Deletion of repressor activator protein 1 modulates vascular function in mouse aorta

First joint meeting between the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) and the British Pharmacological Society (BPS) , in association with the Hong Kong Pharmacology Society (HKPS) and the Asia Pacific Federation of Pharmacologists (APFP)Conference Theme: Tomorrow's medicines: pharmacology, patients and populationsOral presentations 9: Cardiovascular and Respiratory 4published_or_final_versio

Knockdown of repressor activator protein 1 facilitated foam cell formation by augmenting cholesterol uptake

This journal issue including abstracts of 18th Annual Scientific Meeting Institute of Cardiovascular Science and MedicineAbstracts for Oral Presentation: no. OP-1OBJECTIVES: Repressor activator protein 1 (Rap1) is a telomere-associated protein with telomeric-regulating functions, but it also displays non-telomeric functions and regulates metabolism. The expression of Rap1 is enhanced in atherosclerotic plaques. Presence of foam cells is an indicator of plaque buildup. This study aims to investigate if Rap1 knockdown has an ...postprin

Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage

RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection

In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyze phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. These are more highly differentiated but express fewer cytotoxicity markers than in blood, but their abundance prior to infection correlates with protection from more severe disease

ICAR: endoscopic skull‐base surgery

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Deletion of repressor activator protein 1 impairs acetylcholine-induced relaxation due to production of reactive oxygen species

Biennial meeting of the ESC Council on Basic Cardiovascular SciencePoster Session 1: Nitric oxide and reactive oxygen species - Vascular: no. 121INTRODUCTION: Repressor activator protein 1 (Rap1) is a telomeric protein which resides within the shelterin complex docked at chromosomal ends. Besides regulating chromosome integrity, it also takes part in metabolic regulation and body-weight homeostasis. Its role, if any, in vascular responsiveness is unknown. PURPOSE: The present study investigated if Rap1 deletion affects vascular responsiveness in mice. METHODS: Rap1 knockout and wild-type littermates on a C57BL/6N background [aged between 12-16 weeks and fed standard chow] were used. Thoracic aortae were harvested and rings (with or without endothelium) were suspended in wire myographs to determine contractions and relaxations (during contractions to 10-6 mol/L phenylephrine). Contractions were expressed as percentage to the reference response obtained with 60mmol/L potassium solution at the beginning of the experiment, while relaxations were expressed as percentage of the contraction to phenylephrine. RESULTS: Relaxations to acetylcholine in aortic rings with endothelium were abolished by NG-nitro-L-arginine methyl ester (L-NAME; 10-4 M; nitric oxide synthase inhibitor) and diminished significantly in Rap1 knockout compared to wild type preparations. Relaxations to other endothelium-dependent vasodilators [insulin, UK14304 (α2 adrenergic agonist), A23187 (calcium ionophore)] were not significantly different between aortae of Rap1 knockout compared to wild type mice. Likewise, relaxations to exogenous nitric oxide donors were similar in aortae without endothelium of both groups. In Rap1 knockout aortae, treatment with reactive oxygen species scavengers could significantly restore acetylcholine-induced relaxations. CONCLUSION: Deletion of Rap1 results in impaired acetylcholine-induced endothelium-dependent relaxations. This impairment can be attributed to the increased production of reactive oxygen species reducing the bioavailability of nitric oxide, without changes in the responsiveness of vascular smooth muscle to the endothelium-derived mediator

Repressor activator protein 1 suppresses foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake

Conference Theme: The Crossroads of Lipid Metabolism and Diabetes (D6)Repressor activator protein 1 suppresses foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptak

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

10.3389/fimmu.2021.734551Frontiers in Immunology12734551-complete

Prostaglandin E2-EP4 signaling reduces inflammation in mouse adipose tissue

This journal suppl. contain abstracts of EDHF 2012 - 10th Anniversary MeetingInflammation of adipose tissue plays a causative role in inducing metabolic syndrome associated with obesity. Thus examining ways to control or inhibit adipose tissue inflammation is of clinical interest. In the present study, we were interested to see if endogenous prostaglandin E2 (PGE2) modulates inflammation via activation of EP4 receptors in mouse adipose tissue. PGE2 (5-500nM) attenuated lipopolysaccharide (LPS)-induced mRNA and protein expression of chemokines in mouse adipose tissue, including interferon-γ-inducible protein 10 (IP10) and macrophage-inflammatory protein (MIP)-1α. Such response was reversed with L161,982 (100nM, a selective EP4 antagonist), mimicked with two structurally different selective EP4 agonists [CAY10580 (10μM) and CAY10598 (10μM)], and was absence in adipose tissue derived from EP4-deficient mice. These findings consolidated the requirement of EP4 in the response. PGE2 significantly reduced LPS-induced chemokines in mature adipocytes, rather than in stromal vascular cells. Antiinflammatory effect of PGE2 in adipose tissue was mimicked with 8-bromo-cyclic adenosine monophosphoate (cAMP) but was insensitive to H98 (a protein kinase A inhibitor). The use of adipose tissue from high-fat fed mice confirmed that EP4-dependent anti-inflammatory response is sustained during diet-induced obesity. Furthermore, adipose tissue and systemic inflammation is enhanced in high-fat fed EP4 deficient mice as compared to wild-type littermates, providing in vivo evidences that PGE2-EP4 signaling modulates inflammation. Our work illustrated that PGE2 via activation of EP4 is a potential endogenous anti-inflammatory mediator in mouse adipose tissue and targeting EP4 could be a strategy to mitigate adipose tissue inflammation