Monocyte rolling, adhesion, and transmigration across the endothelium are mediated by specific interactions between surface adhesion molecules. This process is fundamental to innate immunity and to ...inflammatory disease, including atherosclerosis, where monocyte egress into the intimal space is central to formation of fatty plaques. Monocytes are a heterogeneous population of three distinct subsets of cells, all of which play different roles in atherosclerosis progression. However, it is not well understood how interactions between different monocyte subsets and the endothelium are regulated. Furthermore, it is appreciated that endothelial adhesion molecules are heavily N-glycosylated, but beyond regulating protein trafficking to the cell surface, whether and if so how these N-glycans contribute to monocyte recruitment is not known. This review discusses how changes in endothelial N-glycosylation may impact vascular and monocytic inflammation. It will also discuss how regulating N-glycoforms on the endothelial surface may allow for the recruitment of specific monocyte subsets to sites of inflammation, and how further understanding in this area may lead to the development of glyco-specific therapeutics in the treatment of cardiovascular disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Necrotizing enterocolitis (NEC) is an idiopathic, inflammatory bowel necrosis of premature infants. Clinical studies have linked NEC with antecedent red blood cell (RBC) transfusions, but the ...underlying mechanisms are unclear. Here we report a neonatal murine model to investigate this association. C57BL/6 mouse pups rendered anemic by timed phlebotomy and then given RBC transfusions develop NEC-like intestinal injury with prominent necrosis, inflammation, and submucosal edema/separation of the lamina propria in the ileocecal region and colon within 12-24 h. The anemic intestine is infiltrated by inflammatory macrophages, which are activated in situ by RBC transfusions via a Toll-like receptor (TLR)-4-mediated mechanism and cause bowel injury. Chelation of RBC degradation products with haptoglobin, absence of TLR4, macrophage depletion, and inhibition of macrophage activation is protective. Intestinal injury worsens with increasing severity and the duration of anemia prior to transfusion, indicating a need for the re-evaluation of current transfusion guidelines for premature infants.
BACKGROUND:Impaired endothelium-dependent vasodilation is a hallmark of obesity-induced hypertension. The recognition that Ca signaling in endothelial cells promotes vasodilation has led to the ...hypothesis that endothelial Ca signaling is compromised during obesity, but the underlying abnormality is unknown. In this regard, transient receptor potential vanilloid 4 (TRPV4) ion channels are a major Ca influx pathway in endothelial cells, and regulatory protein AKAP150 (A-kinase anchoring protein 150) enhances the activity of TRPV4 channels.
METHODS:We used endothelium-specific knockout mice and high-fat diet–fed mice to assess the role of endothelial AKAP150-TRPV4 signaling in blood pressure regulation under normal and obese conditions. We further determined the role of peroxynitrite, an oxidant molecule generated from the reaction between nitric oxide and superoxide radicals, in impairing endothelial AKAP150-TRPV4 signaling in obesity and assessed the effectiveness of peroxynitrite inhibition in rescuing endothelial AKAP150-TRPV4 signaling in obesity. The clinical relevance of our findings was evaluated in arteries from nonobese and obese individuals.
RESULTS:We show that Ca influx through TRPV4 channels at myoendothelial projections to smooth muscle cells decreases resting blood pressure in nonobese mice, a response that is diminished in obese mice. Counterintuitively, release of the vasodilator molecule nitric oxide attenuated endothelial TRPV4 channel activity and vasodilation in obese animals. Increased activities of inducible nitric oxide synthase and NADPH oxidase 1 enzymes at myoendothelial projections in obese mice generated higher levels of nitric oxide and superoxide radicals, resulting in increased local peroxynitrite formation and subsequent oxidation of the regulatory protein AKAP150 at cysteine 36, to impair AKAP150-TRPV4 channel signaling at myoendothelial projections. Strategies that lowered peroxynitrite levels prevented cysteine 36 oxidation of AKAP150 and rescued endothelial AKAP150-TRPV4 signaling, vasodilation, and blood pressure in obesity. Peroxynitrite-dependent impairment of endothelial TRPV4 channel activity and vasodilation was also observed in the arteries from obese patients.
CONCLUSIONS:These data suggest that a spatially restricted impairment of endothelial TRPV4 channels contributes to obesity-induced hypertension and imply that inhibiting peroxynitrite might represent a strategy for normalizing endothelial TRPV4 channel activity, vasodilation, and blood pressure in obesity.
Human monocytes have been classified into three distinct groups, classical (anti-inflammatory; CD14
/CD16
), nonclassical (patrolling; CD14
/CD16
), and intermediate (proinflammatory; CD14
/CD16
). ...Adhesion of nonclassical/intermediate monocytes with the endothelium is important for innate immunity, and also vascular inflammatory disease. However, there is an incomplete understanding of the mechanisms that regulate CD16
versus CD16
monocyte adhesion to the inflamed endothelium. Here, we tested the hypothesis that a high-mannose (HM)
-glycoform of intercellular adhesion molecule-1 (ICAM-1) on the endothelium mediates the selective recruitment of CD16
monocytes. Using TNF-α treatment of human umbilical vein endothelial cells (HUVECs), and using proximity ligation assay for detecting proximity of specific
-glycans and ICAM-1, we show that TNF-α induces HM-ICAM-1 formation on the endothelial surface in a time-dependent manner. We next measured CD16
or CD16
monocyte rolling and adhesion to TNF-α-treated HUVECs in which HM- or hybrid ICAM-1
-glycoforms were generated using the α-mannosidase class I and II inhibitors, kifunensine and swainsonine, respectively. Expression of HM-ICAM-1 selectively enhanced CD16
monocyte adhesion under flow with no effect on CD16
monocytes noted. CD16
monocyte adhesion was abrogated by blocking either HM epitopes or ICAM-1. A critical role for HM-ICAM-1 in mediating CD16
monocyte rolling and adhesion was confirmed using COS-1 cells engineered to express HM or complex ICAM-1
-glycoforms. These data suggest that HM-ICAM-1 selectively recruits nonclassical/intermediate CD16
monocytes to the activated endothelium.
