Posts Tagged: inflammation

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Cytosolic reactive oxygen species (ROS) production and regulation of cytosolic metabolic pathways. Cytosolic ROS are formed most notably through NOX (nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) activity and influence metabolic processes including glycolysis and downstream oxidative phosphorylation, pentose phosphate pathway activity, and autophagy. ACC indicates acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; ATM, ataxia-telangiectasia mutated; CAMKKβ, Ca2+/calmodulin-dependent protein kinase β; CoA, coenzyme A; CRAC, calcium release–activated channel; ER, endoplasmic reticulum; GLUT1, glucose transporter 1; HIF1α, hypoxia-inducible factor 1α; HK, hexokinase; IP3R, inositol 1,4,5-trisphosphate receptor; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NOS, nitric oxide synthase; OONO, peroxynitrite; OxPL, oxidized phospholipid; PDK-1, phosphoinositide-dependent kinase-1; PFK, phosphofructo kinase; PI3K, phosphoinositide 3-kinase; PKM2, pyruvate kinase 2; PPP, pentose phosphate pathway; STIM1, stromal interaction molecule 1; and TSC2, tuberous sclerosis protein 2. [Powerpoint File]

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Peroxisomal reactive oxygen species (ROS) and metabolism. Peroxisomal ROS are produced as by-products of enzymatic reactions within β-oxidation, polyamine synthesis, d-amino acid deamination, and hypoxanthine oxidation and have been found to be key regulators of pexophagy. ACOX indicates acyl-coenzyme A (CoA) oxidases; ATM, ataxia-telangiectasia mutated; CAT, catalase; CoA, coenzyme A; DAO, d-amino acid oxidase; GPX, glutathione peroxidase; LC3, light chain 3; mTOR, mammalian target of rapamycin; PAO, polyamine oxidase; PEX, peroxin; PRDX, peroxiredoxin; SOD, superoxide dismutase; TSC1, tuberous sclerosis protein 1; ULK1, uncoordinated 51-like kinase 1; and XAO, xanthine oxidase. [Powerpoint File]

 

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Endoplasmic reticulum and reactive oxygen species (ROS). The endoplasmic reticulum (ER) is highly sensitive to redox status, and altered ROS signaling can influence protein folding, Ca2+ release, and mitochondrial respiration. ATF6 indicates activating transcription factor 6; CAMKKII, Ca2+/calmodulin-dependent protein kinase II; Cyto, cytoplasm; ER, endoplasmic reticulum; ERO1, ER oxidoreductin 1; GPX, glutathione peroxidase; GRP78, glucose-regulated protein, 78 kDa; GSH, glutathione; GSSG, glutathione disulfide; IMS, intermembrane space; IP3R, inositol 1,4,5-trisphosphate receptor; IRE1α, inositol-requiring enzyme 1α; MCU, mitochondrial calcium uniporter; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; OxPL, oxidized phospholipid; p66shc, SHC-transforming protein 1 isoform p66; PDI, protein disulfide isomerase; PERK, protein kinase R (PKR)–like endoplasmic reticulum kinase; and Prdx, peroxiredoxin [Powerpoint File]

Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease

Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease

José J. Fuster, Kenneth Walsh

Somatic mutations in blood cells as a shared mechanism of hematologic cancer and cardiovascular disease. A, The accumulation of somatic mutations in hematopoietic progenitor and stem cells is an inevitable consequence of the process of aging. Some of these random mutations confer a competitive advantage to the mutant cells, leading to its clonal expansion. This phenomenon can be defined as somatic mutation-driven clonal hematopoiesis. B, Most individuals exhibiting somatic mutation-driven clonal hematopoiesis only carry 1 driver mutation (eg, in DNMT3A, TET2, ASXL1, or JAK2). Although this situation greatly increases the risk of acquiring additional driver mutations and eventually developing a hematologic cancer, this condition is infrequent, even in individuals with clonal hematopoiesis. The main cause of death in individuals exhibiting somatic mutation-driven clonal hematopoiesis is atherosclerotic cardiovascular disease. Grey shade in the figure indicates decreasing frequency. HSPC indicates hematopoietic stem/progenitor cell. [Powerpoint File]

