The inflammatory response is a complex, tightly regulated process activated by tissue wounding, foreign body invasion, and sterile inflammation. Over the decades, great progress has been made to ...advance our understanding of this process. One often overlooked aspect of inflammation is its sequel: resolution. We know that dysregulated resolution often results in numerous chronic degenerative diseases such as arthritis, cancer, and asthma. However, identification of components and mechanisms of resolving pathways lags behind those of proinflammatory processes, yet represents overlooked therapeutic opportunities. One approach is identification of endogenous, negative compensatory mechanisms, which are activated in response to inflammation for the purpose of resolution of that inflammatory stimuli. This review will focus on literature that describes expression and function of interleukin-19, a proposed anti-inflammatory cytokine, in numerous inflammatory diseases. The literature concerning IL-19 is complex, context-dependent, and often contradictory. The expression and function of IL-19 in the inflammatory response are in no way settled. We will attempt to clarify the role that this interesting and understudied cytokine plays in resolution of inflammation and discuss its mechanisms of action in different cell types. We will present a hypothesis that endogenous IL-19 expression in response to inflammatory stimuli is a cellular compensatory mechanism to dampen inflammation. We further present studies suggesting that while endogenously expressed IL-19 may be a response to inflammation, pharmacological levels may be necessary to effectively resolve the inflammatory cascade.
Adiponectin is an abundant plasma protein secreted from adipocytes that elicits protective effects in the vasculature and myocardium. In obesity and insulin-resistant states, adiponectin levels are ...reduced and loss of its protective effects might contribute to the excess cardiovascular risk observed in these conditions. Adiponectin ameliorates the progression of macrovascular disease in rodent models, consistent with its correlation with improved vascular outcomes in epidemiological studies. The mechanisms of adiponectin signaling are multiple and vary among its cellular sites of action. In endothelial cells, adiponectin enhances production of nitric oxide, suppresses production of reactive oxygen species, and protects cells from inflammation that results from exposure to high glucose levels or tumor necrosis factor, through activation of AMP-activated protein kinase and cyclic AMP-dependent protein kinase (also known as protein kinase A) signaling cascades. In the myocardium, adiponectin-mediated protection from ischemia-reperfusion injury is linked to cyclo-oxygenase-2-mediated suppression of tumor necrosis factor signaling, inhibition of apoptosis by AMP-activated protein kinase, and inhibition of excess peroxynitrite-induced oxidative and nitrative stress. In this Review, we provide an update of studies of the signaling effects of adiponectin in endothelial cells and cardiomyocytes.
OBJECTIVE:Stress granules (SGs) are dynamic cytoplasmic aggregates containing mRNA, RNA-binding proteins, and translation factors that form in response to cellular stress. SGs have been shown to ...contribute to the pathogenesis of several human diseases, but their role in vascular diseases is unknown. This study shows that SGs accumulate in vascular smooth muscle cells (VSMCs) and macrophages during atherosclerosis.
APPROACH AND RESULTS:Immunohistochemical analysis of atherosclerotic plaques from LDLR mice revealed an increase in the stress granule-specific markers Ras-G3BP1 (GTPase-activating protein SH3 domain-binding protein) and PABP (poly-A-binding protein) in intimal macrophages and smooth muscle cells that correlated with disease progression. In vitro, PABP+ and G3BP1+ SGs were rapidly induced in VSMC and bone marrow–derived macrophages in response to atherosclerotic stimuli, including oxidized low-density lipoprotein and mediators of mitochondrial or oxidative stress. We observed an increase in eIF2α (eukaryotic translation initiation factor 2-alpha) phosphorylation, a requisite for stress granule formation, in cells exposed to these stimuli. Interestingly, SG formation, PABP expression, and eIF2α phosphorylation in VSMCs is reversed by treatment with the anti-inflammatory cytokine interleukin-19. Microtubule inhibitors reduced stress granule accumulation in VSMC, suggesting cytoskeletal regulation of stress granule formation. SG formation in VSMCs was also observed in other vascular disease pathologies, including vascular restenosis. Reduction of SG component G3BP1 by siRNA significantly altered expression profiles of inflammatory, apoptotic, and proliferative genes.
