The Toll of Vascular Insufficiency: Implications for the Management of Peripheral Arterial Disease

Peripheral artery disease (PAD) can result in limb loss within six months of diagnosis in a subset of patients who cannot undergo endovascular or surgical revascularization yet continues to maintain a marginal position in cardiovascular research. While a body of literature continues to grow describing the role of danger signaling and innate immunity in cardiac biology, the role of these pathways in the ischemic myopathy associated with PAD has not been extensively studied. The following report will review the current literature on the role of Toll‐like receptor (TLR) signaling in cardiovascular biology as well as in nonischemic myopathy. While attenuation of TLR signaling has not been shown to be clinically useful in the treatment of infectious inflammation, it may show promise in the management of severe arterial insufficiency.

• Publication year

  2016

• Venue

  Journal of Immunological Research

• Publication date

  2016-02-21

• Fields of study

  Medicine

• Identifiers
  DOI 10.1155/2016/8249015PMID 26998496PMCID 4779544
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• MD-2 is required for disulfide HMGB1–dependent TLR4 signaling

  2015cited by this paper
• TLR4 Deters Perfusion Recovery and Upregulates Toll-like Receptor 2 (TLR2) in Ischemic Skeletal Muscle and Endothelial Cells

  2015cited by this paper
• MyD88 and TRIF mediate divergent inflammatory and regenerative responses to skeletal muscle ischemia

  2014cited by this paper
• Impact of amputation level and comorbidities on functional status of nursing home residents after lower extremity amputation.

  2014cited by this paper
• TLR4 Accessory Molecule RP105 (CD180) Regulates Monocyte-Driven Arteriogenesis in a Murine Hind Limb Ischemia Model

  2014cited by this paper
• Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns*

  2014cited by this paper
• Role of Toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle.

  2014cited by this paper
• Functional status of elderly adults before and after interventions for critical limb ischemia.

  2013cited by this paper
• Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

  2013influential reference
• HMGB1 and TLR4 mediate skeletal muscle recovery in a murine model of hindlimb ischemia.

  2013cited by this paper
• Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases

  2013cited by this paper
• Lack of association between TLR4 Asp299Gly polymorphism and atherosclerosis: evidence from meta-analysis.

  2012cited by this paper
• TLR2 and TLR4 Mediate Differential Responses to Limb Ischemia through MyD88-Dependent and Independent Pathways

  2012cited by this paper
• Toll-Like Receptor (TLR) 2 and TLR4 Differentially Regulate Doxorubicin Induced Cardiomyopathy in Mice

  2012cited by this paper
• TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis

  2012cited by this paper
• Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy*

  2012cited by this paper
• Toll-Like Receptor 4 Activation in Microvascular Endothelial Cells Triggers a Robust Inflammatory Response and Cross Talk With Mononuclear Cells via Interleukin-6

  2012cited by this paper
• Toll‐like receptor 4 and myeloid differentiation factor 88 provide mechanistic insights into the cause and effects of interleukin‐6 activation in mouse liver regeneration

  2011cited by this paper
• High-Mobility Group Box-1 Mediates Toll-Like Receptor 4–Dependent Angiogenesis

  2011cited by this paper
• Activation of Endothelial Toll-Like Receptor 3 Impairs Endothelial Function

  2011influential reference
• Activated protein C inhibits high mobility group box 1 signaling in endothelial cells.

  2011cited by this paper
• Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia.

  2011cited by this paper
• Endogenous HMGB1 regulates autophagy

  2010cited by this paper
• Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands

  2010cited by this paper
• Increased Toll-Like Receptor (TLR) Activation and TLR Ligands in Recently Diagnosed Type 2 Diabetic Subjects

  2010cited by this paper
• Histidine-rich glycoprotein inhibited high mobility group box 1 in complex with heparin-induced angiogenesis in matrigel plug assay.

  2009cited by this paper
• HMGB1 loves company

  2009cited by this paper
• Lipoprotein Accumulation in Macrophages via Toll-Like Receptor-4-Dependent Fluid Phase Uptake

  2009cited by this paper
• Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis

  2009influential reference
• The role of innate immunity in atherogenesis11 Guest editor for this article was Linda Curtiss, the Scripps Research Institute. Published, JLR Papers in Press, December 22, 2008.

  2009cited by this paper
• Toll-like receptor-4 and lipoprotein accumulation in macrophages.

  2009cited by this paper
• Toll-Like Receptors 4 and 5 Induce Distinct Types of Vasculitis

  2009cited by this paper
• Results of a Double-Blind, Placebo-Controlled Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia

  2008cited by this paper
• Advanced Glycation End-Product of Low Density Lipoprotein Activates the Toll-Like 4 Receptor Pathway Implications for Diabetic Atherosclerosis

  2008cited by this paper
• Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow‐derived cells and parenchymal cells

  2008cited by this paper
• High-Mobility Group Box-1 in Ischemia-Reperfusion Injury of the Heart

  2008cited by this paper
• Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction

  2008cited by this paper
• Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

  2008cited by this paper
• Continuous pharmacodynamic activity of eritoran tetrasodium, a TLR4 antagonist, during intermittent intravenous infusion into normal volunteers

  2008cited by this paper
• Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial Disease. A Phase II Randomized, Double-Blind, Controlled Study of Adenoviral Delivery of Vascular Endothelial Growth factor 121 in patients With Disabling Intermittent Claudication.

  2008cited by this paper
• Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin.

  2007cited by this paper
• Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease.

  2007cited by this paper
• Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress

  2007cited by this paper
• Systemic inflammation and remote organ injury following trauma require HMGB1.