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Lisa Honold, Matthias Nahrendorf

Macrophage mediators and crosstalk after myocardial infarction. TNF-α (tumor necrosis factor α) acts on cardiomyocytes and can induce hypertrophy and cell death. TGF-β (transforming growth factor-β) induces conversion of fibroblasts to myofibroblasts that produce collagen necessary for scar formation. Proteolytic enzymes like MMPs (matrix metalloproteinases) contribute to tissue remodeling, whereas VEGF (vascular endothelial growth factor) acts on endothelial cells and stimulates angiogenesis. [Powerpoint File]

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Lisa Honold, Matthias Nahrendorf

Macrophages in cardiovascular disease. During myocardial infarction (MI), atherosclerosis and stroke, monocytes are supplied by medullary and extramedullary hematopoiesis in bone marrow and spleen. Monocytes infiltrate diseased tissues, differentiate into macrophages and proliferate locally. In MI, resident cardiac macrophages are lost, whereas arterial macrophages in atherosclerosis persist. Cerebral microglia are activated after stroke and contribute to disease progression and healing. In obesity, macrophage accumulation in adipose tissue stems from local proliferation of resident and recruitment of monocyte-derived macrophages. [Powerpoint File]

Autophagy and Mitophagy in Cardiovascular Disease

Autophagy and Mitophagy in Cardiovascular Disease

José Manuel Bravo-San Pedro, Guido Kroemer, Lorenzo Galluzzi

Detrimental effects of autophagy or mitophagy inhibition on cardiovascular health. Multiple genetic interventions that limit autophagic or mitophagic flux at the whole-body level or in specific compartments of the cardiovascular system have been associated with the spontaneous development of cardiovascular disorders. AP indicates autophagosome; APL, autophagolysosome; Atg5, autophagy related 5; Bnip3l, BCL2 interacting protein 3 like; Dnml1, dynamin 1 like; Fbxo32, F-box protein 32; L, lysosome; Lamp2, lysosomal-associated membrane protein 2; Mfn1, mitofusin 1; Park2, Parkinson disease (autosomal recessive, juvenile) 2, parkin; Pink1, PTEN-induced putative kinase 1; Sirt6, sirtuin 6; Tfrc, transferrin receptor; and Trp53, transformation-related protein 53. [Powerpoint File]

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Xiaoming Hu, T. Michael De Silva, Jun Chen, Frank M. Faraci

Structural alterations in endothelial cells are critical for blood–brain barrier (BBB) opening early after ischemic stroke. A, The opening of paracellular pathways: cytoskeletal rearrangements and related signaling in endothelial cells. B, The transcellular pathway of BBB leakage. ADF indicates actin-depolymerizing factor; CaM, calmodulin; LIMK, LIM kinase; MLC, myosin light chain; MLCK, MLC kinase; MLCP, MLC phosphatase; MMP, matrix metallopeptidase; ROCK: Rho kinase; TESK1, testicular protein kinase 1; and ZO, zonula occluden. [Powerpoint File]

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Xiaoming Hu, T. Michael De Silva, Jun Chen, Frank M. Faraci

Pericytes play multifaceted roles in ischemia and reperfusion. Pericytes display both beneficial and detrimental functions during ischemia and reperfusion phases, and contribute significantly to the blood–brain barrier damage and repair. 1. Pericyte contraction and dilation regulate cerebral blood flow in the ischemic and perilesion areas. 2. Pericyte protects other neurovascular unit (NVU) components through releasing protective/trophic factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF), angiopoietin (Ang-1), and glial cell line-derived neurotrophic factor (GDNF). 3. Phagocytotic pericytes help to eliminate dead or injured tissue in the ischemic core, which in turn mitigates local inflammation and reduce secondary tissue damage. 4. Pericyte–endothelial cell interaction promotes angiogenesis after stroke. 5) Pericytes have the potential to serve as an origin of NVU components during tissue repair after ischemic stroke. Illustration credit: Ben Smith. [Powerpoint File]

