Publications by authors named "Roberto F Machado"

133 Publications

Biomarkers of clinical severity in treated and untreated sickle cell disease: a comparison by genotypes of a single center cohort and African Americans in the NHANES study.

Br J Haematol 2021 Jul 15. Epub 2021 Jul 15.

Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, IL, USA.

Haemolysis and vaso-occlusion underlie multi-organ system complications in sickle cell disease (SCD). We assessed real-world biomarkers in University of Illinois adult SCD patients, categorised as severe (HbSS/Sβ -thalassaemia; n = 342) or mild (HbSC/Sβ -thalassaemia; n = 100) genotypes and stratified according to treatment. African-American controls from the National Health and Nutrition Examination Survey (NHANES) were matched with each genotype category. Most measures of haemolysis, anaemia, inflammation and function of kidneys, liver and lungs differed markedly in untreated severe genotype patients compared to NHANES controls. These same biomarkers were significantly closer to the NHANES control range in untreated mild versus severe genotype patients, but they were not improved in severe genotype patients receiving treatment with hydroxycarbamide or blood transfusions, except that haemoglobin and HbF were higher with hydroxycarbamide. Systolic blood pressures did not differ among the SCD and NHANES groups, but diastolic pressures were higher in mild genotype patients. Ferritin in severe genotype patients on chronic transfusions was 50-fold higher than NHANES controls. The cross-sectional real-world biomarkers of patients on hydroxycarbamide or transfusions were not markedly improved compared to untreated patients. This may be due partly to poor compliance or more severe disease. Our findings highlight the need for more effective treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17682DOI Listing
July 2021

The different facets of sickle cell disease-related pulmonary hypertension.

Curr Opin Pulm Med 2021 Jul 1. Epub 2021 Jul 1.

Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana, USA.

Purpose Of Review: Sickle cell disease (SCD), one of the most common genetic diseases in the world, is characterized by repeated episodes of hemolysis and vaso-occlusion. Hemolytic anemia is a risk factor for the development of pulmonary hypertension, and currently SCD-related pulmonary hypertension is classified as World Health Organization group 5 pulmonary hypertension. Patients with SCD-related pulmonary hypertension have unique hemodynamics, multiple comorbidities, and distinct phenotypes that may contribute to the development of pulmonary hypertension.

Recent Findings: SCD-related pulmonary hypertension is defined as a mean pulmonary artery pressure >20 mmHg, a pulmonary artery occlusion pressure ≤15 mmHg and relatively low pulmonary vascular resistance (>2 Wood units) rather than the traditional definition of ≥3 Wood units, an important distinction due to a baseline high-cardiac output state in the setting of chronic anemia and low vascular resistance. Diastolic dysfunction is frequently identified in this patient population and right heart catheterization is essential to determine if combined pre- and postcapillary pulmonary hypertension is present. Thromboembolism is common among patients with SCD, and screening for chronic thromboembolic pulmonary hypertension is essential. Data regarding advanced therapies are limited. Primary treatment options include targeting correction of their primary hemoglobinopathy as well as aggressive management of underlying comorbid conditions.

Summary: SCD-related pulmonary hypertension is common among patients with SCD and is associated with increased mortality. A high index of suspicion is warranted during evaluation to identify all potential factors that may be contributing to disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCP.0000000000000795DOI Listing
July 2021

Sphingosine Kinase 1 Regulates the Pulmonary Vascular Immune Response.

Cell Biochem Biophys 2021 Jun 16. Epub 2021 Jun 16.

Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

The aberrant proliferation of pulmonary artery smooth muscle (PASMCs) cells is a defining characteristic of pulmonary arterial hypertension (PAH) and leads to increased vascular resistance, elevated pulmonary pressure, and right heart failure. The sphingosine kinase 1 (SPHK1)/sphingosine-1 phosphate/sphingosine-1 phosphate receptor 2 pathway promotes vascular remodeling and induces PAH. The aim of this study was to identify genes and cellular processes that are modulated by over-expression of SPHK1 in human PASMCs (hPASMCs). RNA was purified and submitted for RNA sequencing to identify differentially expressed genes. Using a corrected p-value threshold of <0.05, there were 294 genes significantly up-regulated while 179 were significantly down-regulated. Predicted effects of these differentially expressed genes were evaluated using the freeware tool Enrichr to assess general gene set over-representation (enrichment) and ingenuity pathway analysis (IPA™) for upstream regulator predictions. We found a strong change in genes that regulated the cellular immune response. IL6, STAT1, and PARP9 were elevated in response to SPHK1 over-expression in hPASMCs. The gene set enrichment mapped to a few immune-modulatory signaling networks, including IFNG. Furthermore, PARP9 and STAT1 protein were elevated in primary hPASMCs isolated from PAH patients. In conclusion, these data suggest a role of Sphk1 regulates pulmonary vascular immune response in PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12013-021-01006-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206894PMC
June 2021

Regional Variation in Methamphetamine-associated Pulmonary Arterial Hypertension: Who'd Better Call Saul?

Ann Am Thorac Soc 2021 04;18(4):584-585

Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1513/AnnalsATS.202011-1415EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009004PMC
April 2021

IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.

Blood 2021 03;137(9):1208-1218

Department of Medicine, Indiana University, Indianapolis, IN.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020005944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933768PMC
March 2021

Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which Is Associated with Increased Severity of Murine Acute Respiratory Distress Syndrome.

Am J Respir Cell Mol Biol 2021 01;64(1):89-99

Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois.

A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease. Lungs harvested from current versus former/never-smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle-treated controls. In separate studies, endothelial (EC)-specific WWOX knockout (KO) versus WWOX flox control mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31 CD45cells. These were grown in culture, confirmed to be WWOX deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing as well as an FITC dextran transwell assay for their barrier properties during methicillin-resistant or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to cells from WWOX flox controls during either methicillin-resistant or LPS treatment as measured by both electric cell impedance sensing and the transwell assay. The increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2020-0145OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780991PMC
January 2021

Associations Between Mean Arterial Pressure and Poor ICU Outcomes in Critically Ill Patients With Cirrhosis: Is 65 The Sweet Spot?

Crit Care Med 2020 09;48(9):e753-e760

Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN.

Objectives: Mean arterial pressure is critically important in patients with cirrhosis in the ICU, however, there is limited data to guide therapies and targets.

Design: Retrospective observational study.

Setting: Tertiary care ICU.

Patients: Two hundred and seventy-three critically ill patients with cirrhosis.

Interventions: None.

Measurements And Main Results: We performed a comprehensive time-weighted mean arterial pressure analysis (time-weighted-average-mean arterial pressure and cumulative-time-below various mean arterial pressure-thresholds) during the first 24-hours after ICU admission (median: 25 mean arterial pressure measurements per-patient). Time-weighted-average-mean arterial pressure captures both the severity and duration of hypotension below a mean arterial pressure threshold and cumulative-time-below is the total time spent below a mean arterial pressure threshold. Individual univariable and multivariable logistic regression models were assessed for each time-weighted-average-mean arterial pressure and cumulative-time-below mean arterial pressure threshold (55, 60, 65, 70, and 75 mm Hg) for ICU-mortality. Time-weighted-average-mean arterial pressure: for 1 mm Hg decrease in mean arterial pressure below 75, 70, 65, 60, and 55 mm Hg, the odds for ICU-mortality were 14%, 18%, 26%, 41%, and 74%, respectively (p < 0.01, all thresholds). The association between time-weighted-average-mean arterial pressure and ICU-mortality for each threshold remained significant after adjusting for model for end-stage liver disease-sodium score, mechanical ventilation, vasopressor use, renal replacement therapy, grade 3/4 hepatic encephalopathy, WBC count, and albumin. Cumulative-time-below: odds for ICU-mortality were 4%, 6%, 10%, 12%, and 12% for each-hour spent below 75, 70, 65, 60, and 55 mm Hg, respectively. In the adjusted models, significant associations only remained for mean arterial pressure less than 65 mm Hg (odds ratio, 1.07; 95% CI, 1.00-1.14; p = 0.05) and < 60 mm Hg (odds ratio, 1.10; 95% CI, 1.01-1.18; p = 0.04).

