Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression
Valentina Maria CasoValentina ManzoTiziana Pecchillo CimminoValeria ContiPio CasoGabriella EspositoVincenzo RussoAmelia FilippelliRosario AmmendolaFabio Cattaneo
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Abstract:
G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases.Keywords:
Proinflammatory cytokine
Formyl peptide receptor
A major role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes is to catalyze the production of superoxides and other reactive oxygen species (ROS). These ROS, in turn, play a key role as messengers in cell signal transduction and cell cycling, but when they are produced in excess they can lead to oxidative stress (OS). Oxidative stress in the kidneys is now considered a major cause of renal injury and inflammation, giving rise to a variety of pathological disorders. In this review, we discuss the putative role of oxalate in producing oxidative stress via the production of reactive oxygen species by isoforms of NADPH oxidases expressed in different cellular locations of the kidneys. Most renal cells produce ROS, and recent data indicate a direct correlation between upregulated gene expressions of NADPH oxidase, ROS, and inflammation. Renal tissue expression of multiple NADPH oxidase isoforms most likely will impact the future use of different antioxidants and NADPH oxidase inhibitors to minimize OS and renal tissue injury in hyperoxaluria-induced kidney stone disease.
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Stroke is a leading cause of death and disability in humans. The excessive production of reactive oxygen species (ROS) is an important contributor to oxidative stress and secondary brain damage after stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme complex consisting of membrane subunits and cytoplasmic subunits, regulates neuronal maturation and cerebrovascular homeostasis. However, NADPH oxidase overproduction contributes to neurotoxicity and cerebrovascular disease. NADPH oxidase has been implicated as the principal source of ROS in the brain, and numerous studies have shown that the knockout of NADPH exerts a protective effect in the model of ischemic stroke. In this review, we summarize the mechanism of activation of the NADPH oxidase family members, the pathophysiological effects of NADPH oxidase isoforms in ischemic stroke, and the studies of NADPH oxidase inhibitors to explore potential clinical applications.
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NOX1
NOX4
Vascular tissue
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G protein-coupled receptors (GPCR) are the largest group of cell surface receptors, which link cells to their environment. Reactive oxygen species (ROS) can act as important cellular signaling molecules. The family of NADPH oxidases generates ROS in response to activated cell surface receptors. Recent Advances: Various signaling pathways linking GPCRs and activation of NADPH oxidases have been characterized.Still, a more detailed analysis of G proteins involved in the GPCR-mediated activation of NADPH oxidases is needed. In addition, a more precise discrimination of NADPH oxidase activation due to either upregulation of subunit expression or post-translational subunit modifications is needed. Also, the role of noncanonical modulators of NADPH oxidase activation in the response to GPCRs awaits further analyses.As GPCRs are one of the most popular classes of investigational drug targets, further detailing of G protein-coupled mechanisms in the activation mechanism of NADPH oxidases as well as better understanding of the link between newly identified NADPH oxidase interaction partners and GPCR signaling will provide new opportunities for improved efficiency and decreased off target effects of therapies targeting GPCRs.
Cell Signaling
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The vascular endothelium plays an important role in the regulation of inflammatory responses after trauma and hemorrhage. Interactions of neutrophils with endothelial cells (ECs) contribute to the activation of specific EC responses involved in innate immunity. We have previously reported that oxidants derived from the neutrophil reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a critical regulator to EC activation. Our objective was to test the role of neutrophil NADPH oxidase-derived oxidants in mediating and enhancing hemorrhagic shock (HS)-induced activation of lung endothelial NADPH oxidase. Mice were subjected to HS and neutrophil depletion. The mice were also replenished with the neutrophil from NADPH oxidase-deficient mice. The resultant activation of lung NADPH oxidase was analyzed. The in vivo studies were also recapitulated with in vitro neutrophil-EC coculture system. HS induces NADPH oxidase activation in neutrophils and lung through high-mobility group box 1/Toll-like receptor 4-dependent signaling. In neutropenic mice, shock-induced NADPH oxidase activation in the lung was reduced significantly, but was restored upon repletion with neutrophils obtained from wild-type mice subjected to shock, but not with neutrophils from shock mice lacking the gp91(phox) subunit of NADPH oxidase. The findings were recapitulated in mouse lung vascular ECs cocultured with neutrophils. The data further demonstrate that neutrophil-derived oxidants are key factors mediating augmented High mobility group box 1 (HMGB1)-induced endothelial NADPH oxidase activation through a Rac1-dependent, but p38 mitogen-activated protein kinase-independent, pathway. Oxidant signaling by neutrophil NADPH oxidase is an important determinant of activation of endothelial NADPH oxidase after HS.
