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  • Ovid Technologies (Wolters Kluwer Health)  (3)
  • 1
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    Abstract 557: Pharmacological Inhibition of ADAM17 by a Human-Cross Reactive Antibody and Selective Inhibitor JG26 Prevents Vascular Fibrosis Induced by Angiotensin II in vivo and in vitro
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Abstract: In cultured vascular smooth muscle cells (VSMCs), we have shown that a metalloprotease, ADAM17, mediates EGF receptor (EGFR) transactivation induced by angiotensin II (AngII). We have also shown that in mice with AngII infusion, EGFR inhibitor erlotinib prevents vessel remodeling independently from hypertension. In the present study, we hypothesized that pharmacological inhibition of ADAM17 prevents AngII-induced vascular fibrosis in vivo and in vitro. A novel human-cross reactive ADAM17 inhibitory antibody, A9(B8), (10 mg/kg ip on day 1 and 7) was utilized in C57Bl/6 mice with AngII infusion (1000 ng/kg/min for 2 weeks). A novel ADAM17 inhibitor JG26 (1 μM) was utilized in cultured rat aortic VSMCs stimulated with 100 nM AngII. A9(B8) but not control IgG treatment attenuated perivascular fibrosis and vascular hypertrophy in mouse coronary arteries (assessed by Sirius Red staining) infused with AngII. A9(B8) also attenuated cardiac hypertrophy (assessed by echocardiogram and heart body weight ratio) but not hypertension in mice with AngII infusion. In VSMCs, 30 min pretreatment of JG26 inhibited AngII-induced extracellular collagen accumulation at 48 h (assessed by a Sirius Red quantification kit). JG26 also inhibited AngII-induced EGFR transactivation (2 and 10 min) and ERK activation (10 min) in VSMCs. We conclude that inhibition of ADAM17 is an effective approach to attenuate pathophysiological cardiovascular remodeling in an AngII-dependent model of hypertension. These data highlight ADAM17 as a novel therapeutic target to prevent end-organ damage associated with hypertension.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.557
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1494427-3
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  • 2
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    Online Resource
    Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by Angiotensin II
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Hypertension Vol. 68, No. 4 ( 2016-10), p. 949-955
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 68, No. 4 ( 2016-10), p. 949-955
    Abstract: Angiotensin II (AngII) has been strongly implicated in hypertension and its complications. Evidence suggests the mechanisms by which AngII elevates blood pressure and enhances cardiovascular remodeling and damage may be distinct. However, the signal transduction cascade by which AngII specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis, remains insufficiently understood. In vascular smooth muscle cells, a metalloproteinase ADAM17 mediates epidermal growth factor receptor transactivation, which may be responsible for cardiovascular remodeling but not hypertension induced by AngII. Thus, the objective of this study was to test the hypothesis that activation of vascular ADAM17 is indispensable for vascular remodeling but not for hypertension induced by AngII. Vascular ADAM17–deficient mice and control mice were infused with AngII for 2 weeks. Control mice infused with AngII showed cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis. These phenotypes were prevented in vascular ADAM17–deficient mice independent of blood pressure alteration. AngII infusion enhanced ADAM17 expression, epidermal growth factor receptor activation, and endoplasmic reticulum stress in the vasculature, which were diminished in ADAM17-deficient mice. Treatment with a human cross-reactive ADAM17 inhibitory antibody also prevented cardiovascular remodeling and endoplasmic reticulum stress but not hypertension in C57Bl/6 mice infused with AngII. In vitro data further supported these findings. In conclusion, vascular ADAM17 mediates AngII-induced cardiovascular remodeling via epidermal growth factor receptor activation independent of blood pressure regulation. ADAM17 seems to be a unique therapeutic target for the prevention of hypertensive complications.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.116.07620
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2094210-2
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  • 3
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    Online Resource
    Deficient Natural Killer Cell NKp30‐Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Hepatology Vol. 69, No. 3 ( 2019-03), p. 1165-1179
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 69, No. 3 ( 2019-03), p. 1165-1179
    Abstract: The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor‐3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7‐H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T‐cell immunoglobulin and mucin‐domain containing‐3. Moreover, NKp30‐positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30‐mediated functionality. Tumor‐infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30‐mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non‐neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7‐H6‐expressing HCC cells significantly down‐modulated NKp30, that was prevented by small interfering RNA–mediated knockdown, suggesting a role for this ligand in inhibiting NKp30‐mediated responses. Interestingly, B7‐H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.30235
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1472120-X
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