Conclusions: These data suggest that maintaining a mean arterial pressure of greater than 65 mm Hg may be a reasonable target in patients with cirrhosis admitted to the ICU. However, further prospective randomized trials are needed to determine the optimal mean arterial pressure-targets in this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004442DOI Listing
September 2020

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

Arterioscler Thromb Vasc Biol 2020 06 9;40(6):1543-1558. Epub 2020 Apr 9.

Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (G.H., A.F., T.C., Y.B., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis.

Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.

Conclusions: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.119.313883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255946PMC
June 2020

Transcriptome-wide analysis associates ID2 expression with combined pre- and post-capillary pulmonary hypertension.

Sci Rep 2019 12 20;9(1):19572. Epub 2019 Dec 20.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Heart failure with preserved ejection fraction (HFpEF) patients who develop pulmonary hypertension (PH) have an increased risk of death, with combined pre- and post-capillary PH (CpcPH) having the highest risk. However, the mechanism behind PH development in HFpEF is poorly understood. We aimed to identify transcriptomic associations with PH development in HFpEF. Blood was collected from 30 HFpEF patients: 10 without PH, 10 with isolated post-capillary PH, and 10 with CpcPH. Gene expression measurements were completed using transcriptome-wide RNA sequencing. Gene expression differences were compared using a quasi-likelihood method adjusting for age, sex, race, and smoking-status. Biological pathways were compared using global gene expression differences. A replication in 34 additional heart failure patients and a validation in lung tissue from a representative mouse model were completed using quantitative PCR. Six differentially expressed genes were identified when comparing transcriptomics between subjects with CpcPH and those without PH. When tested in additional subjects, only the association with ID2 replicated. Consistent with clinical findings, Id2 expression was also upregulated in mice with HFpEF and PH. Pathway analysis identified proliferative and mitochondrial pathways associated with CpcPH. Thus, these patients may possess systemic pathophysiological differences similar to those observed in pulmonary arterial hypertension patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-55700-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925238PMC
December 2019

Low Dose Carbon Monoxide Exposure in Idiopathic Pulmonary Fibrosis Produces a CO Signature Comprised of Oxidative Phosphorylation Genes.

Sci Rep 2019 10 15;9(1):14802. Epub 2019 Oct 15.

Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA.

Compelling preclinical studies indicate that low-dose carbon monoxide (CO) abrogates experimental lung fibrosis. We recently reported the results of a multicenter, double-blinded, clinical trial of inhaled CO in patients with idiopathic pulmonary fibrosis (IPF). Identifying no significantly changes in metalloproteinase-7 (MMP7) serum concentration, or secondary endpoints of physiologic measurements, hospitalization, death, or patient-reported outcomes. In the present study, we evaluated the effect of low dose CO exposure (100-200 ppm) for 12 weeks on genome-wide gene expression in peripheral blood mononuclear cells (PBMC) derived from these IPF study subjects. We conducted transcriptome profiling on 38 IPF subjects with time points available at 0, 12, and 24 weeks. Total RNA isolated from PBMCs was hybridized onto the Affymetrix Human Gene 2.0 ST Array. We identified 621 genes significantly upregulated in the 24-week CO exposed group compared with the 12-week. Pathway analysis demonstrated association with Oxidative Phosphorylation (adjusted P < 0.05). We identified a clear CO signature dominated with 23 oxidative phosphorylation-related genes (FDR <10%). We confirmed the expression of nine selected gene products using Nanostring's nCounter analysis system. These findings suggest this signature may serve as a potential genomic biomarker for CO exposure and for potential titration of dosage to allow precision testing of therapies in future low dose CO therapeutic studies in IPF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-50585-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794274PMC
October 2019

Identifying Clinical and Research Priorities in Sickle Cell Lung Disease. An Official American Thoracic Society Workshop Report.

