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

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    A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subject
    (Elsevier, 2022) Belvitch, Patrick; Casanova, Nancy; Sun, Xiaoguang; Camp, Sara M.; Sammani, Saad; Brown, Mary E.; Mascarhenas, Joseph; Lynn, Heather; Adyshev, Djanybek; Siegler, Jessica; Desai, Ankit; Seyed-Saadat, Laleh; Rizzo, Alicia; Bime, Christian; Shekhawat, Gajendra S.; Dravid, Vinayak P.; Reilly, John P.; Jones, Tiffanie K.; Feng, Rui; Letsiou, Eleftheria; Meyer, Nuala J.; Ellis, Nathan; Garcia, Joe G. N.; Dudek, Steven M.; Medicine, School of Medicine
    The cortactin gene (CTTN), encoding an actin-binding protein critically involved in cytoskeletal dynamics and endothelial cell (EC) barrier integrity, contains single nucleotide polymorphisms (SNPs) associated with severe asthma in Black patients. As loss of lung EC integrity is a major driver of mortality in the Acute Respiratory Distress Syndrome (ARDS), sepsis, and the acute chest syndrome (ACS), we speculated CTTN SNPs that alter EC barrier function will associate with clinical outcomes from these types of conditions in Black patients. In case-control studies, evaluation of a nonsynonymous CTTN coding SNP Ser484Asn (rs56162978, G/A) in a severe sepsis cohort (725 Black subjects) revealed significant association with increased risk of sepsis mortality. In a separate cohort of sickle cell disease (SCD) subjects with and without ACS (177 SCD Black subjects), significantly increased risk of ACS and increased ACS severity (need for mechanical ventilation) was observed in carriers of the A allele. Human lung EC expressing the cortactin S484N transgene exhibited: (i) delayed EC barrier recovery following thrombin-induced permeability; (ii) reduced levels of critical Tyr486 cortactin phosphorylation; (iii) inhibited binding to the cytoskeletal regulator, nmMLCK; and (iv) attenuated EC barrier-promoting lamellipodia dynamics and biophysical responses. ARDS-challenged Cttn+/- heterozygous mice exhibited increased lung vascular permeability (compared to wild-type mice) which was significantly attenuated by IV delivery of liposomes encargoed with CTTN WT transgene but not by CTTN S484N transgene. In summary, these studies suggest that the CTTN S484N coding SNP contributes to severity of inflammatory injury in Black patients, potentially via delayed vascular barrier restoration.
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    Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood
    (Springer Nature, 2021-12-07) Kariotis, Sokratis; Jammeh, Emmanuel; Swietlik, Emilia M.; Pickworth, Josephine A.; Rhodes, Christopher J.; Otero, Pablo; Wharton, John; Iremonger, James; Dunning, Mark J.; Pandya, Divya; Mascarenhas, Thomas S.; Errington, Niamh; Thompson, A. A. Roger; Romanoski, Casey E.; Rischard, Franz; Garcia, Joe G. N.; Yuan, Jason X.-J.; Schwantes An, Tae-Hwi; Desai, Ankit A.; Coghlan, Gerry; Lordan, Jim; Corris, Paul A.; Howard, Luke S.; Condliffe, Robin; Kiely, David G.; Church, Colin; Pepke-Zaba, Joanna; Toshner, Mark; Wort, Stephen; Gräf, Stefan; Morrell, Nicholas W.; Wilkins, Martin R.; Lawrie, Allan; Wang, Dennis; UK National PAH Cohort Study Consortium; Medicine, School of Medicine
    Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.