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis

Marc R. Dweck, Elena Aikawa, David E. Newby, Jason M. Tarkin, James H.F. Rudd, Jagat Narula, Zahi A. Fayad

The link between inflammation, microcalcification, and macrocalcification. A large necrotic core, a thin fibrous cap, and an intense inflammation are key precipitants of acute plaque rupture and myocardial infarction. Intimal calcification is thought to occur as a healing response to this intense necrotic inflammation. However, the early stages of microcalcification (detected by 18F-fluoride positron emission tomography) are conversely associated with an increased risk of rupture. In part, this is because of residual plaque inflammation and in part because microcalcification itself increases mechanical stress in the fibrous cap further increasing propensity to rupture. With progressive calcification, plaque inflammation becomes pacified and the necrotic core walled off from the blood pool. The latter stages of macrocalcification (detected by computed tomographic) are, therefore, associated with plaque stability and a lower risk of that plaque rupturing (Illustration credit: Ben Smith). [Powerpoint FIle]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Schematic representation of the heme oxygenase pathway. Heme, either derived from intracellular sources, such as hemoproteins and mitochondria, or from damaged tissues and red blood cell hemolysis (extracellular sources) is used by heme oxygenase enzymes (HO-1 and HO-2) to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is converted to bilirubin by biliverdin reductase (BVR), whereas iron is stored in the ferritin protein. Although heme oxygenase enzymes were initially localized in the endoplasmic reticulum, recent reports suggest that HO-1 can be found under certain conditions in other cellular compartments such as the nucleus.19 [Powerpoint File]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Interaction of carbon monoxide (CO) with mitochondria. CO at high concentrations is known to inhibit mitochondrial respiration by competing with oxygen for the binding to cytochrome c oxidase (complex IV). In contrast, controlled delivery of CO gas and CO-releasing moleculess at nontoxic concentrations can protect cardiac tissue by promoting mitochondrial biogenesis, uncoupling activity, and metabolic switch (see text for details). The molecular mechanism(s) underlying these effects remains to be defined. However, the interaction of CO with mitochondrial targets different from cytochrome c oxidase is likely as the electron transport chain contains other heme-complexes that may display distinct sensitivities to CO. ROS indicates reactive oxygen species. [Powerpoint File]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Heme release and cardiac repair. Ischemia-reperfusion injury leads to the sudden release of cellular contents including heme, mitochondrial DNA, and ATP. These cellular danger-associated molecular patterns (DAMPs) have each been shown to induce heme oxygenase-1 (HO-1). HO-1 expression and the subsequent generation CO, biliverdin (BV), and bilirubin (BR) target a variety of cell types that impact cellular repair and tissue regeneration. [Powerpoint File]