Ann Am Thorac Soc 2019 09;16(9):e17-e32

Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality. We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: ) acute chest syndrome, ) lower airways disease and pulmonary function, ) sleep-disordered breathing and hypoxia, and ) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus. Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation. Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1513/AnnalsATS.201906-433STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812163PMC
September 2019

Validation of a composite vascular high-risk profile for adult patients with sickle cell disease.

Am J Hematol 2019 12 17;94(12):E312-E314. Epub 2019 Sep 17.

Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194466PMC
December 2019

MicroRNA410 Inhibits Pulmonary Vascular Remodeling via Regulation of Nicotinamide Phosphoribosyltransferase.

Sci Rep 2019 07 9;9(1):9949. Epub 2019 Jul 9.

Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, 46202, USA.

Nicotinamide phosphoribosyltransferase (NAMPT) upregulation in human pulmonary artery endothelial cells (hPAECs) is associated with pulmonary arterial hypertension (PAH) progression and pulmonary vascular remodeling. The underlying mechanisms regulating NAMPT expression are still not clear. In this study, we aimed to study the regulation of NAMPT expression by microRNA410 (miR410) in hPAECs and explore the role of miR410 in the pathogenesis of experimental pulmonary hypertension. We show that miR410 targets the 3' UTR of NAMPT and that, concomitant with NAMPT upregulation, miR410 is downregulated in lungs of mice exposed to hypoxia-induced pulmonary hypertension (HPH). Our results also demonstrate that miR410 directly inhibits NAMPT expression. Overexpression of miR410 in hPAECs inhibits basal and VEGF-induced proliferation, migration and promotes apoptosis of hPAECs, while miR410 inhibition via antagomirs has the opposite effect. Finally, administration of miR410 mimics in vivo attenuated induction of NAMPT in PAECs and prevented the development of HPH in mice. Our results highlight the role of miR410 in the regulation of NAMPT expression in hPAECs and show that miR410 plays a potential role in PAH pathobiology by targeting a modulator of pulmonary vascular remodeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46352-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616369PMC
July 2019

Injury-Induced Shedding of Extracellular Vesicles Depletes Endothelial Cells of Cav-1 (Caveolin-1) and Enables TGF-β (Transforming Growth Factor-β)-Dependent Pulmonary Arterial Hypertension.

Arterioscler Thromb Vasc Biol 2019 06;39(6):1191-1202

From the Department of Anesthesiology (S.D.S.O., M.C., R.D.M.), University of Illinois at Chicago.

Objective- To determine whether pulmonary arterial hypertension is associated with endothelial cell (EC)-Cav-1 (caveolin-1) depletion, EC-derived extracellular vesicle cross talk with macrophages, and proliferation of Cav-1 depleted ECs via TGF-β (transforming growth factor-β) signaling. Approach and Results- Pulmonary vascular disease was induced in Sprague-Dawley rats by exposure to a single injection of VEGFRII (vascular endothelial growth factor receptor II) antagonist SU5416 (Su) followed by hypoxia (Hx) plus normoxia (4 weeks each-HxSu model) and in WT (wild type; Tie2.Cre; Cav1 ) and EC- Cav1 (Tie2.Cre; Cav1 ) mice (Hx: 4 weeks). We observed reduced lung Cav-1 expression in the HxSu rat model in association with increased Cav-1+ extracellular vesicle shedding into the circulation. Whereas WT mice exposed to hypoxia exhibited increased right ventricular systolic pressure and pulmonary microvascular thickening compared with the group maintained in normoxia, the remodeling was further increased in EC- Cav1 mice indicating EC Cav-1 expression protects against hypoxia-induced pulmonary hypertension. Depletion of EC Cav-1 was associated with reduced BMPRII (bone morphogenetic protein receptor II) expression, increased macrophage-dependent TGF-β production, and activation of pSMAD2/3 signaling in the lung. In vitro, in the absence of Cav-1, eNOS (endothelial NO synthase) dysfunction was implicated in the mechanism of EC phenotype switching. Finally, reduced expression of EC Cav-1 in lung histological sections from human pulmonary arterial hypertension donors was associated with increased plasma concentration of Cav-1, extracellular vesicles, and TGF-β, indicating Cav-1 may be a plasma biomarker of vascular injury and key determinant of TGF-β-induced pulmonary vascular remodeling. Conclusions- EC Cav-1 depletion occurs, in part, via Cav-1+ extracellular vesicle shedding into the circulation, which contributes to increased TGF-β signaling, EC proliferation, vascular remodeling, and pulmonary arterial hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.312038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297129PMC
June 2019