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    Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease
    (Elsevier, 2022) Hemnes, Anna R.; Leopold, Jane A.; Radeva, Milena K.; Beck, Gerald J.; Abidov, Aiden; Aldred, Micheala A.; Barnard, John; Rosenzweig, Erika B.; Borlaug, Barry A.; Chung, Wendy K.; Comhair, Suzy A. A.; Desai, Ankit A.; Dubrock, Hilary M.; Erzurum, Serpil C.; Finet, J. Emanuel; Frantz, Robert P.; Garcia, Joe G. N.; Geraci, Mark W.; Gray, Michael P.; Grunig, Gabriele; Hassoun, Paul M.; Highland, Kristin B.; Hill, Nicholas S.; Hu, Bo; Kwon, Deborah H.; Jacob, Miriam S.; Jellis, Christine L.; Larive, A. Brett; Lempel, Jason K.; Maron, Bradley A.; Mathai, Stephen C.; McCarthy, Kevin; Mehra, Reena; Nawabit, Rawan; Newman, John H.; Olman, Mitchell A.; Park, Margaret M.; Ramos, Jose A.; Renapurkar, Rahul D.; Rischard, Franz P.; Sherer, Susan G.; Tang, W. H. Wilson; Thomas, James D.; Vanderpool, Rebecca R.; Waxman, Aaron B.; Wilcox, Jennifer D.; Yuan, Jason X-J; Horn, Evelyn M.; PVDOMICS Study Group; Medicine, School of Medicine
    Background: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. Objectives: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. Methods: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. Results: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. Conclusions: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification.
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    eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling
    (Springer, 2022-01-13) Bermudez, Tadeo; Sammani, Saad; Song, Jin H.; Hernon, Vivian Reyes; Kempf, Carrie L.; Garcia, Alexander N.; Burt, Jessica; Hufford, Matthew; Camp, Sara M.; Cress, Anne E.; Desai, Ankit A.; Natarajan, Viswanathan; Jacobson, Jeffrey R.; Dudek, Steven M.; Cancio, Leopoldo C.; Alvarez, Julie; Rafikov, Ruslan; Li, Yansong; Zhang, Donna D.; Casanova, Nancy G.; Bime, Christian; Garcia, Joe G. N.; Medicine, School of Medicine
    Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.
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    eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling
    (Springer Nature, 2022-01-13) Bermudez, Tadeo; Sammani, Saad; Song, Jin H.; Reyes Hernon, Vivian; Kempf, Carrie L.; Garcia, Alexander N.; Burt, Jessica; Hufford, Matthew; Camp, Sara M.; Cress, Anne E.; Desai, Ankit A.; Natarajan, Viswanathan; Jacobson, Jeffrey R.; Dudek, Steven M.; Cancio, Leopoldo C.; Alvarez, Julie; Rafikov, Ruslan; Li, Yansong; Zhang, Donna D.; Casanova, Nancy G.; Bime, Christian; Garcia, Joe G. N.; Medicine, School of Medicine
    Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.
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    Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension
    (American Physiological Society, 2021) Wang, Ziyi; Chen, Jiyuan; Babicheva, Aleksandra; Jain, Pritesh P.; Rodriguez, Marisela; Ayon, Ramon J.; Ravellette, Keeley S.; Wu, Linda; Balistrieri, Francesca; Tang, Haiyang; Wu, Xiaomin; Zhao, Tengteng; Black, Stephen M.; Desai, Ankit A.; Garcia, Joe G. N.; Sun, Xin; Shyy, John Y-J; Valdez-Jasso, Daniela; Thistlethwaite, Patricia A.; Makino, Ayako; Wang, Jian; Yuan, Jason X-J; Medicine, School of Medicine
    Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here, we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared with normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag-1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, whereas downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag-1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Intraperitoneal injection of a Piezo1 channel blocker, GsMTx4, ameliorated experimental PH in mice. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.
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    IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias
    (American Society of Hematology, 2021) Gupta, Akash; Fei, Yu-Dong; Kim, Tae Yun; Xie, An; Batai, Ken; Greener, Ian; Tang, Haiyang; Ciftci-Yilmaz, Sultan; Juneman, Elizabeth; Indik, Julia H.; Shi, Guanbin; Christensen, Jared; Gupta, Geetanjali; Hillery, Cheryl; Kansal, Mayank M.; Parikh, Devang S.; Zhou, Tong; Yuan, Jason X-J; Kanthi, Yogendra; Bronk, Peter; Koren, Gideon; Kittles, Rick; Duarte, Julio D.; Garcia, Joe G. N.; Machado, Roberto F.; Dudley, Samuel C.; Choi, Bum-Rak; Desai, Ankit A.; Medicine, School of Medicine
    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.