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Pulmonary Vascular Platform Models the Effects of Flow and Pressure on Endothelial Dysfunction in Associated Pulmonary Arterial Hypertension.
D'Amico RW, Faley S, Shim HN, Prosser JR, Agrawal V, Bellan LM, West JD
(2018) Int J Mol Sci 19:
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, Cell Line, Disease Models, Animal, Endothelial Cells, Hypertension, Pulmonary, Mice, Sequence Analysis, RNA
Show Abstract · Added April 2, 2019
Endothelial dysfunction is a known consequence of bone morphogenetic protein type II receptor () mutations seen in pulmonary arterial hypertension (PAH). However, standard 2D cell culture models fail to mimic the mechanical environment seen in the pulmonary vasculature. Hydrogels have emerged as promising platforms for 3D disease modeling due to their tunable physical and biochemical properties. In order to recreate the mechanical stimuli seen in the pulmonary vasculature, we have created a novel 3D hydrogel-based pulmonary vasculature model ("artificial arteriole") that reproduces the pulsatile flow rates and pressures seen in the human lung. Using this platform, we studied both and WT endothelial cells to better understand how the addition of oscillatory flow and physiological pressure influenced gene expression, cell morphology, and cell permeability. The addition of oscillatory flow and pressure resulted in several gene expression changes in both WT and cells. However, for many pathways with relevance to PAH etiology, cells responded differently when compared to the WT cells. cells were also found not to elongate in the direction of flow, and instead remained stagnant in morphology despite mechanical stimuli. The increased permeability of the layer was successfully reproduced in our artificial arteriole, with the addition of flow and pressure not leading to significant changes in permeability. Our artificial arteriole is the first to model many mechanical properties seen in the lung. Its tunability enables several new opportunities to study the endothelium in pulmonary vascular disease with increased control over environmental parameters.
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MeSH Terms
Myeloid-Derived Suppressor Cells and Pulmonary Hypertension.
Bryant AJ, Mehrad B, Brusko TM, West JD, Moldawer LL
(2018) Int J Mol Sci 19:
MeSH Terms: Animals, Dendritic Cells, Humans, Hypertension, Pulmonary, Myeloid-Derived Suppressor Cells, Receptors, Interleukin-8B, Signal Transduction
Show Abstract · Added April 2, 2019
Myeloid⁻derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow⁻derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.
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A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.
Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J
(2018) Eur Respir J 51:
MeSH Terms: Adult, Aged, Animals, Biomarkers, Cytokines, Female, Gene Expression, Humans, Hypertension, Pulmonary, Male, Middle Aged, Peptidyl-Dipeptidase A, Pilot Projects, Proof of Concept Study, Proto-Oncogene Proteins, Pulmonary Artery, Receptors, G-Protein-Coupled, Superoxide Dismutase, Swine, Vascular Resistance
Show Abstract · Added March 26, 2019
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 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.
Copyright ©ERS 2018.
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20 MeSH Terms
Precision Modeling of Pulmonary Hypertension Pathology with Induced Pluripotent Stem Cell-derived Cells.
West JD, Carrier EJ
(2018) Am J Respir Crit Care Med 198: 154-155
MeSH Terms: Bone Morphogenetic Protein Receptors, Type II, Humans, Hypertension, Hypertension, Pulmonary, Induced Pluripotent Stem Cells, Mutation, Phenotype
Added March 26, 2019
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7 MeSH Terms
Update in Pulmonary Vascular Disease 2016 and 2017.
Brittain EL, Thennapan T, Maron BA, Chan SY, Austin ED, Spiekerkoetter E, Bogaard HJ, Guignabert C, Paulin R, Machado RF, Yu PB
(2018) Am J Respir Crit Care Med 198: 13-23
MeSH Terms: Humans, Hypertension, Pulmonary, Lung, Vascular Diseases
Added June 7, 2018
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4 MeSH Terms
Autonomic Nervous System in Pulmonary Arterial Hypertension: Time to Rest and Digest.
Hemnes AR, Brittain EL
(2018) Circulation 137: 925-927
MeSH Terms: Autonomic Nervous System, Familial Primary Pulmonary Hypertension, Humans, Hypertension, Pulmonary, Vascular Remodeling, Ventricular Dysfunction, Right
Added June 7, 2018
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Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA.
Wauchope OR, Mitchener MM, Beavers WN, Galligan JJ, Camarillo JM, Sanders WD, Kingsley PJ, Shim HN, Blackwell T, Luong T, deCaestecker M, Fessel JP, Marnett LJ
(2018) Nucleic Acids Res 46: 3458-3467
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, DNA Adducts, DNA, Mitochondrial, Electron Transport, Endothelial Cells, Gene Expression Regulation, Humans, Hypertension, Pulmonary, Lipid Peroxidation, Mice, Mice, Transgenic, Mitochondria, Mutagenesis, Oxidants, Oxidative Stress, Purine Nucleosides, Reactive Oxygen Species, Superoxides
Show Abstract · Added March 14, 2018
Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.
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19 MeSH Terms
Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.
Whitaker ME, Nair V, Sinari S, Dherange PA, Natarajan B, Trutter L, Brittain EL, Hemnes AR, Austin ED, Patel K, Black SM, Garcia JGN, Yuan Md PhD JX, Vanderpool RR, Rischard F, Makino A, Bedrick EJ, Desai AA
(2018) Am J Med 131: 702.e7-702.e13
MeSH Terms: Diabetes Mellitus, Female, Heart Ventricles, Humans, Hypertension, Pulmonary, Male, Pulmonary Artery, Retrospective Studies, Risk Factors, Ventricular Dysfunction, Right, Ventricular Remodeling
Show Abstract · Added June 7, 2018
BACKGROUND - Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction.
METHODS - Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension.
RESULTS - A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes.
CONCLUSION - Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension.
Copyright © 2018 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Redefining pulmonary hypertension.
Maron BA, Brittain EL, Choudhary G, Gladwin MT
(2018) Lancet Respir Med 6: 168-170
MeSH Terms: Arterial Pressure, Diagnostic Errors, Humans, Hypertension, Pulmonary, Pulmonary Artery, Reference Standards, Respiratory Function Tests
Added June 7, 2018
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7 MeSH Terms
Cardiovascular care of patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI) therapy.
Barber MC, Mauro MJ, Moslehi J
(2017) Hematology Am Soc Hematol Educ Program 2017: 110-114
MeSH Terms: Aged, Dasatinib, Female, Fusion Proteins, bcr-abl, Humans, Hypertension, Pulmonary, Imidazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Middle Aged, Protein Kinase Inhibitors, Pyridazines, Pyrimidines
Show Abstract · Added April 22, 2018
Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include "treatment-free remission." Importantly, later-generation BCR-ABL1 TKIs have been associated with CV complications. Dasatinib has been associated with pleural/pericardial effusions and pulmonary hypertension, whereas nilotinib and ponatinib have been linked to the development of vascular occlusive events. There is currently a dearth of data with respect to the mechanisms of drug toxicities, the subsets of patients at risk, and prevention and treatment strategies to mitigate CV complications in patients with CML. Nevertheless, optimal patient CV risk assessment needs to become a more central tenet of patient care in CML. We propose several practical considerations for the practicing oncologist relative to the CV health of patients with CML, especially those on chronic TKI therapy.
© 2016 by The American Society of Hematology. All rights reserved.
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13 MeSH Terms