A locus on chromosome 5 shows African ancestry-limited association with alloimmunization in sickle cell disease.

Blood Adv 2018 12;2(24):3637-3647

Department of Molecular and Human Genetics and.

Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum = 2.0 × 10 and 8.4 × 10, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, = 6.6 × 10), and this extended to individuals forming multiple (>3) alloantibodies ( = 9.4 × 10). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative acting enhancer predicted to regulate transcription of and the lncRNA , both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018020594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306880PMC
December 2018

How I treat hypoxia in adults with hemoglobinopathies and hemolytic disorders.

Blood 2018 10 11;132(17):1770-1780. Epub 2018 Sep 11.

Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN.

Hemoglobinopathies are caused by genetic mutations that result in abnormal hemoglobin molecules, resulting in hemolytic anemia. Chronic complications involving the lung parenchyma, vasculature, and cardiac function in hemoglobinopathies result in impaired gas exchange, resulting in tissue hypoxia. Hypoxia is defined as the deficiency in the amount of oxygen reaching the tissues of the body and is prevalent in patients with hemoglobinopathies, and its cause is often multifactorial. Chronic hypoxia in hemoglobinopathies is often a sign of disease severity and is associated with increased morbidity and mortality. Therefore, a thorough understanding of the pathophysiology of hypoxia in these disease processes is important in order to appropriately treat the underlying cause and prevent complications. In this article, we discuss management of hypoxia based on three different cases: sickle cell disease, β-thalassemia, and hereditary spherocytosis. These cases are used to review the current understanding of the disease pathophysiology, demonstrate the importance of a thorough clinical history and physical examination, explore diagnostic pathways, and review the current management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-03-818195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202915PMC
October 2018

and acute kidney injury in sickle cell anemia.

Blood 2018 10 23;132(15):1621-1625. Epub 2018 Aug 23.

Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, and.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-05-853929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182266PMC
October 2018

Hemolysis and hemolysis-related complications in females vs. males with sickle cell disease.

Am J Hematol 2018 11 17;93(11):E376-E380. Epub 2018 Oct 17.

Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196103PMC
November 2018

Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure.

Arterioscler Thromb Vasc Biol 2018 09;38(9):2065-2078

From the Robert M. Berne Cardiovascular Research Center (L.J.D., A.S.K., H.R.A.-P., T.C.S.K., S.R.J., R.B.W., M.E.G., S.A.M., A.K.B., B.E.I.).

Objective- Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator of arteriolar vasoconstriction, vascular resistance, and blood pressure. Importantly, α-adrenergic receptor stimulation, which uniquely couples with Panx1 (pannexin 1) channel-mediated ATP release in resistance arteries, also requires localization to membrane caveolae. Here, we test whether localization of Panx1 to Cav1 (caveolin-1) promotes channel function (stimulus-dependent ATP release and adrenergic vasoconstriction) and is important for blood pressure homeostasis. Approach and Results- We use in vitro VSMC culture models, ex vivo resistance arteries, and a novel inducible VSMC-specific Cav1 knockout mouse to probe interactions between Panx1 and Cav1. We report that Panx1 and Cav1 colocalized on the VSMC plasma membrane of resistance arteries near sympathetic nerves in an adrenergic stimulus-dependent manner. Genetic deletion of Cav1 significantly blunts adrenergic-stimulated ATP release and vasoconstriction, with no direct influence on endothelium-dependent vasodilation or cardiac function. A significant reduction in mean arterial pressure (total=4 mm Hg; night=7 mm Hg) occurred in mice deficient for VSMC Cav1. These animals were resistant to further blood pressure lowering using a Panx1 peptide inhibitor Px1IL2P, which targets an intracellular loop region necessary for channel function. Conclusions- Translocalization of Panx1 to Cav1-enriched caveolae in VSMCs augments the release of purinergic stimuli necessary for proper adrenergic-mediated vasoconstriction and blood pressure homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.311290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202122PMC
September 2018