Monocyte subsets have been associated with cardiovascular disease, yet it is unknown how different subsets are recruited to the endothelium. This study demonstrates the formation of distinct ICAM-1
-glycoforms in the activated endothelium and reveals a key role for high mannose ICAM-1 in mediating proinflammatory CD16
monocyte adhesion. Presented data identify roles for endothelial
-glycans in recruiting specific monocyte subsets during inflammation.
Hydrogen sulfide mediates the vasoactivity of garlic Benavides, Gloria A; Squadrito, Giuseppe L; Mills, Robert W ...
Proceedings of the National Academy of Sciences - PNAS,
11/2007, Volume:
104, Issue:
46
Journal Article
Peer reviewed
Open access
The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remain unclear. Here we show that human RBCs convert ...garlic-derived organic polysulfides into hydrogen sulfide (H₂S), an endogenous cardioprotective vascular cell signaling molecule. This H₂S production, measured in real time by a novel polarographic H₂S sensor, is supported by glucose-maintained cytosolic glutathione levels and is to a large extent reliant on reduced thiols in or on the RBC membrane. H₂S production from organic polysulfides is facilitated by allyl substituents and by increasing numbers of tethering sulfur atoms. Allyl-substituted polysulfides undergo nucleophilic substitution at the α carbon of the allyl substituent, thereby forming a hydropolysulfide (RSnH), a key intermediate during the formation of H₂S. Organic polysulfides (R-Sn-R'; n > 2) also undergo nucleophilic substitution at a sulfur atom, yielding RSnH and H₂S. Intact aorta rings, under physiologically relevant oxygen levels, also metabolize garlic-derived organic polysulfides to liberate H₂S. The vasoactivity of garlic compounds is synchronous with H₂S production, and their potency to mediate relaxation increases with H₂S yield, strongly supporting our hypothesis that H₂S mediates the vasoactivity of garlic. Our results also suggest that the capacity to produce H₂S can be used to standardize garlic dietary supplements.
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Inorganic nitrate and nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides. The nitrate-nitrite-NO pathway is emerging as an ...important mediator of blood flow regulation, cell signaling, energetics and tissue responses to hypoxia. The latest advances in our understanding of the biochemistry, physiology and therapeutics of nitrate, nitrite and NO were discussed during a recent 2-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Nitric oxide (NO) and hydrogen sulfide (H2S) are gasotransmitter molecules important in numerous physiological and pathological processes. Although these molecules were first known as environmental ...toxicants, it is now evident that that they are intricately involved in diverse cellular functions with impact on numerous physiological and pathogenic processes. NO and H2S share some common characteristics but also have unique chemical properties that suggest potential complementary interactions between the two in affecting cellular biochemistry and metabolism. Central among these is the interactions between NO, H2S, and thiols that constitute new ways to regulate protein function, signaling, and cellular responses. In this review, we discuss fundamental biochemical principals, molecular functions, measurement methods, and the pathophysiological relevance of NO and H2S.
Inorganic nitrate (NO3−), nitrite (NO2−) and NO are nitrogenous species with a diverse and interconnected chemical biology. The formation of NO from nitrate and nitrite via a reductive ...‘nitrate–nitrite–NO’ pathway and resulting in vasodilation is now an established complementary route to traditional NOS‐derived vasodilation. Nitrate, found in our diet and abundant in mammalian tissues and circulation, is activated via reduction to nitrite predominantly by our commensal oral microbiome. The subsequent in vivo reduction of nitrite, a stable vascular reserve of NO, is facilitated by a number of haem‐containing and molybdenum‐cofactor proteins. NO generation from nitrite is enhanced during physiological and pathological hypoxia and in disease states involving ischaemia–reperfusion injury. As such, modulation of these NO vascular repositories via exogenously supplied nitrite and nitrate has been evaluated as a therapeutic approach in a number of diseases. Ultimately, the chemical biology of nitrate and nitrite is governed by local concentrations, reaction equilibrium constants, and the generation of transient intermediates, with kinetic rate constants modulated at differing physiological pH values and oxygen tensions.
Linked Articles
This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The major role of red blood cells (RBCs) is to deliver oxygen and remove carbon dioxide within organisms through the unique properties of hemoglobin. Although beneficial within RBCs, when outside ...hemoglobin and its breakdown products (heme, iron) induce proinflammatory responses affecting various cellular responses. Although these effects are considered to be prominent in disorders with increased hemolysis, recent evidence suggests that this process may be active in nonhemolytic disorders such as acute lung injury/acute respiratory distress syndrome. This perspectives article focuses on data related to red cell products in nonhemolytic disorders and the potential to target these factors in acute lung injury/acute respiratory distress syndrome.
SOD2 acetylation and deacetylation Hjelmeland, Anita B.; Patel, Rakesh P.
Proceedings of the National Academy of Sciences - PNAS,
11/2019, Volume:
116, Issue:
47
Journal Article
Peer reviewed
Open access
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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