CONCLUSIONS:These results indicate that SG formation is a common feature of the vascular response to injury and disease, and that modification of inflammation reduces stress granule formation in VSMC.
The prevalence of obesity and associated cardiometabolic diseases continues to rise, despite efforts to improve global health. The adipose tissue is now regarded as an endocrine organ since its ...multitude of secretions, lipids chief among them, regulate systemic functions. The loss of normal adipose tissue phenotypic flexibility, especially related to lipid homeostasis, appears to trigger cardiometabolic pathogenesis. The goal of this manuscript is to review lipid balance maintenance by the lean adipose tissue's propensity for phenotype switching, obese adipose tissue's narrower range of phenotype flexibility, and what initial factors account for the waning lipid regulatory capacity. Metabolic, hypoxic, and inflammatory factors contribute to the adipose tissue phenotype being made rigid. A better grasp of normal adipose tissue function provides the necessary context for recognizing the extent of obese adipose tissue dysfunction and gaining insight into how pathogenesis evolves.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Dyslipidemia, vascular inflammation, obesity, and insulin resistance often overlap and exacerbate each other. Mutations in low density lipoprotein receptor adaptor protein-1 (LDLRAP1) lead to LDLR ...malfunction and are associated with the autosomal recessive hypercholesterolemia disorder in humans. However, direct causality on atherogenesis in a defined preclinical model has not been reported. The objective of this study was to test the hypothesis that deletion of LDLRAP1 will lead to hypercholesteremia and atherosclerosis. LDLRAP1
mice fed a high-fat Western diet had significantly increased plasma cholesterol and triglyceride concentrations accompanied with significantly increased plaque burden compared with wild-type controls. Unexpectedly, LDLRAP1
mice gained significantly more weight compared with controls. Even on a chow diet, LDLRAP1
mice were insulin-resistant, and calorimetric studies suggested an altered metabolic profile. The study showed that LDLRAP1 is highly expressed in visceral adipose tissue, and LDLRAP1
adipocytes are significantly larger, have reduced glucose uptake and AKT phosphorylation, but have increased CD36 expression. Visceral adipose tissue from LDLRAP1
mice was hypoxic and had gene expression signatures of dysregulated lipid storage and energy homeostasis. These data are the first to indicate that lack of LDLRAP1 directly leads to atherosclerosis in mice and also plays an unanticipated metabolic regulatory role in adipose tissue. LDLRAP1 may link atherosclerosis and hypercholesterolemia with common comorbidities of obesity and insulin resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neovascularization and inflammation are independent biological processes but are linked in response to injury. The role of inflammation-dampening cytokines in the regulation of angiogenesis remains ...to be clarified. The purpose of this work was to test the hypothesis that IL-19 can induce angiogenesis in the absence of tissue hypoxia and to identify potential mechanisms. Using the aortic ring model of angiogenesis, we found significantly reduced sprouting capacity in aortic rings from IL-19(-/-) compared with wild-type mice. Using an in vivo assay, we found that IL-19(-/-) mice respond to vascular endothelial growth factor (VEGF) significantly less than wild-type mice and demonstrate decreased capillary formation in Matrigel plugs. IL-19 signals through the IL-20 receptor complex, and IL-19 induces IL-20 receptor subunit expression in aortic rings and cultured human vascular smooth muscle cells, but not endothelial cells, in a peroxisome proliferator-activated receptor-γ-dependent mechanism. IL-19 activates STAT3, and IL-19 angiogenic activity in aortic rings is STAT3-dependent. Using a quantitative RT-PCR screening assay, we determined that IL-19 has direct proangiogenic effects on aortic rings by inducing angiogenic gene expression. M2 macrophages participate in angiogenesis, and IL-19 has indirect angiogenic effects, as IL-19-stimulated bone marrow-derived macrophages secrete proangiogenic factors that induce greater sprouting of aortic rings than unstimulated controls. Using a quantitative RT-PCR screen, we determined that IL-19 induces expression of angiogenic cytokines in bone marrow-derived macrophages. Together, these data suggest that IL-19 can promote angiogenesis in the absence of hypoxia by at least two distinct mechanisms: 1) direct effects on vascular cells and 2) indirect effects by stimulation of macrophages.