  2007cited by this paper
• Prevalence of Peripheral Arterial Disease and Risk Factors in Persons Aged 60 and Older: Data from the National Health and Nutrition Examination Survey 1999–2004

  2007cited by this paper
• Multiple Effects of High Mobility Group Box Protein 1 in Skeletal Muscle Regeneration

  2007cited by this paper
• High-Mobility Group Box 1 Activates Integrin-Dependent Homing of Endothelial Progenitor Cells

  2007cited by this paper
• Bacteria-derived Peptidoglycans Constitute Pathogen-associated Molecular Patterns Triggering Innate Immunity in Arabidopsis*

  2007cited by this paper
• Toll Receptor Polymorphisms and Carotid Artery Intima-Media Thickness

  2007cited by this paper
• Expression of toll‐like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL‐8 release, and up‐regulation of NKG2D‐ligands

  2006influential reference
• Multiple Toll-like receptor ligands induce an IL-6 transcriptional response in skeletal myocytes.

  2006cited by this paper
• MyD88 and NOS2 are essential for toll-like receptor 4-mediated survival effect in cardiomyocytes.

  2006cited by this paper
• Cutting Edge: Extracellular High Mobility Group Box-1 Protein Is a Proangiogenic Cytokine1

  2006cited by this paper
• Molecular basis for invertebrate innate immune recognition of (1-->3)-beta-D-glucan as a pathogen-associated molecular pattern.

  2006cited by this paper
• The cytokine activity of HMGB1

  2005cited by this paper
• Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule.

  2005cited by this paper
• High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal

  2005influential reference
• The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion

  2005cited by this paper
• HMGB1: guiding immunity from within.

  2005cited by this paper
• Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation

  2004cited by this paper
• Innate immunity and angiogenesis.

  2004cited by this paper
• Prevalence of and Risk Factors for Peripheral Arterial Disease in the United States: Results From the National Health and Nutrition Examination Survey, 1999–2000

  2004cited by this paper
• RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways

  2004cited by this paper
• Toll-like receptor downstream signaling

  2004cited by this paper
• Cutting Edge: Direct Interaction of TLR4 with NAD(P)H Oxidase 4 Isozyme Is Essential for Lipopolysaccharide-Induced Production of Reactive Oxygen Species and Activation of NF-κB1

  2004cited by this paper
• LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF

  2003cited by this paper
• Variants of Toll-Like Receptor 4 Modify the Efficacy of Statin Therapy and the Risk of Cardiovascular Events

  2003cited by this paper
• TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase.

  2003cited by this paper
• TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis.

  2003cited by this paper
• Cell Therapy of α-Sarcoglycan Null Dystrophic Mice Through Intra-Arterial Delivery of Mesoangioblasts

  2003cited by this paper
• Reversing established sepsis with antagonists of endogenous high-mobility group box 1

  2003influential reference
• Molecular regulation of vessel maturation

  2003cited by this paper
• Inhibition of Endotoxin Response by E5564, a Novel Toll-Like Receptor 4-Directed Endotoxin Antagonist

  2003cited by this paper
• Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial.

  2002cited by this paper
• Therapeutic angiogenesis for critical limb ischemia: invited commentary.

  2002cited by this paper
• Expression of Toll-Like Receptors in Human Atherosclerotic Lesions: A Possible Pathway for Plaque Activation

  2002influential reference
• Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation

  2002cited by this paper
• Innate immune recognition.

  2002cited by this paper
• The High Mobility Group (Hmg) Boxes of the Nuclear Protein Hmg1 Induce Chemotaxis and Cytoskeleton Reorganization in Rat Smooth Muscle Cells

  2001cited by this paper
• The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5

  2001cited by this paper
• Role of TLR-2 in the Activation of Nuclear Factor κB by Oxidative Stress in Cardiac Myocytes*

  2001influential reference
• Coregulation of Neurite Outgrowth and Cell Survival by Amphoterin and S100 Proteins through Receptor for Advanced Glycation End Products (RAGE) Activation*

  2000cited by this paper
• The pathophysiology of the collateral circulation (arteriogenesis)

  2000cited by this paper
• HMG-1 as a late mediator of endotoxin lethality in mice.

  1999cited by this paper
• Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium.

  1999cited by this paper
• Toll-like Receptor 2 Functions as a Pattern Recognition Receptor for Diverse Bacterial Products*

  1999cited by this paper
• Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs.

  1998cited by this paper
• Isolation and some characteristics of an adhesive factor of brain that enhances neurite outgrowth in central neurons.

  1987cited by this paper
• The FASEB Journal • Research Communication Antagonism of RAGE suppresses peripheral nerve regeneration

  year unknowncited by this paper

• Type 2 cytokines promote angiogenesis in ischemic muscle via endothelial IL-4Rα signaling.

  2023cites this paper
• Bisphenol P exposure in C57BL/6 mice caused gut microbiota dysbiosis and induced intestinal barrier disruption via LPS/TLR4/NF-κB signaling pathway.

  2023cites this paper
• Platelet-Rich Plasma for Wound Healing

  2021cites this paper
• Implementation of Ankle-Brachial Index to Screen for Peripheral Artery Disease in High-Risk Asymptomatic Populations

  2019cites this paper
• Modulation of Immune-Inflammatory Responses in Abdominal Aortic Aneurysm: Emerging Molecular Targets

  2018cites this paper
• Mechanisms of cardioprotection via modulation of the immune response.

  2017cites this paper
• Biological and pathophysiological roles of end-products of DHA oxidation.

  2017cites this paper