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

Sumanth D. Prabhu, Nikolaos G. Frangogiannis

Toll-like receptor (TLR) and nucleotide-binding oligomerization domain–like receptor (NLR) signaling. Danger-associated molecular patterns (DAMPs) released from necrotic and damaged cells and extracellular matrix bind to the TLRs, which comprised an extracellular leucine-rich repeat (LRR) domain, a transmembrane (TM) domain, and a conserved cytoplasmic Toll/interleukin (IL)-1R (TIR) domain, which serves as docking site for other TIR-containing cytoplasmic adaptor proteins (top left). The binding of DAMPs, and often coreceptors such as CD14 and MD2, to TLR4 engages the adaptor myeloid differentiation factor 88 (MyD88) via the adaptor TIR domain-containing adaptor protein (TIRAP). MyD88 recruits IL-1R–associated kinase (IRAK) 4 and the IRAK1/2 and TNF receptor associated factor (TRAF) 6 complex, which activates transforming growth factor activated kinase 1 (TAK1). TAK1, a mitogen-activated protein kinase (MAPK) KK, then activates the MAPK cascade and also phosphorylates IκB kinase (IKK), that leads to nuclear factor-κB (NF-κB) p65 and p50 nuclear translocation and the transcription of a panel of inflammatory genes, including cytokines, chemokines, cell adhesion molecules, and complement factor B. Furthermore, after endocytosis, TLR4 signals in a MyD88-independent manner via the cytoplasmic adaptor TRIF, in turn recruited through the bridging adaptor TRAM. This pathway results in noncanonical IKK and NF-κB activation, as well as the induction of type I interferon (IFN) via TANK-binding kinase (TBK) 1 and the transcription factor IFN-regulatory factor (IRF) 3. Except for TLR3, the other TLRs also signal, directly or indirectly as depicted, via MyD88. Endolysosomal TLR3 activates IRF3 signaling via TRIF and TBK1, whereas endolysosomal TLR7/8 and TLR9 also induce type I IFN via TRAF3 and IRF7 in a MyD88-dependent manner (not pictured). In addition to TLRs, intracellular NLRs respond to a variety of DAMPs via the formation of multiprotein inflammasomes, comprised an activated NLR protein, the adaptor protein apoptosis speck-like protein containing a caspase-recruitment domain (ASC), and procaspase-1. One proposed model of NLRP3 inflammasome activation results from stimulation of the purinergic P2X7 ion channel by extracellular ATP, resulting in K+ efflux, recruitment of the pannexin-1 pore, DAMP entry into cytosol, and activation of NLRP3. This activates caspase-1, which then converts pro–IL-18 and pro–IL-1β to active IL-18 and IL-1β. As discussed in the text, cell-type–specific innate immune signaling can result in distinctive, and sometimes divergent, in vivo physiological responses during acute MI. Schema derived from Mann,13 Newton and Dixit,14 Schroder and Tschopp,18 Chao,76 and Mann83 (Illustration credit: Ben Smith). [Powerpoint File]

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

Sumanth D. Prabhu, Nikolaos G. Frangogiannis

Cellular effectors and molecular signals that repress and resolve inflammation after myocardial infarction leading to the transition from the inflammatory to the proliferative phase of cardiac repair. Recruitment of anti-inflammatory monocyte (Mo) subsets (1), T-cell subpopulations, such as regulatory T cells (Tregs) (2) and invariant Natural Killer T cells (iNKT; 3) contributes to repression of the postinfarction inflammatory response. Moreover, members of the transforming growth factor (TGF)-β family (such as TGF-β1 and growth differentiation factor (GDF)-15 inhibit neutrophil transmigration by attenuating expression of adhesion molecules by endothelial cells (ECs) (4). Recruitment of pericytes (P) by microvascular ECs is mediated through platelet-derived growth factor (PDGF) receptor-β actions and may also contribute to suppression of postinfarction inflammation (5). Macrophages (Ma) acquire an anti-inflammatory phenotype, secreting TGF-β, interleukin (IL)-10, and proresolving lipid mediators, on ingestion of apoptotic neutrophils (aN) (6). Dendritic cells (DCs) are also activated after infarction and secrete anti-inflammatory cytokines (7). Cardiomyocytes (CM) in the border zone may contribute to suppression and spatial containment of the postinfarction inflammatory response by secreting mediators that promote an anti-inflammatory macrophage phenotype (such as regenerating islet-derived-3β [Reg-3β]; 8). Fibroblasts (F) also exhibit dynamic phenotypic alterations that mark the transition from the inflammatory to the proliferative phase (9). During the inflammatory phase, inflammatory cytokines (such as IL-1β and TNF-α) and activation of toll-like receptor (TLR)–dependent signaling by matrix fragments may activate a proinflammatory fibroblast phenotype. Stimulation of fibroblasts with IL-1β induces matrix metallproteinase expression and chemokine synthesis, while reducing α-smooth muscle actin levels. During the proliferative phase, activation of TGF-β–dependent cascades stimulates a matrix-preserving myofibroblast (MF) phenotype. [Powerpoint File]