Browsing by Author "Garcia, Joe G.N."

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    Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody
    (European Respiratory Society, 2021-05-06) Quijada, Hector; Bermudez, Tadeo; Kempf, Carrie L.; Valera, Daniel G.; Garcia, Alexander N.; Camp, Sara M.; Song, Jin H.; Franco, Evelyn; Burt, Jessica K.; Sun, Belinda; Mascarenhas, Joseph B.; Burns, Kimberlie; Gaber, Amir; Oita, Radu C.; Reyes Hernon, Vivian; Barber, Christy; Moreno-Vinasco, Liliana; Sun, Xiaoguang; Cress, Anne E.; Martin, Diego; Liu, Zhonglin; Desai, Ankit A.; Natarajan, Viswanathan; Jacobson, Jeffrey R.; Dudek, Steven M.; Bime, Christian; Sammani, Saad; Garcia, Joe G.N.; Medicine, School of Medicine
    Rationale: The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target. Methods: Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo. Results: Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models. Conclusions: These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.
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    Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome
    (Elsevier, 2017-02) Szilágyi, Keely L.; Liu, Cong; Zhang, Xu; Wang, Ting; Fortman, Jeffrey D.; Zhang, Wei; Garcia, Joe G.N.; Medicine, School of Medicine
    Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome with a considerable case fatality rate (∼30%-40%). Health disparities exist with African descent (AD) subjects exhibiting greater mortality than European descent (ED) individuals. Myosin light chain kinase is encoded by MYLK, whose genetic variants are implicated in ARDS pathogenesis and may influence ARDS mortality. As baseline population-specific epigenetic changes, that is, cytosine modifications, have been observed between AD and ED individuals, epigenetic variations in MYLK may provide insights into ARDS disparities. We compared methylation levels of MYLK cytosine-guanine dinucleotides (CpGs) between ARDS patients and intensive care unit (ICU) controls overall and by ethnicity in a nested case-control study of 39 ARDS cases and 75 non-ARDS ICU controls. Two MYLK CpG sites (cg03892735 and cg23344121) were differentially modified between ARDS subjects and controls (P < 0.05; q < 0.25) in a logistic regression model, where no effect modification by ethnicity or age was found. One CpG site was associated with ARDS in patients aged <58 years, cg19611163 (intron 19, 20). Two CpG sites were associated with ARDS in EDs only, gene body CpG (cg01894985, intron 2, 3) and CpG (cg16212219, intron 31, 32), with higher modification levels exhibited in ARDS subjects than controls. Cis-acting modified cytosine quantitative trait loci (mQTL) were identified using linear regression between local genetic variants and modification levels for 2 ARDS-associated CpGs (cg23344121 and cg16212219). In summary, these ARDS-associated MYLK CpGs with effect modification by ethnicity and local mQTL suggest that MYLK epigenetic variation and local genetic background may contribute to health disparities observed in ARDS.
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    Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension
    (American Thoracic Society, 2020-06-01) Karnes, Jason H.; Wiener, Howard W.; Schwantes-An, Tae-Hwi; Natarajan, Balaji; Sweatt, Andrew J.; Chaturvedi, Abhishek; Arora, Amit; Batai, Ken; Nair, Vineet; Steiner, Heidi E.; Giles, Jason B.; Yu, Jeffrey; Hosseini, Maryam; Pauciulo, Michael W.; Lutz, Katie A.; Coleman, Anna W.; Feldman, Jeremy; Vanderpool, Rebecca; Tang, Haiyang; Garcia, Joe G.N.; Yuan, Jason X.J; Kittles, Rick; de Jesus Perez, Vinicio; Zamanian, Roham T.; Rischard, Franz; Tiwari, Hemant K.; Nichols, William C.; Benza, Raymond L.; Desai, Ankit A.; Medicine, School of Medicine
    Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.
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    NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review
    (Elsevier, 2021) Oldham, William M.; Hemnes, Anna R.; Aldred, Micheala A.; Barnard, John; Brittain, Evan L.; Chan, Stephen Y.; Cheng, Feixiong; Cho, Michael H.; Desai, Ankit A.; Garcia, Joe G.N.; Geraci, Mark W.; Ghiassian, Susan D.; Hall, Kathryn T.; Horn, Evelyn M.; Jain, Mohit; Kelly, Rachel S.; Leopold, Jane A.; Lindstrom, Sara; Modena, Brian D.; Nichols, William C.; Rhodes, Christopher J.; Sun, Wei; Sweatt, Andrew J.; Vanderpool, Rebecca R.; Wilkins, Martin R.; Wilmot, Beth; Zamanian, Roham T.; Fessel, Joshua P.; Aggarwal, Neil R.; Loscalzo, Joseph; Xiao, Lei; Medicine, School of Medicine
    The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.
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    Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes
    (Sage, 2020-12-07) Romanoski, Casey E.; Qi, Xinshuai; Sangam, Shreya; Vanderpool, Rebecca R.; Stearman, Robert S.; Conklin, Austin; Gonzalez-Garay, Manuel; Rischard, Franz; Ayon, Ramon J.; Wang, Jian; Simonson, Tatum; Babicheva, Aleksandra; Shi, Yinan; Tang, Haiyang; Makino, Ayako; Kanthi, Yogendra; Geraci, Mark W.; Garcia, Joe G.N.; Yuan, Jason X.-J.; Desai, Ankit A.; Medicine, School of Medicine
    Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.
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    UCHL1, a deubiquitinating enzyme, regulates lung endothelial cell permeability in vitro and in vivo
    (American Physiological Society, 2021) Mitra, Sumegha; Epshtein, Yulia; Sammani, Saad; Quijada, Hector; Chen, Weiguo; Bandela, Mounica; Desai, Ankit A.; Garcia, Joe G.N.; Jacobson, Jeffrey R.; Biochemistry and Molecular Biology, School of Medicine
    Increasing evidence suggests an important role for deubiquitinating enzymes (DUBs) in modulating a variety of biological functions and diseases. We previously identified the upregulation of the DUB ubiquitin carboxyl terminal hydrolase 1 (UCHL1) in murine ventilator-induced lung injury (VILI). However, the role of UCHL1 in modulating vascular permeability, a cardinal feature of acute lung injury (ALI) in general, remains unclear. We investigated the role of UCHL1 in pulmonary endothelial cell (EC) barrier function in vitro and in vivo and examined the effects of UCHL1 on VE-cadherin and claudin-5 regulation, important adherens and tight junctional components, respectively. Measurements of transendothelial electrical resistance confirmed decreased barrier enhancement induced by hepatocyte growth factor (HGF) and increased thrombin-induced permeability in both UCHL1-silenced ECs and in ECs pretreated with LDN-57444 (LDN), a pharmacological UCHL1 inhibitor. In addition, UCHL1 knockdown (siRNA) was associated with decreased expression of VE-cadherin and claudin-5, whereas silencing of the transcription factor FoxO1 restored claudin-5 levels. Finally, UCHL1 inhibition in vivo via LDN was associated with increased VILI in a murine model. These findings support a prominent functional role of UCHL1 in regulating lung vascular permeability via alterations in adherens and tight junctions and implicate UCHL1 as an important mediator of ALI.