OBJECTIVE—Angiotensin II (Ang II) and tumor necrosis factor (TNF)-α levels increase endothelial permeability, and we hypothesized that adiponectin suppressed these responses in a cAMP-dependent ...manner.
METHODS AND RESULTS—The effect of adiponectin on transendothelial electric resistance (TEER) and diffusion of albumin through human umbilical vein and bovine aortic endothelial cell monolayers induced by Ang II (100 nmol/L) or TNF-α (5 ng/mL) was measured. Treatment with the globular domain of adiponectin (3 μg/mL) for 16 hours abrogated the adverse TEER effect of TNF-α (−35 versus −12 Ω/cm at 45 minutes, P<0.05) and Ang II (−25 versus −5 Ω/cm at 45 minutes, P<0.01) and partially suppressed the increased diffusion of albumin with Ang II (40% versus 10% change, P<0.05) or TNF-α (40% versus 20% change, P<0.05). Full-length adiponectin also suppressed Ang II–induced monolayer hyperpermeability. Adiponectin treatment also suppressed Ang II–induced increased actin stress fiber development, intercellular gap formation, and β-tubulin disassembly. Adiponectin increased cAMP levels, and its effects were abrogated by inhibition of adenylyl cyclase or cAMP-dependent protein kinase signaling.
CONCLUSIONS—Adiponectin protects the endothelial monolayer from Ang II or TNF-α-induced hyperpermeability by modulating microtubule and cytoskeleton stability via a cAMP/ PKA signaling cascade.
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Lack of compensatory vascularization causes hypoxia with adipose tissue dysfunction in obesity. Dysfunctional adipocytes instigate systemic low-grade inflammation which is associated ...with increased morbidity and mortality of metabolic disorders and related cardiovascular disease. A remaining challenge in the field is how to preserve adipocyte metabolic function by suppressing the negative aspect of inflammation, without blocking its angiogenic function. We investigated the role of IL-19, a uniquely immuno-modulatory, pro-angiogenic interleukin expressed also in adipose tissue. We hypothesize that IL-19 acts as a novel adipokine whose expression in expanding adipose depots is essential for maintaining glucose homeostasis. We report that IL-19 is expressed in adipose tissue at both the transcript and protein level and its expression is increased in inflamed visceral adipose tissue but not subcutaneous adipose tissue (p<0.05). Utilizing
Il19
-/-
knockout mice, we found the loss of IL-19 leads to a metabolic phenotype characterized by reduced glucose and insulin tolerance, increased adipose tissue hypoxia and fibrosis, decreased adipose tissue vessel density and increased adipocyte hypertrophy both in response to standard chow diet and chronic high fat diet (p<0.05). Acute treatment with IL-19 reduced glucose and insulin intolerance in obese wild-type mice (p<0.05). In primary murine epididymal adipocytes the addition of IL-19 leads to increased glucose uptake (p<0.05). These metabolic actions of IL-19 were linked to upregulation of the insulin type-2 receptor and subsequent increased expression/phosphorylation of the protein kinase B (Akt) in adipocytes. Overall, these data propose that IL-19 has novel therapeutic potential in that it can effectively allow adipose tissue expansion without concomitant inflammation and insulin insensitivity.