Risk factors for vitamin D deficiency in sickle cell disease.

Br J Haematol 2018 06 16;181(6):828-835. Epub 2018 May 16.

Department of Medicine, Hematology/Oncology, University of Illinois at Chicago, Chicago, IL, USA.

Vitamin D deficiency (VDD), 25-OHD levels <20 ng/ml, is prevalent among patients with sickle cell disease (SCD) and is linked to acute and chronic pain and bone fracture in this population. There is limited literature regarding VDD-associated risk factors for SCD. We examined potential clinical and genomic parameters associated with VDD in 335 adults with SCD in a cross-sectional study. VDD was present in 65% of adult SCD patients, and 25-OHD levels independently and positively correlated with older age (P < 0·001) and vitamin D supplementation (P < 0·001). 25-OHD levels were higher in SCD patients over 40 years of age compared to the general African-American population. Both lower 25-OHD levels and increased pain frequency were associated with increased expression of SLC6A5 encoding glycine transporter-2 (GlyT2), a protein involved in neuronal pain pathways. Lower 25-OHD levels were also associated with increased expression of CYP3A4, and with decreased expression of GC (also termed DBP) and VDR, three genes involved in vitamin D metabolism. We conclude that vitamin D supplementation should be an almost universal feature of the care of young adults with SCD, and that further research is warranted into genomic factors that regulate vitamin D metabolism in SCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002929PMC
June 2018

A Review of Transcriptome Analysis in Pulmonary Vascular Diseases.

Methods Mol Biol 2018 ;1783:259-277

Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Transcriptome analysis is a powerful tool in the study of pulmonary vascular disease and pulmonary hypertension. Pulmonary hypertension is a disease process that consists of several unique pathologies sharing a common clinical definition, that of elevated pressure within the pulmonary circulation. As such, it has become increasingly important to identify both similarities and differences among the different classes of pulmonary hypertension. Transcriptome analysis has been an invaluable tool both in the basic science research on animal models as well as clinical research among the various different groups of pulmonary hypertension. This work has identified new potential candidate genes, implicated numerous biochemical and molecular pathways in diseased onset and progression, developed gene signatures to appropriately classify types of pulmonary hypertension and severity of illness, and identified novel gene mutations leading to hereditary forms of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-7834-2_13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039103PMC
February 2019

Endothelial nitric oxide synthase genotype is associated with pulmonary hypertension severity in left heart failure patients.

Pulm Circ 2018 Apr-Jun;8(2):2045894018773049

6 Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

The biological mechanisms behind the development of pulmonary hypertension in the setting of left heart failure (HF-PH), including combined pre- and post-capillary pulmonary hypertension (Cpc-PH), remains unclear. This study aimed to use candidate polymorphisms in nitric oxide synthase (NOS) genes to explore the role of NOS in HF-PH. DNA samples from 118 patients with HF-PH were genotyped for the NOS3 rs1799983 and NOS2 rs3730017 polymorphisms. A multiple regression model was used to compare hemodynamic measurements between genotype groups. Patients with the T/T genotype at rs1799983 possessed a nearly 10 mmHg increased transpulmonary gradient (TPG) compared to those with other genotypes ( P = 0.006). This finding was replicated in an independent cohort of 94 HF-PH patients ( P = 0.005). However, when tested in a cohort of 162 pre-capillary pulmonary arterial hypertension patients, no association was observed. In a combined analysis of both HF-PH cohorts, mean pulmonary artery pressure (mPAP), diastolic pulmonary gradient (DPG), and CpcPH status were also associated with rs1799983 genotype ( P = 0.005, P = 0.03, and P = 0.02, respectively). In patients with HF-PH, the NOS3 rs1799983 polymorphism is associated with TPG, and potentially mPAP and DPG as well. These findings suggest that endothelial NOS (encoded by NOS3) may be involved in the pulmonary vascular remodeling observed in Cpc-PH and warrants further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2045894018773049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946646PMC
May 2018