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NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase), is the major source of superoxide anion (O2.‐), wich is a free radical and reacts with Nitric Oxide (NO) decreasing its bioavailability in endothelial cells producing severe cardiovascular diseases such as hypertension. It had been reported that Apocynin inhibit NADPH oxidase, however, has not been used as a therapeutic treatment, due to Apocynin needs to be converts to its dimeric form by Mieloperoxidasa (MPO) and this enzyme has low affinity for Apocynin. Therefore, in this work were synthesized a set of Apocynin ethers with the main to compounds as obtain better NADPH oxidase inhibitor than Apocynin and avoiding the MPO dimerization. The inhibitory activity of the compounds was evaluated by Electron Paramagnetic Resonance (EPR) employed homogenized of aortic tissue contained NADPH oxidase of spontaneously hypertensive (SHR/NHsd) and normotensive (WKY/NHsd) rats.
Apocynin
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Important roles for reactive oxygen species (ROS) in physiology and pathophysiology have been increasingly recognized. Under normal conditions, ROS serve as signaling molecules in the regulation of cellular functions. However, enhanced ROS production as a result of the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contributes significantly to the pathogeneses of vascular diseases. Although it has become evident that increased ROS is associated with erectile dysfunction (ED), the sources of ROS in the penis remain largely unknown. In recent years, emergent evidence suggests the possible role of NADPH oxidase in inducing ED. In this review, we examine the relationship between ROS and ED in different disease models and discuss the current evidence basis for NADPH oxidase-derived ROS in ED.
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Pathophysiology
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Background Our previous study demonstrated that microglial activation is closely associated with photoreceptor apoptosis in rd mice.Recent studies on central nervous system (CNS) showed that activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a key role in the microglia activation and neural cell death.However,the mechanism of NADPH oxidase during the retinal degeneration and the effect of NADPH oxidase inhibitor on photoreceptor apoptosis are concerned.Objective The aim of this study was to further explore the production of reactive oxygen species (ROS) by NADPH oxidase in the retinal degenerative process of rd mice and protection of NADPH oxidase inhibitor on photoreceptors.Methods Sixty rd mice at postnatal day 9 (P9) were randomized into the experimental group and the control group by throwing coins method.Apocynin,a NADPH oxidase inhibitor,was intraperitoneally injected in the dose of 10 mg/kg (0.01 ml/kg) once daily for 5 days (P13) in the experimental group,and the equal amount of PBS was used in the same way in the control group,and 10 C57BL/6N mice without injection of any drugs served as the wild type mice group.All the mice were sacrificed in P14 for the preparation of retinal sections.The expression of ROS in the retina was detected by dihydroethidium (DHE) fluorescence staining.Expression level of rhodopsin mRNA in the photoreceptor of the mice was determined by real-time PCR,and the thickness of retinal outer nuclear layer (ONL) in the mice of the experimental group and the control group was measured using hematoxylin & eosin staining.The use and care of the animals complied with the Statement of Association for Research in Vision and Ophthalmology.Results DHE staining showed that the ROS presented with the red fluorescence in the mouse retinas.In the rd mice of the experimental group,the ROS fluorescence intensity was dramatically enhanced in comparison with C57BL/6N mice,but weakened in comparison with the rd mice of the control group.Real-time PCR revealed that the relative expressing level of rhodopsin mRNA in the photoreceptor was (4.21±0.33) in the experimental group and (0.93±0.24) in the control group,showing a significant difference between them (t =2.360,P =0.000).The thickness value of retinal ONL was (35.95±1.63)μm in the mice of the experimental group,which was significantly higher than that in the mice of the control group ([23.17±1.38] μm) (t=3.850,P=0.016).Conclusions In the retinal degeneration of rd mice,activation of NADPH oxidase increases the ROS production.Apocynin can slow the apoptosis procedure of photoreceptor cells of rd mice.
Key words:
Retinal degeneration/genetics; rd Mice; Nicotinamide adenine dinucleotide phosphate oxidase/inhibitor; Reactive oxygen species; Microglia
Apocynin
Outer nuclear layer
Photoreceptor cell
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NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) plays pivotal roles in antioxidation and reductive biosynthesis. However, the effect of NADPH treatment on cell survival is unknown. In this study, we determined the effect of NADPH treatment on the survival of glioma cells. Treatment of C6 glioma cells with as low as 1 μM NADPH for 24 hrs induced a significant decrease in the survival of the glioma cells, while NADPH treatment had no effect on the survival of primary astrocyte cultures. We also found that NADPH treatment increased intracellular oxidative stress. Three antioxidants and the NADPH oxidase inhibitor, apocynin, attenuated the effect of NADPH. Poly(ADP-ribose) polymerase (PARP) activation appears to be a downstream effector of the oxidative stress, since PARP inhibitors reduced the effect of NADPH. Calcium chelator, BAPTA-AM, also attenuated the effect of NADPH. Collectively, these data indicate a novel property of NADPH: NADPH decreases glioma cell survival by inducing the NADPH oxidase-dependent increase in oxidative stress and by PARP activation. These results also suggest a potential therapeutic effect of NADPH on gliomas.
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