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  • Ovid Technologies (Wolters Kluwer Health)  (7)
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  • Ovid Technologies (Wolters Kluwer Health)  (7)
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  • 1
    Online Resource
    Online Resource
    Foxp1 is Required for Renal Intercalated Dell Differentiation and Acid-Base Regulation
    Ovid Technologies (Wolters Kluwer Health) ; 2024
    In:  Journal of the American Society of Nephrology
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health)
    Abstract: Kidney collecting ducts are comprised of principal cells and intercalated cells, with intercalated cells playing a crucial role in kidney acid-base regulation through H + and HCO 3 - secretion. Despite its significance, the molecular mechanisms controlling intercalated cell development remain incompletely understood. Methods To investigate the specific role of Foxp1 in kidney tubular system, we specifically deleted Foxp1 expression in kidney distal nephrons and collecting ducts. We examined the effects of Foxp1 on intercalated cell differentiation and urine acidification. RNA sequencing and Chip-seq were used to identify Foxp1 target genes. To dissect the genetic network that regulates intercalated cell differentiation, Dmrt2 -deficient mice were generated to determine the role of Dmrt2 in intercalated cell differentiation. Foxp1 deficient mice were cross with Notch2 deficient mice to dissect the relation between Foxp1 and Notch signaling. Results Foxp1 is selectively expressed in intercalated cells in collecting ducts. Absence of Foxp1 in kidney tubules led to the abolishment of intercalated cell differentiation in the collecting ducts, resulting in distal renal tubular acidosis. Foxp1 regulates the expression of Dmrt2 and Hmx2 , two genes encoding transcription factors specifically expressed in type A and B intercalated cell cells, respectively. Further genetic analysis revealed that Dmrt2 is essential for type A intercalated cell differentiation, and Foxp1 is necessary downstream of Notch for the regulation of intercalated cell differentiation. Conclusions Foxp1 is required for the renal intercalated cell differentiation and participated in acid-base regulation. Foxp1 regulated downstream transcriptional factors, Dmrt2 and Hmx2, which involved in the specification of distinct subsets of intercalated cells.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.0000000000000319
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2024
    detail.hit.zdb_id: 2029124-3
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  • 2
    Online Resource
    Online Resource
    Sphingomyelin Synthase 2 Inhibition Ameliorates Cerebral Ischemic Reperfusion Injury Through Reducing the Recruitment of Toll‐Like Receptor 4 to Lipid Rafts
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Journal of the American Heart Association Vol. 8, No. 22 ( 2019-11-19)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 22 ( 2019-11-19)
    Abstract: Inflammation is recognized as an important contributor of ischemia/reperfusion (I/R) damage after ischemic stroke. Sphingomyelin synthase 2 ( SMS 2), the key enzyme for the biosynthesis of sphingomyelin, can function as a critical mediator of inflammation. In the present study, we investigated the role of SMS 2 in a mouse model of cerebral I/R. Methods and Results Cerebral I/R was induced by 60‐minute transient middle cerebral artery occlusion in SMS 2 knockout ( SMS 2 ‐/‐ ) mice and wild‐type mice. Brain injury was determined by neurological deficits and infarct volume at 24 and 72 hours after transient middle cerebral artery occlusion. Microglia activation and inflammatory factors were detected by immunofluorescence staining, flow cytometry, western blot, and RT ‐ PCR . SMS 2 deficiency significantly improved neurological function and minimized infarct volume at 72 hours after transient middle cerebral artery occlusion. The neuroprotective effects of SMS 2 deficiency were associated with (1) suppression of microglia activation through Toll‐like receptor 4/nuclear factor kappa‐light‐chain‐enhancer of activated B cells pathway and (2) downregulation of the level of galactin‐3 and other proinflammatory cytokines. The mechanisms underlying the beneficial effects of SMS 2 deficiency may include altering sphingomyelin components in lipid raft fractions, thus impairing the recruitment of Toll‐like receptor 4 to lipid rafts and subsequently reducing Toll‐like receptor 4/myeloid differentiation factor 2 complex formation on the surface of microglia. Conclusions SMS 2 deficiency ameliorated inflammatory injury after cerebral I/R in mice, and SMS 2 may be a key modulator of Toll‐like receptor 4/nuclear factor kappa‐light‐chain‐enhancer of activated B cells activation by disturbing the membrane component homeostasis during cerebral I/R.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.119.012885