Death of the Endothelium in Sepsis: Understanding the Crime Scene.

Am J Respir Cell Mol Biol 2018 07;59(1):3-4

2 Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine Indiana University Indianapolis, Indiana.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2018-0051EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039871PMC
July 2018

Vascular complications of sickle cell disease.

Clin Hemorheol Microcirc 2018 ;68(2-3):205-221

Department of Medicine, Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University, Indianapolis, IN, USA.

Sickle cell disease (SCD) is a monogenetic disorder caused by a mutation in the β-globin gene HBB leading to polymerization of red blood cells causing damage to cell membranes, increasing its rigidity and intravascular hemolysis. Multiple lines of evidence suggest that SCD can be viewed as pan-vasculopathy associated with multiple mechanisms but driven by hemoglobin S polymerization. Here we review the pathophysiology, clinical manifestations and management strategies for cerebrovascular disease, pulmonary hypertension and renal disease associated with SCD. These "vascular phenotypes" reflect the systemic nature of the complications of SCD and are a major threat to the well-being of patients with the disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/CH-189008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194475PMC
May 2018

Update in Pulmonary Vascular Disease 2016 and 2017.

Am J Respir Crit Care Med 2018 07;198(1):13-23

5 Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201801-0062UPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034126PMC
July 2018

Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models.

Transl Res 2018 07 2;197:1-11. Epub 2018 Feb 2.

Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.

Homozygosity for the hemoglobin (Hb) S mutation (HbSS, sickle cell anemia) results in hemoglobin polymerization under hypoxic conditions leading to vaso-occlusion and hemolysis. Sickle cell anemia affects 1:500 African Americans and is a strong risk factor for kidney disease, although the mechanisms are not well understood. Heterozygous inheritance (HbAS; sickle cell trait) affects 1:10 African Americans and is associated with an increased risk for kidney disease in some reports. Using transgenic sickle mice, we investigated the histopathologic, ultrastructural, and gene expression differences with the HbS mutation. Consistent with progressive glomerular damage, we observed progressively greater urine protein concentrations (P = 0.03), glomerular hypertrophy (P = 0.002), and glomerular cellularity (P = 0.01) in HbAA, HbAS, and HbSS mice, respectively. Ultrastructural studies demonstrated progressive podocyte foot process effacement, glomerular basement membrane thickening with reduplication, and tubular villous atrophy with the HbS mutation. Gene expression studies highlighted the differential expression of several genes involved in prostaglandin metabolism (AKR1C18), heme and iron metabolism (HbA-A2, HMOX1, SCL25A37), electrolyte balance (SLC4A1, AQP6), immunity (RSAD2, C3, UBE2O), fatty acid metabolism (FASN), hypoxia hall-mark genes (GCK, SDC3, VEGFA, ETS1, CP, BCL2), as well as genes implicated in other forms of kidney disease (PODXL, ELMO1, FRMD3, MYH9, APOA1). Pathway analysis highlighted increased gene enrichment in focal adhesion, extracellular matrix-receptor interaction, and axon guidance pathways. In summary, using transgenic sickle mice, we observed that inheritance of the HbS mutation is associated with glomerular and tubular damage and identified several candidate genes and pathways for future investigation in sickle cell trait and sickle cell anemia-related kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trsl.2018.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003843PMC
July 2018

Micro-RNA-1 is decreased by hypoxia and contributes to the development of pulmonary vascular remodeling via regulation of sphingosine kinase 1.