Abstract only Introduction: Atherosclerotic vascular syndromes account for 50% of all deaths in the United States, and are a considerable medical and socioeconomic problem contributing to mortality ...of several conditions, including myocardial infarction and stroke. It is accepted that atherosclerosis and symptoms of metabolic syndrome, such as obesity, insulin resistance, and hypercholesterolemia often coincide with and exacerbate one another, however the molecular events in common with these conditions are not yet fully understood. One event that may link these two disorders is lipid receptor trafficking and signaling of the LDL receptor (LDLR), which plays a key role in LDL uptake and regulation of plasma LDL concentration. Low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) is a cytosolic adaptor protein which interacts with the cytoplasmic tail of the LDLR, mediating internalization of the LDL-LDLR complex and connecting it to the cell’s endocytic machinery. The purpose of this study was to characterize the effects of LDLRAP1 global knockout on atherogenesis and metabolic function in order to gain a better understanding of the molecular mechanisms that interconnect atherosclerosis and metabolic syndrome. Results: LDLRAP1 global knockout mice fed a high-fat western diet (HFD) for 16 weeks displayed increased atherosclerotic plaque burden (p<0.0001), serum cholesterol (p<0.0001) and triglyceride levels (p<0.01), and expression of lipid receptors SR-A1 and CD36 (p<0.05), and gained significantly more weight compared to controls (p<0.0001). LDLRAP1 -/- adipose also displayed decreased glucose uptake (p<0.01) and pAKT and AKT protein levels (p<0.05). Both before and after a HFD, LDLRAP1 -/- mice were also significantly insulin resistant (p<0.01) with concomitant dysregulated insulin signaling in adipose tissue, and displayed metabolic differences as quantified by metabolic cage analysis (p<0.05). Conclusions: These data suggest that in addition to a function in cholesterol internalization, LDLRAP1 participates in regulating adipose metabolism and insulin sensitivity. This implicates LDLRAP1 as a key molecule and potential therapeutic target in treatment of diseases which constitute metabolic syndrome.
BackgroundObesity causes a functional disorder of the white adipose tissue (WAT). Hypertrophic adipocytes, immune cells, and dysfunctional endothelium of the WAT microcirculation all contribute to ...cytokine secretion, which causes a state of chronic low-grade systemic inflammation with peripheral IR, termed “metaflammation”. Inflammatory cytokines downregulate the activity of the insulin sensitive glucose transporter GLUT4. GLUT4 expression in WAT plays a critical role in whole-body insulin sensitivity and glucose homeostasis, two metabolic parameters heavily implicated in cardiovascular disease. We tested the hypothesis that IL-19, a cytokine uniquely provided with immunomodulatory and pro-angiogenic action, directly stimulates glucose uptake in adipocytes thus improving whole-body insulin sensitivity.ResultsWe report that IL-19 is expressed in adipose tissue at both the transcript and protein level and its expression is increased in inflamed visceral adipose tissue but not subcutaneous adipose tissue (p<0.001). Utilizing Il19 knockout mice, we found the loss of IL-19 leads to a metabolic phenotype characterized by reduced glucose and insulin tolerance, reduced GLUT4 mRNA levels, along with increased adipocyte hypertrophy and adipose tissue fibrosis both in response to standard chow diet and chronic high fat diet (p<0.05). Treatment of diet induced obese (DIO) WT mice with 10 ng/g IL-19 for 7 consecutive days reduced glucose and insulin intolerance (p<0.05). In primary WT murine epididymal adipocytes the addition of IL-19 increased glucose uptake (p<0.01), a phenomenon that was not observed with the other IL-20 sub-family members, IL-20 and IL-24, who share the same receptor. Fasentin, a GLUT4 inhibitor, reduced glucose uptake in response to IL-19 stimulation in primary murine epididymal adipocytes (p<0.05) further confirming a role for GLUT4 in the primary metabolic action of IL-19.ConclusionsThese data are the first to demonstrate the primary metabolic action of IL-19 on adipose tissue glucose uptake, a well-established player in systemic insulin sensitivity. Further studies are necessary to fully understand the role that endogenous and pharmacological doses of IL-19 might play in cardiometabolic disorders.
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