Oxidative stress plays a key role in the pathogenesis of respiratory diseases; however, studies on antioxidant vitamins and respiratory outcomes have been conflicting. We evaluated whether lower ...serum levels of vitamins A, C, D, and E are associated with respiratory morbidity and mortality in the U.S. adult population.
We conducted a pooled analysis of data from the 1988-1994 and 1999-2006 National Health and Nutrition Examination Survey (participants aged ≥ 20 years). We estimated covariate-adjusted odds ratios (aOR) per interquartile decrease in each serum vitamin level to quantify associations with respiratory morbidity, and covariate-adjusted hazard ratios (aHR) to quantify associations with respiratory mortality assessed prospectively through 2015. Vitamin supplementation and smoking were evaluated as potential effect modifiers.
Lower serum vitamin C increased the odds of wheeze among all participants (overall aOR: 1.08, 95% CI: 1.01-1.16). Among smokers, lower serum α-tocopherol vitamin E increased the odds of wheeze (aOR: 1.11, 95% CI: 1.04-1.19) and chronic bronchitis/emphysema (aOR: 1.13, 95% CI: 1.03-1.24). Conversely, lower serum γ-tocopherol vitamin E was associated with lower odds of wheeze and chronic bronchitis/emphysema (overall aORs: 0.85, 95% CI: 0.79-0.92 and 0.85, 95% CI: 0.76-0.95, respectively). Lower serum vitamin C was associated with increased chronic lower respiratory disease (CLRD) mortality in all participants (overall aHR: 1.27, 95% CI: 1.07-1.51), whereas lower serum 25-hydroxyvitamin D (25-OHD) tended to increase mortality from CLRD and influenza/pneumonia among smokers (aHR range: 1.33-1.75). Mortality from influenza/ pneumonia increased with decreasing serum vitamin A levels in all participants (overall aHR: 1.21, 95% CI: 0.99-1.48). In pooled analysis, vitamin C deficiency and 25-OHD insufficiency were associated with mortality from influenza/pneumonia, increasing mortality risk up to twofold.
Our analysis of nationally representative data on over 34,000 participants showed that lower serum levels of vitamins A, C, D, and α-tocopherol vitamin E are associated with increased respiratory morbidity and/or mortality in U.S. adults. The results underscore the importance of antioxidant vitamins in respiratory health.
The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we ...show that
-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that
-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate
-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host
-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.
20-Hydroxyeicosatetraenoic acid (20-HETE), one of the principle cytochrome P450 eicosanoids, is a potent vasoactive lipid whose vascular effects include stimulation of smooth muscle contractility, ...migration, and proliferation, as well as endothelial cell dysfunction and inflammation. Increased levels of 20-HETE in experimental animals and in humans are associated with hypertension, stroke, myocardial infarction, and vascular diseases.
To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists. The present study was undertaken to identify a receptor to which 20-HETE binds and through which it activates a signaling cascade that culminates in many of the functional outcomes attributed to 20-HETE in vitro and in vivo.
Using crosslinking analogs, click chemistry, binding assays, and functional assays, we identified G-protein receptor 75 (GPR75), currently an orphan G-protein-coupled receptor (GPCR), as a specific target of 20-HETE. In cultured human endothelial cells, 20-HETE binding to GPR75 stimulated Gα
protein dissociation and increased inositol phosphate accumulation and GPCR-kinase interacting protein-1-GPR75 binding, which further facilitated the c-Src-mediated transactivation of epidermal growth factor receptor. This results in downstream signaling pathways that induce angiotensin-converting enzyme expression and endothelial dysfunction. Knockdown of GPR75 or GPCR-kinase interacting protein-1 prevented 20-HETE-mediated endothelial growth factor receptor phosphorylation and angiotensin-converting enzyme induction. In vascular smooth muscle cells, GPR75-20-HETE pairing is associated with Gα
- and GPCR-kinase interacting protein-1-mediated protein kinase C-stimulated phosphorylation of MaxiKβ, linking GPR75 activation to 20-HETE-mediated vasoconstriction. GPR75 knockdown in a mouse model of 20-HETE-dependent hypertension prevented blood pressure elevation and 20-HETE-mediated increases in angiotensin-converting enzyme expression, endothelial dysfunction, smooth muscle contractility, and vascular remodeling.
