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Atherosclerosis is a pathologic condition caused by chronic inflammation in response to lipid deposition in the arterial wall. There are many known contributing factors such as long-term abnormal glucose levels, smoking, hypertension, and hyperlipidemia. Under the influence of such factors, immune and non-immune effectors cells are activated and participate during the progression of atherosclerosis. Protein kinase C (PKC) family isoforms are key players in the signal transduction pathways of cellular activation and have been associated with several aspects of the atherosclerotic vascular disease. This review article summarizes the current knowledge of PKC isoforms functions during atherogenesis, and addresses differential roles and disputable observations of PKC isoforms. Among PKC isoforms, both PKCβ and PKCδ are the most attractive and potential therapeutic targets. This commentary discusses in detail the outcomes and current status of clinical trials on PKCβ and PKCδ inhibitors in atherosclerosis-associated disorders like diabetes and myocardial infarction. The risk and benefit of these inhibitors for clinical purposes will be also discussed. This review summarizes what is already being done and what else needs to be done in further targeting PKC isoforms, especially PKCβ and PKCδ, for therapy of atherosclerosis and atherosclerosis-associated vasculopathies in the future. 相似文献
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Derek W. Gilroy Matthew L. Edin Roel P. H. De Maeyer Jonas Bystrom Justine Newson Fred B. Lih Melanie Stables Darryl C. Zeldin David Bishop-Bailey 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(23):E3240-E3249
Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24–48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid- and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1+, Ly6chi, CCR2hi, CCL2hi, and CX3CR1lo. In addition, expression of F4/80 and the recruitment of T cells, B cells, and dendritic cells were suppressed. sEH (Ephx2)−/− mice, which have elevated epoxy-oxylipins, demonstrated opposing effects to epoxI-treated mice: reduced Ly6chi monocytes and elevated F4/80hi macrophages and B, T, and dendritic cells. Ly6chi and Ly6clo monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity.Monocytes and monocyte-derived macrophages play a critical role in chronic inflammation, in part via the production and release of lipid mediators (1). One such lipid precursor, arachidonic acid, is metabolized into families of biologically active mediators by the cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) pathways (2, 3). CYPs metabolize arachidonic acid by: (i) an epoxygenase activity that catalyzes the conversion of arachidonic acid to epoxyeicosatrienoic acids (EETs); (ii) a lipoxygenase-like activity that metabolizes arachidonic acid to midchain hydroxyeicosatetraenoic acids (HETEs); and (iii) ω- and ω-1-hydroxylase activity, which produces ω-terminal HETEs (3). In addition to arachidonic acid, CYPs with epoxygenase activity can also metabolize alternative polyunsaturated fatty acids such as linoleic acid and docosahexaenoic acid into a series of products including epoxyoctadacamonoenoic acids (EpOMEs) and 19,20-epoxydocosapentaenoic acid (EpDPE), respectively, whose functions remain poorly understood (3–5).The main polyunsaturated fatty acid-metabolizing CYPs belong to the CYP2 family, in particular the CYP2J and CYP2C subfamilies (3, 4, 6, 7). Moreover, these CYP-lipid–metabolizing enzymes are the primary sources of eicosanoids in small blood vessels, the kidney, liver, lung, intestines, heart, and pancreas (3, 7). In most organs, EETs and related epoxygenase products are metabolically unstable and are rapidly metabolized. The major pathway that regulates EET metabolism is that catalyzed by epoxide hydrolases (8), which convert EETs to less biologically active dihydroxyeicosatrienoic acids (DHETs) (9). EpOMEs similarly get converted into dihydroxyoctadecenoic acids (DiHOMEs), whereas 19,20-EpDPE gets converted into 19,20-dihydroxydocosapentaenoic acid (DiHDPA). Elevating the levels of endogenous CYP products by disrupting (knockout) or inhibiting soluble epoxide hydrolase (sEH) reduces neointima formation (10), atherosclerosis, abdominal aortic aneurysm, dyslipidemia (11), hypertension (12), and diabetes (13) in different mouse models, all of which to some extent one could argue have a degree of nonresolving inflammation.Over the last 15 y there has been a vast increase in our knowledge of fatty acid mediators that regulate inflammatory processes, particularly newly identified mediators such as the resolvins that mediate the resolution of inflammation (14–16). However, unlike cyclooxygenase and lipoxygenase products, the roles of CYP450 pathways in chronic inflammation remain unclear. The arachidonic acid products of the CYP epoxygenases, the EETs, can regulate vascular tone, smooth muscle cell mitogenesis, platelet aggregation, steroidogenesis, and endothelial and vascular smooth muscle cell activation (4, 5, 7, 17–19). We recently published that in human monocytes and macrophages, epoxygenases and some of their arachidonic acid products were antiinflammatory through their ability to activate the peroxisome proliferator-activated receptor (PPAR), in particular PPARα (20, 21). Overexpression of epoxygenase enzymes CYP2J2 and CYP2C8 or genetic disruption of sEH (sEH−/−) inhibits LPS-induced pulmonary inflammation (22, 23), and sEH−/− mice or treatment with sEH inhibitors is highly effective against inflammatory and neuropathic pain (24–27).Monocytes are heterogeneous in mice and in humans (28). In mice, monocyte subsets can be divided based on the expression of Ly6c, Gr1, CC-chemokine receptor 2 (CCR2), and CX3C-chemokine receptor 1 (CX3CR1). Ly6chi monocytes are Gr1+, CCR2+, and CX3CR1lo, whereas Ly6clo monocytes are Gr1−, CCR2−, and CX3CR1hi (29, 30). Lipid mediators that regulate the recruitment and phenotype of monocytes are poorly understood.Herein, using a sterile model of inflammatory resolution dependent on monocyte recruitment, we found that CYP-epoxygenase products not only accumulate in a temporal manner with monocyte recruitment but also limit proinflammatory monocyte recruitment and promote a proresolution phenotype in cells of the monocyte lineage. 相似文献
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Rebecca Dann Tarik Hadi Emilie Montenont Ludovic Boytard Dornaszadat Alebrahim Jordyn Feinstein Nicole Allen Russell Simon Krista Barone Kunihiro Uryu Yu Guo Caron Rockman Bhama Ramkhelawon Jeffrey S. Berger 《Journal of the American College of Cardiology》2018,71(1):53-65
Background
Peripheral artery disease (PAD), a diffuse manifestation of atherothrombosis, is a major cardiovascular threat. Although platelets are primary mediators of atherothrombosis, their role in the pathogenesis of PAD remains unclear.Objectives
The authors sought to investigate the role of platelets in a cohort of symptomatic PAD.Methods
The authors profiled platelet activity, mRNA, and effector roles in patients with symptomatic PAD and in healthy controls. Patients with PAD and carotid artery stenosis were recruited into ongoing studies (NCT02106429 and NCT01897103) investigating platelet activity, platelet RNA, and cardiovascular disease.Results
Platelet RNA sequence profiling mapped a robust up-regulation of myeloid-related protein (MRP)-14 mRNA, a potent calcium binding protein heterodimer, in PAD. Circulating activated platelets were enriched with MRP-14 protein, which augmented the expression of the adhesion mediator, P-selectin, thereby promoting monocyte–platelet aggregates. Electron microscopy confirmed the firm interaction of platelets with monocytes in vitro and colocalization of macrophages with MRP-14 confirmed their cross talk in atherosclerotic manifestations of PAD in vivo. Platelet-derived MRP-14 was channeled to monocytes, thereby fueling their expression of key PAD lesional hallmarks and increasing their directed locomotion, which were both suppressed in the presence of antibody-mediated blockade. Circulating MRP-14 was heightened in the setting of PAD, significantly correlated with PAD severity, and was associated with incident limb events.Conclusions
The authors identified a heightened platelet activity profile and unraveled a novel immunomodulatory effector role of platelet-derived MRP-14 in reprograming monocyte activation in symptomatic PAD. (Platelet Activity in Vascular Surgery and Cardiovascular Events [PACE]; NCT02106429; and Platelet Activity in Vascular Surgery for Thrombosis and Bleeding [PIVOTAL]; NCT01897103) 相似文献97.
