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Renal Medullary Interstitial COX-2 (Cyclooxygenase-2) Is Essential in Preventing Salt-Sensitive Hypertension and Maintaining Renal Inner Medulla/Papilla Structural Integrity.
Zhang MZ, Wang S, Wang Y, Zhang Y, Ming Hao C, Harris RC
(2018) Hypertension 72: 1172-1179
MeSH Terms: Animals, Apoptosis, Aquaporin 2, Blood Pressure, Cyclooxygenase 2, Epithelial Sodium Channels, Hypertension, Kidney Medulla, Mice, Mice, Transgenic
Show Abstract · Added November 8, 2018
COX (cyclooxygenase)-derived prostaglandins regulate renal hemodynamics and salt and water homeostasis. Inhibition of COX activity causes blood pressure elevation. In addition, chronic analgesic abuse can induce renal injury, including papillary necrosis. COX-2 is highly expressed in the kidney papilla in renal medullary interstitial cells (RMICs). However, its role in blood pressure and papillary integrity in vivo has not been definitively studied. In mice with selective, inducible RMIC COX-2 deletion, a high-salt diet led to an increase in blood pressure that peaked at 4 to 5 weeks and was associated with increased papillary expression of AQP2 (aquaporin 2) and ENac (epithelial sodium channel) and decreased expression of cystic fibrosis transmembrane conductance regulator. With continued high-salt feeding, the mice with RMIC COX-2 deletion had progressive decreases in blood pressure from its peak. After return to a normal-salt diet for 3 weeks, blood pressure remained low and was associated with a persistent urinary concentrating defect. Within 2 weeks of institution of a high-salt diet, increased apoptotic RMICs and collecting duct cells could be detected in papillae with RMIC deletion of COX-2, and by 9 weeks of high salt, there was a striking loss of the papillae. Therefore, RMIC COX-2 expression plays a crucial role in renal handling water and sodium homeostasis, preventing salt-sensitive hypertension and maintaining structural integrity of papilla.
1 Communities
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10 MeSH Terms
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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MeSH Terms
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
Links between Immunologic Memory and Metabolic Cycling.
Cottam MA, Itani HA, Beasley AA, Hasty AH
(2018) J Immunol 200: 3681-3689
MeSH Terms: Adaptive Immunity, Animals, Body Weight, Humans, Hypertension, Immunity, Innate, Immunologic Memory, Metabolic Diseases
Show Abstract · Added March 26, 2019
Treatments for metabolic diseases, such as diet and therapeutics, often provide short-term therapy for metabolic stressors, but relapse is common. Repeated bouts of exposure to, and relief from, metabolic stimuli results in a phenomenon we call "metabolic cycling." Recent human and rodent data suggest metabolic cycling promotes an exaggerated response and ultimately worsened metabolic health. This is particularly evident with cycling of body weight and hypertension. The innate and adaptive immune systems have a profound impact on development of metabolic disease, and current data suggest that immunologic memory may partially explain this association, especially in the context of metabolic cycling. In this Brief Review, we highlight recent work in this field and discuss potential immunologic mechanisms for worsened disease prognosis in individuals who experience metabolic cycling.
Copyright © 2018 by The American Association of Immunologists, Inc.
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8 MeSH Terms
Clinical Features Associated With Nascent Left Ventricular Diastolic Dysfunction in a Population Aged 40 to 55 Years.
Mosley JD, Levinson RT, Brittain EL, Gupta DK, Farber-Eger E, Shaffer CM, Denny JC, Roden DM, Wells QS
(2018) Am J Cardiol 121: 1552-1557
MeSH Terms: Adult, Age Distribution, Cohort Studies, Databases, Factual, Diabetes Mellitus, Type 2, Echocardiography, Female, Heart Failure, Diastolic, Humans, Hypertension, Incidence, Kaplan-Meier Estimate, Linear Models, Male, Middle Aged, Multivariate Analysis, Prognosis, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Distribution, Stroke Volume, Survival Analysis, United States, Ventricular Dysfunction, Left
Show Abstract · Added June 7, 2018
Diastolic dysfunction (DD), an abnormality in cardiac left ventricular (LV) chamber compliance, is associated with increased morbidity and mortality. Although DD has been extensively studied in older populations, co-morbidity patterns are less well characterized in middle-aged subjects. We screened 156,434 subjects with transthoracic echocardiogram reports available through Vanderbilt's electronic heath record and identified 6,612 subjects 40 to 55 years old with an LV ejection fraction ≥50% and diastolic function staging. We tested 452 incident and prevalent clinical diagnoses for associations with early-stage DD (n = 1,676) versus normal function. There were 44 co-morbid diagnoses associated with grade 1 DD including hypertension (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.78 to 2.28, p <5.3 × 10-29), type 2 diabetes (OR 1.96, 95% CI 1.68 to 2.29, p = 2.1 × 10-17), tachycardia (OR 1.38, 95% CI 0.53 to 2.19, p = 2.9 × 10-6), obesity (OR 1.76, 95% CI 1.51 to 2.06, p = 1.7 × 10-12), and clinical end points, including end-stage renal disease (OR 3.29, 95% CI 2.19 to 4.96, p = 1.2 × 10-8) and stroke (OR 1.5, 95% CI 1.12 to 2.02, p = 6.9 × 10-3). Among the 60 incident diagnoses associated with DD, heart failure with preserved ejection fraction (OR 4.63, 95% CI 3.39 to 6.32, p = 6.3 × 10-22) had the most significant association. Among subjects with normal diastolic function and blood pressure at baseline, a blood pressure measurement in the hypertensive range at the time of the second echocardiogram was associated with progression to stage 1 DD (p = 0.04). In conclusion, DD was common among subjects 40 to 55 years old and was associated with a heavy burden of co-morbid disease.
Copyright © 2018 Elsevier Inc. All rights reserved.
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25 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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2 Members
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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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1 Members
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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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6 MeSH Terms
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