clustering revealed the presence of eight unique PAEC clusters that were typified by proliferative, angiogenic or quiescent phenotypes. While control and PAH harbored many similar subgroups of endothelial cells, PAH had greater proportions of angiogenic and proliferative subsets. These findings identify that only specific subgroups of PAH PAEC have gene expression different than healthy PAEC, and suggest these subpopulations lead to the pathologic functions leading to remodeling.

scholarly journals A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension

2018 ◽  
Vol 51 (6) ◽  
pp. 1702638 ◽  
Author(s):  
Anna R. Hemnes ◽  
Anandharajan Rathinasabapathy ◽  
Eric A. Austin ◽  
Evan L. Brittain ◽  
Erica J. Carrier ◽  
...  
Keyword(s):  
Pilot Study ◽  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Converting Enzyme ◽  
Open Label ◽  
Angiotensin Converting Enzyme 2 ◽  
Markers Of Inflammation ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1–7) (Ang-(1–7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1–7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg−1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2–4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

Abstract 18587: Downregulation of Pulmonary Artery Endothelial Catechol-o-methyltransferase Activity by Aldosterone Increases Norepinephrine Levels in Pulmonary Arterial Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Samantha Torquato ◽  
Kiyotake Ishikawa ◽  
Jaume Aguerro ◽  
Bradley A Maron ◽  
Joseph Loscalzo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Methyltransferase Activity ◽  
Comt Activity ◽  
Pulmonary Arterial

Elevated levels of norepinephrine (NE) occur in pulmonary arterial hypertension (PAH) and are determined, in part, by the activity of catechol- O -methyltransferase (COMT). COMT degrades catecholamines, is negatively regulated by calcium, and is expressed by pulmonary artery endothelial cells (PAEC). As hyperaldosteronism occurs in PAH and aldosterone (ALDO) influences calcium levels, we hypothesized that ALDO decreases COMT activity to increase NE levels in PAH. Accordingly, human PAEC were treated with ALDO (10 -7 mol/L), a level that is achieved clinically in PAH, for up to 72 h. Compared to vehicle-treated PAEC, ALDO decreased COMT activity by 59.2 ± 6.2% (p<0.01) to increase NE levels in the medium (122.4 ± 11.8 vs. 210.7 ± 15.5 pg/mL/mg protein, p<0.01). This occurred as a result of an ALDO-mediated decrease in COMT protein expression by 52.6 ± 9.3% (p<0.01) as well as an increase in intracellular calcium levels (102.9 ± 21.0 vs. 167.7 ± 17.8 nmol/L, p<0.05) to inhibit activity. These effects were abrogated by coincubation with spironolactone. To determine the in vivo relevance of these findings, COMT was examined in the rat monocrotaline model of PAH with confirmed hyperALDO. COMT was decreased (47.6 ± 10.2 %control, p<0.05) in remodeled pulmonary arterioles with a concomitant increase in lung NE levels (432.8 ± 44.5 vs. 899.7 ± 34.2 pg/mL, p<0.01) compared to control rats. In the porcine pulmonary vein banding model of pulmonary hypertension (PH-pigs) with elevated mean pulmonary artery pressure (15[13-15] vs. 35[27-43], p<0.01) and pulmonary vascular resistance (PVR) index (1.97[1.74-2.28] vs. 5.78[2.61-8.75], p <0.05), ALDO levels were also increased (27.1 ± 5.1 vs. 60.8 ± 10.6 pg/mL, p<0.03) in advance of right heart failure as compared to sham controls. PH-pigs demonstrated a 48.3 ± 9.9% (p<0.02) decrease in pulmonary vascular COMT expression and an increase in NE levels (114.6 ± 20.2 vs. 1,622.6 ± 489.2 pg/mL, p<0.02) that correlated positively with ALDO levels (R 2 =0.58, p<0.02). These findings were confirmed in patients with PAH. Together, these data indicate that there is crosstalk in the pulmonary vasculature between ALDO and the sympathetic nervous system to regulate NE levels in PAH, and thus, have implications for therapeutic interventions.

Abstract 382: Cyclophilin A (CypA) is a Pathogenic Mediator of Pulmonary Arterial Hypertension

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chao Xue
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Specific Inhibitor ◽  
Cyclophilin A ◽  
Pulmonary Vasculature ◽  
Tunel Staining ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial

Rationale: Pulmonary arterial hypertension (PAH) is a devastating disease in which oxidative stress has been proposed to mediate pathological changes to the pulmonary vasculature such as endothelial cell (EC) apoptosis, endothelial to mesenchymal transition (EndMT), vascular smooth muscle cell (VSMC) proliferation, and inflammation. Our previous study showed that cyclophilin A (CypA) was secreted from EC and VSMC in response to oxidative stress, and much of the secreted CypA was acetylated (AcK-CypA). Furthermore, CypA was increased in the plasma of patients with PAH. Objective: To evaluate the cell- s pecific role of CypA in PAH and compare the relative effects of AcK-CypA and CypA on EC apoptosis, development of an inflammatory EC phenotype and EndMT. Methods and Results: Transgenic overexpression of CypA in EC, but not SMC, caused a PAH phenotype including increased pulmonary artery pressure, α-smooth muscle actin expression in small arteries, and CD45 positive cells in the lungs. Mechanistic analysis using cultured mouse lung microvascular EC showed that CypA and AcK-CypA increased apoptosis measured by caspase 3 cleavage and TUNEL staining. MM284, a specific inhibitor of extracellular CypA, prevented EC apoptosis. In addition, CypA and AcK-CypA promoted an EC inflammatory phenotype assessed by increased VCAM1 and ICAM1 expression, phosphorylation of p65, and degradation of IkB. Furthermore, CypA and AcK-CypA promoted EndMT assayed by change in cell morphology, increased mesenchymal markers and EndMT related transcription factors. At all concentrations, AcK-CypA stimulated greater increases in apoptosis, inflammation and EndMT than CypA. Conclusions: EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation and EndMT. Our results suggest that inhibiting extracellular secreted CypA is a novel therapeutic approach for PAH.

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

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

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

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