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2653953-6
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  • 3
    Online Resource
    Online Resource
    Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1–Endothelin-1 Signal Pathway
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation Vol. 140, No. 8 ( 2019-08-20), p. 665-680
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 140, No. 8 ( 2019-08-20), p. 665-680
    Abstract: Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms. Methods: Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Results: Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II–induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1–promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Conclusions: EC-Foxp1 regulates the TGF-β1–endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC–Foxp1–TGF-β1–endothelin-1 pathway might provide a future novel therapy for heart failure.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.119.039767
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1466401-X
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  • 4
    Online Resource
    Online Resource
    A Case Report : Systemic Lymph Node Tuberculosis Mimicking Lymphoma on 18F-FDG PET/CT
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Medicine Vol. 95, No. 9 ( 2016-03), p. e2912-
    Details
    In: Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 95, No. 9 ( 2016-03), p. e2912-
    Type of Medium: Online Resource
    ISSN: 0025-7974
    URL: Article
    DOI: 10.1097/MD.0000000000002912
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2049818-4
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  • 5
    Online Resource
    Online Resource
    Cell-Specific Effects of GATA (GATA Zinc Finger Transcription Factor Family)-6 in Vascular Smooth Muscle and Endothelial Cells on Vascular Injury Neointimal Formation
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 39, No. 5 ( 2019-05), p. 888-901
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 39, No. 5 ( 2019-05), p. 888-901
    Abstract: Transcription factor GATA (GATA zinc finger transcription factor family)-6 is highly expressed in vessels and rapidly downregulated in balloon-injured carotid arteries and viral delivery of GATA-6 to the vessels limited the neointimal formation, however, little is known about its cell-specific regulation of in vivo vascular smooth muscle cell (VSMC) phenotypic state contributing to neointimal formation. This study aims to determine the role of vascular cell-specific GATA-6 in ligation- or injury-induced neointimal hyperplasia in vivo. Approach and Results— Endothelial cell and VSMC-specific GATA-6 deletion mice are generated, and the results indicate that endothelial cell-specific GATA-6 deletion mice exhibit significant decrease of VSMC proliferation and attenuation of neointimal formation after artery ligation and injury compared with the wild-type littermate control mice. PDGF (platelet-derived growth factor)-B is identified as a direct target gene, and endothelial cell-GATA-6-PDGF-B pathway regulates VSMC proliferation and migration in a paracrine manner which controls the neointimal formation. In contrast, VSMC-specific GATA-6 deletion promotes injury-induced VSMC transformation from contractile to proliferative synthetic phenotype leading to increased neointimal formation. CCN (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed family)-5 is identified as a novel target gene, and VSMC-specific CCN-5 overexpression in mice reverses the VSMC-GATA-6 deletion-mediated increased cell proliferation and migration and finally attenuates the neointimal formation. Conclusions— This study gives us a direct in vivo evidence of GATA-6 cell lineage-specific regulation of PDGF-B and CCN-5 on VSMC phenotypic state, proliferation and migration contributing to neointimal formation, which advances our understanding of in vivo neointimal hyperplasia, meanwhile also provides opportunities for future therapeutic interventions.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.118.312263
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1494427-3
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  • 6
    Online Resource
    Online Resource
    KANK4 Promotes Arteriogenesis by Potentiating VEGFR2 Signaling in a TALIN-1–Dependent Manner
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. 6 ( 2022-06), p. 772-788
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. 6 ( 2022-06), p. 772-788