This is the first report to identify a GPCR target for an eicosanoid of this class. The discovery of 20-HETE-GPR75 pairing presented here provides the molecular basis for the signaling and pathophysiological functions mediated by 20-HETE in hypertension and cardiovascular diseases.
Coronary reactive hyperemia (CRH) is impaired in cardiovascular diseases, and angiotensin-II (Ang-II) exacerbates it. However, it is unknown how Ang-II affects CRH in Tie2-sEH Tr ...(human-sEH-overexpressed) versus wild-type (WT) mice. sEH-overexpression resulted in CRH reduction in Tie2-sEH Tr versus WT. We hypothesized that Ang-II exacerbates CRH reduction in Tie2-sEH Tr versus WT. The Langendorff system measured coronary flow in Tie2-sEH Tr and WT. The hearts were exposed to 15-second ischemia, and CRH was assessed in 10 mice each. Repayment volume was reduced by 40.50% in WT treated with Ang-II versus WT (7.42 ± 0.8 to 4.49 ± 0.8 mL/g) and 48% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (5.18 ± 0.4 to 2.68 ± 0.3 mL/g). Ang-II decreased repayment duration by 50% in WT-treated with Ang-II versus WT (2.46 ± 0.5 to 1.24 ± 0.4 minutes) and 54% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (1.66 ± 0.4 to 0.76 ± 0.2 minutes). Peak repayment flow was reduced by 11.2% in WT treated with Ang-II versus WT (35.98 ± 0.7 to 32.11 ± 1.4 mL/g) and 4% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (32.18 ± 0.6 to 30.89 ± 1.5 mL/g). Furthermore, coronary flow was reduced by 43% in WT treated with Ang-II versus WT (14.2 ± 0.5 to 8.15 ± 0.8 mL/min/g) and 32% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (12.1 ± 0.8 to 8.3 ± 1.2 mL/min/g). Moreover, the Ang-II-AT 1 -receptor and CYP4A were increased in Tie2-sEHTr. Our results demonstrate that Ang-II exacerbates CRH reduction in Tie2-sEH Tr mice.
EET signaling in cancer Panigrahy, Dipak; Greene, Emily R.; Pozzi, Ambra ...
Cancer and metastasis reviews,
12/2011, Letnik:
30, Številka:
3-4
Journal Article
Recenzirano
Odprti dostop
Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in tumorigenesis. Endogenously produced lipid autacoids, locally acting small-molecule mediators, play a ...central role in inflammation and tissue homeostasis. These lipid mediators, collectively referred to as eicosanoids, have recently been implicated in cancer. Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This eicosanoid pathway consists of two main branches: ω-hydroxylases which converts arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. EET signaling was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology. To date, most research on eicosanoids in cancer has focused on the COX and LOX pathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as EETs and HETEs, in cancer has received little attention. While CYP epoxygenases are expressed in human cancers and promote human cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis, inflammation, and cancer is discussed.
Epoxyeicosatrienoic acids (EETs) and arachidonic acid-derived cytochrome P450 (CYP) epoxygenase metabolites have diverse biological effects, including anti-inflammatory properties in the vasculature. ...Increasing evidence suggests that inflammation in type 2 diabetes is a key component in the development of insulin resistance. In this study, we investigated whether CYP epoxygenase expression and exogenous EETs can attenuate insulin resistance in diabetic db/db mice and in cultured hepatic cells (HepG2). In vivo, CYP2J2 expression and the accompanying increase in EETs attenuated insulin resistance, as determined by plasma glucose levels, glucose tolerance test, insulin tolerance test, and hyperinsulinemic euglycemic clamp studies. CYP2J2 expression reduced the production of proinflammatory cytokines in liver, including CRP, IL-6, IL-1β, and TNFα, and decreased the infiltration of macrophages in liver. CYP2J2 expression also decreased activation of proinflammatory signaling cascades by decreasing NF-κB and MAPK activation in hepatocytes. Interestingly, CYP2J2 expression and exogenous EET treatment increased glucose uptake and activated the insulin-signaling cascade both in vivo and in vitro, suggesting that CYP2J2 metabolites play a role in glucose homeostasis. Furthermore, CYP2J2 expression upregulated PPARγ, which has been shown to induce adipogenesis, which attenuates dyslipidemias observed in diabetes. All of the findings suggest that CYP2J2 expression attenuates the diabetic phenotype and insulin resistance via inhibition of NF-κB and MAPK signaling pathways and activation of PPARγ.
Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases. EETs and HETEs ...often have opposite biologic effects; EETs are vasodilatory and protect against ischemia/reperfusion injury, while ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. Other oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), hydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular effects. Post-ischemic vasodilation in the heart, known as coronary reactive hyperemia (CRH), protects against potential damage to the heart muscle caused by ischemia. The relationship among CRH response to ischemia, in mice with altered levels of CYP2J epoxygenases has not yet been investigated. Therefore, we evaluated the effect of endothelial overexpression of the human cytochrome P450 epoxygenase CYP2J2 in mice (Tie2-CYP2J2 Tr) on oxylipin profiles and CRH. Additionally, we evaluated the effect of pharmacologic inhibition of CYP-epoxygenases and inhibition of ω-hydroxylases on CRH. We hypothesized that CRH would be enhanced in isolated mouse hearts with vascular endothelial overexpression of human CYP2J2 through modulation of oxylipin profiles. Similarly, we expected that inhibition of CYP-epoxygenases would reduce CRH, whereas inhibition of ω-hydroxylases would enhance CRH. Compared to WT mice, Tie2-CYP2J2 Tr mice had enhanced CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05). Similarly, inhibition of ω-hydroxylases increased repayment volume and repayment duration, in Tie2-CYP2J2 Tr compared to WT mice (P < 0.05). Endothelial overexpression of CYP2J2 significantly changed oxylipin profiles, including increased EETs (P < 0.05), increased EpOMEs (P < 0.05), and decreased 8-iso-PGF2α (P < 0.05). Inhibition of CYP epoxygenases with MS-PPOH attenuated CRH (P < 0.05). Ischemia caused a decrease in mid-chain HETEs (5-, 11-, 12-, 15-HETEs P < 0.05) and HODEs (P < 0.05). These data demonstrate that vascular endothelial overexpression of CYP2J2, through changing the oxylipin profiles, enhances CRH. Inhibition of CYP epoxygenases decreases CRH, whereas inhibition of ω-hydroxylases enhances CRH.
Vascular actions of 20-HETE Hoopes, Samantha L.; Garcia, Victor; Edin, Matthew L. ...
Prostaglandins & other lipid mediators,
07/2015, Letnik:
120
Journal Article
Recenzirano
Odprti dostop
•20-HETE acts in a feed forward mechanism with the renin-angiotensin system to perpetuate hypertension and vascular dysfunction.•20-HETE sensitizes smooth muscle to constrictor stimuli by inhibiting ...large conductance Ca2+-activated K+ channels and increasing Ca2+ entry through L-type Ca2+ channels.•20-HETE induces vascular remodeling through mechanisms independent of changes in blood pressure.•20-HETE enhances vascular inflammation and injury in diabetes and in models of ischemia/reperfusion and cerebrovascular oxidative stress.•20-HETE induces angiogenesis via increased production of reactive oxygen species (ROS). 20-HETE increases ROS though NADPH-oxidase and Rac1/2-dependent mechanisms and increased expression of VEGF and VEGFR2.
20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid that exhibits a myriad of biological effects in the vascular system. This review discusses the current knowledge related to the effects of 20-HETE on vascular reactivity, activation, and remodeling, as well as its role in vascular inflammation and angiogenesis. The information explaining how 20-HETE and the renin-angiotensin system interact to promote hypertension, vasoconstriction, and vascular dysfunction is summarized in this article. 20-HETE enhances vascular inflammation and injury in models of diabetes, ischemia/reperfusion, and cerebrovascular oxidative stress. Recent studies also established a role for 20-HETE in normal and pathological angiogenesis conditions. This review will also discuss the molecular mechanisms through which 20-HETE induces these vascular actions. Potential additional studies are suggested to address shortcomings in the current knowledge of 20-HETE in the vascular system.