Am J Physiol Lung Cell Mol Physiol 2018 03 22;314(3):L461-L472. Epub 2017 Nov 22.

Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University , Indianapolis, Indiana.

Sphingosine kinase 1 (SphK1) upregulation is associated with pathologic pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), but the mechanisms controlling its expression are undefined. In this study, we sought to characterize the regulation of SphK1 expression by micro-RNAs (miRs). In silico analysis of the SphK1 3'-untranslated region identified several putative miR binding sites, with miR-1-3p (miR-1) being the most highly predicted target. Therefore we further investigated the role of miR-1 in modulating SphK1 expression and characterized its effects on the phenotype of pulmonary artery smooth muscle cells (PASMCs) and the development of experimental pulmonary hypertension in vivo. Our results demonstrate that miR-1 is downregulated by hypoxia in PASMCs and can directly inhibit SphK1 expression. Overexpression of miR-1 in human PASMCs inhibits basal and hypoxia-induced proliferation and migration. Human PASMCs isolated from PAH patients exhibit reduced miR-1 expression. We also demonstrate that miR-1 is downregulated in mouse lung tissues during experimental hypoxia-mediated pulmonary hypertension (HPH), consistent with upregulation of SphK1. Furthermore, administration of miR-1 mimics in vivo prevented the development of HPH in mice and attenuated induction of SphK1 in PASMCs. These data reveal the importance of miR-1 in regulating SphK1 expression during hypoxia in PASMCs. A pivotal role is played by miR-1 in pulmonary vascular remodeling, including PASMC proliferation and migration, and its overexpression protects from the development of HPH in vivo. These studies improve our understanding of the molecular mechanisms underlying the pathogenesis of pulmonary hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00057.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900352PMC
March 2018

Associations of α-thalassemia and BCL11A with stroke in Nigerian, United States, and United Kingdom sickle cell anemia cohorts.

Blood Adv 2017 Apr;1(11):693-698

Department of Public Health Sciences, Loyola University Chicago Stritch School of Medicine, Maywood, IL USA.

Alpha-thalassemia and the rs1427407 T allele are commonly observed in sickle cell anemia (SCA) patients and are associated with reduced hemolysis and higher hemoglobin F levels, respectively. We investigated whether a high-risk genetic profile, defined as SCA patients who did not inherit either α-thalassemia or the rs1427407 T allele, had stronger associations with clinical and laboratory variables than the individual genetic components in the University of Ibadan cohort (n=249). We then replicated our findings in SCA cohorts from the University of Illinois at Chicago (UIC)(n=260) and Walk-Treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy (Walk-PHaSST)(n=387). High-risk was associated with higher reticulocytes (15.0% vs. 7.8%, =0.08) and stroke history (6% vs. 1%, =0.02) than standard risk patients and these associations were more significant than the individual genetic components in the University of Ibadan cohort. These findings were replicated in high-risk patients from UIC and Walk-PHaSST for reticulocytes (UIC: 13.5% vs. 11.8%, =0.03; Walk-PHaSST: 9.6% vs. 8.2%, =0.0003) and stroke history (UIC: 32% vs. 22%, =0.07; Walk-PHaSST: 14% vs. 7%, =0.01). On combined analysis, high-risk had strong associations with increased markers of hemolysis (hemoglobin β= -0.29, 95%CI: -0.50 to -0.09; =0.006; reticulocyte% β=2.29, 95%CI: 1.31 to 3.25; =1x10) and stroke history (OR=2.0, 95%CI: 1.3 to 3.0; =0.0002), but no association with frequent vaso-occlusive crises (≥3/year). A high-risk genetic profile is associated with increased hemolysis and stroke history in three independent cohorts. This profile may help identify patients to prioritize for hydroxyurea and for closer monitoring strategies for stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017005231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580997PMC
April 2017
-->