    Abstract: Arteriogenesis plays a critical role in maintaining adequate tissue blood supply and is related to a favorable prognosis in arterial occlusive diseases. Strategies aimed at promoting arteriogenesis have thus far not been successful because the factors involved in arteriogenesis remain incompletely understood. Previous studies suggest that evolutionarily conserved KANK4 (KN motif and ankyrin repeat domain-containing proteins 4) might involve in vertebrate vessel development. However, how the KANK4 regulates vessel function remains unknown. We aim to determine the role of endothelial cell-specifically expressed KANK4 in arteriogenesis. Methods: The role of KANK4 in regulating arteriogenesis was evaluated using Kank4 −/− and KANK4 iECOE mice. Molecular mechanisms underlying KANK4-potentiated arteriogenesis were investigated by employing RNA transcriptomic profiling and mass spectrometry analysis. Results: By analyzing Kank4-EGFP reporter mice, we showed that KANK4 was specifically expressed in endothelial cells. In particular, KANK4 displayed a dynamic expression pattern from being ubiquitously expressed in all endothelial cells of the developing vasculature to being explicitly expressed in the endothelial cells of arterioles and arteries in matured vessels. In vitro microfluidic chip-based vascular morphology analysis and in vivo hindlimb ischemia assays using Kank4 −/− and KANK4 iECOE mice demonstrated that deletion of KANK4 impaired collateral artery growth and the recovery of blood perfusion, whereas KANK4 overexpression leads to increased vessel caliber and blood perfusion. Bulk RNA sequencing and Co-immunoprecipitation/mass spectrometry (Co-IP/MS) analysis identified that KANK4 promoted EC proliferation and collateral artery remodeling through coupling VEGFR2 (vascular endothelial growth factor receptor 2) to TALIN-1, which augmented the activation of the VEGFR2 signaling cascade. Conclusions: This study reveals a novel role for KANK4 in arteriogenesis in response to ischemia. KANK4 links VEGFR2 to TALIN-1, resulting in enhanced VEGFR2 activation and increased EC proliferation, highlighting that KANK4 is a potential therapeutic target for promoting arteriogenesis for arterial occlusive diseases.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.122.317711
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1494427-3
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  • 7
    Online Resource
    Online Resource
    Endothelial Foxp1 Suppresses Atherosclerosis via Modulation of Nlrp3 Inflammasome Activation
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation Research Vol. 125, No. 6 ( 2019-08-30), p. 590-605
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. 6 ( 2019-08-30), p. 590-605
    Abstract: Endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, transcriptional regulation of vascular endothelial inflammation has not been well clarified. Objective: This study aims to explore Foxp (forkhead box P) transcription factor 1 in regulation of endothelial homeostasis, atherogenesis, and its mechanisms. Methods and Results: To assess the importance of Foxp1 in atherosclerosis, Foxp1 expression was analyzed in human coronary artery and mouse artery, and we observed significant downregulation of Foxp1 in atherosclerotic and atherosusceptible endothelium. Endothelial-specific Foxp1 knockout mice ( Foxp1 ECKO ) were bred onto Apoe KO mice to generate endothelial Foxp1-deletion hyperlipidemic model Foxp1 ECKO ;Apoe KO , which displayed significant increases in atherosclerotic lesion formation in aortas and aortic roots with enhanced monocyte adhesion, migration, and infiltration into the vascular wall and formation of inflammatory lipid-laden macrophages. In contrast, endothelial-specific Foxp1 overexpression mice Foxp1 ECTg ;Apoe KO exhibited reduced atherosclerotic lesion formation with less monocyte infiltration. Foxp1 was further identified as a gatekeeper of vessel inflammation by direct regulation of endothelial inflammasome components, including Nlrp3 (NLR [nucleotide-binding and leucine-rich repeat immune receptors] family pyrin domain containing 3), caspase-1, and IL (interleukin)-1β. Moreover, endothelial Foxp1 was found to be regulated by Klf2 (Kruppel-like factor 2). Oscillatory shear stress downregulated Foxp1 expression via repressing Klf2 expression in endothelium, and, therefore, promoted endothelial inflammasome activation, leading to atherosclerotic lesion formation. Simvastatin upregulated the reduced expression of Klf2 and Foxp1 in atherosusceptible vascular endothelium and alleviated vascular inflammation contributing to its inhibitory effect in atherosclerosis. Conclusions: These data are the first in vivo experimental validation of an atheroprotective role of endothelial Klf2 and Foxp1, which reveals a Klf2-Foxp1 transcriptional network in endothelial cells as a novel regulator of endothelial inflammasome activation for atherogenesis, therefore, provides opportunities for therapeutic intervention of atherosclerotic diseases and uncovers a novel atheroprotective mechanism for simvastatin.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.118.314402
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1467838-X
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