目的 探讨外周血清过氧化物酶(myeloperoxidase,MPO)、中性粒细胞(neutrophils,PMN)及单核细胞趋化蛋白-4(monocyte chemoattractant protein-4,MCP-4)在小儿支气管哮喘的血清水平,为临床有效防治提供有效参考。方法 采用酶联免疫吸附法分别测定67例支气管哮喘患儿(哮喘组)和30例健康儿童(正常对照组)血清MPO、PMN及MCP-4水平,并进行比较。结果 1)MPO的血清水平在支气管哮喘急性发作期为[(878.43±18.77)U/L] 高于哮喘缓解组[(678.62±33.36)U/L]及健康对照组[(703.17±18.26)U/L](P均<0.05);2)MCP-4在支气管哮喘急性发作期患儿血清水平[(117.34±18.77)pg/mL]高于哮喘缓解组[(55.67±6.13)pg/mL]及健康对照组[(33.74±2.98)pg/mL](P均<0.05)。3)PMN绝对值在支气管哮喘急性发作期[(10.31±1.98)×109/L]高于哮喘缓解组[(4.63±1.51)×109/L]及健康对照组[(4.82±1.51)×109/L](P均<0.05)。MPO、PMN及MCP-4的升高程度与病情严重程度相关,且两者之间呈正相关(r=0.976,0.989;P均<0.01)。结论 MPO、PMN及MCP-4在支气管哮喘中发挥了重要作用,与气道炎症反应有关,血清MPO、PMN及MCP-4可做为支气管哮喘的生化检测指标。哮喘缓解期仍存在慢性炎症反应。 相似文献
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Li Zhao Yu Tang Na Lei Dandan Zhou Bingrun Chen Tao Gan 《Scandinavian journal of gastroenterology》2020,55(4):442-448
AbstractAims: Granuloma, mainly composed of macrophages, is a histological feature of Crohn’s disease (CD). However, its significance in CD has not been investigated adequately. Our study aims to address this issue by comparing the clinical manifestations and monocyte/macrophage subtypes between granulomatous and non-granulomatous CD.Materials and methods: Demographics, symptoms, endoscopic manifestations, histopathological features, and Montreal classification of patients with and without granulomas were compared. Flow cytometry was used to determine the phagocytosis and subsets of monocytes. ELISA was used to measure the plasma levels of TNF-α, IL-6, IL-1β, IL-10, CCL22, and TGF-β1. Immunohistochemistry was performed to quantify the expression of CD68, CD163 and iNOS.Results: Of the222?CD patients enrolled, granulomas were detected in 90. Compared with non-granulomatous CD patients, those with granulomas had younger age, increased rates of diarrhea and perianal complications, along with higher endoscopic score. Intestinal stenosis and crypt abscess were more frequently observed in granulomatous CD patients. A defective phagocytosis of monocytes was observed in granulomatous CD patients. Meanwhile, higher percentages of intermediate and non-classic monocytes, with a lower percentage of classic monocyte were found in them. Besides, they had higher levels of TGF-β1 and IL-10, a lower level of TNF-α, an increased ratio of CD163+/CD68+cells, and a decreased ratio of iNOS+/CD68+ cells.Conclusions: Granulomatous CD patients exhibited different manifestations compared with their non-granulomatous counterparts. More aggressive therapy may be needed in granulomatous CD patients. Furthermore, the heterogeneity of monocyte/macrophage subsets and altered plasma cytokine may underlie the difference between those two groups. 相似文献
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Keiko Kondo Katsutaro Morino Yoshihiko Nishio Motoyuki Kondo Keiko Nakao Fumiyuki Nakagawa Atsushi Ishikado Osamu Sekine Takeshi Yoshizaki Atsunori Kashiwagi Satoshi Ugi Hiroshi Maegawa 《Metabolism: clinical and experimental》2014