Myeloperoxidase as a Promising Therapeutic Target after Myocardial Infarction.

Coronary artery disease (CAD) and myocardial infarction (MI) remain leading causes of death and disability worldwide. CAD begins with the formation of atherosclerotic plaques within the intimal layer of the coronary arteries, a process driven by persistent arterial inflammation and oxidation. Myeloperoxidase (MPO), a mammalian haem peroxidase enzyme primarily expressed within neutrophils and monocytes, has been increasingly recognised as a key pro-inflammatory and oxidative enzyme promoting the development of vulnerable coronary atherosclerotic plaques that are prone to rupture, and can precipitate a MI.

Myeloperoxidase Gene Deletion Causes Drastic Microbiome Shifts in Mice and Does Not Mitigate Dextran Sodium Sulphate-Induced Colitis.

Neutrophil-myeloperoxidase (MPO) is a heme-containing peroxidase which produces excess amounts of hypochlorous acid during inflammation. While pharmacological MPO inhibition mitigates all indices of experimental colitis, no studies have corroborated the role of MPO using knockout (KO) models. Therefore, we investigated MPO deficient mice in a murine model of colitis.

Heparanase promotes the onset and progression of atherosclerosis in apolipoprotein E gene knockout mice.

Background And Aims: Atherosclerosis is the primary underlying cause of myocardial infarction and stroke, which are the major causes of death globally. Heparanase (Hpse) is a pro-inflammatory extracellular matrix degrading enzyme that has been implicated in atherogenesis. However, to date the precise roles of Hpse in atherosclerosis and its mechanisms of action are not well defined.

ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin.

Background: High cholesterol levels in pancreatic β-cells cause oxidative stress and decrease insulin secretion. β-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves β-cell insulin secretion by reducing oxidative stress.

Impact of Reperfusion on Temporal Immune Cell Dynamics After Myocardial Infarction.

Excessive inflammation and impaired healing of cardiac tissue following a myocardial infarction (MI) can drive the development of heart failure. Cardiac repair begins immediately after the onset of MI and continues for months. The repair process can be divided into the following 3 overlapping phases, each having distinct functions and sequelae: the inflammatory phase, the proliferative phase, and the maturation phase.

Heparanase: A Novel Therapeutic Target for the Treatment of Atherosclerosis.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and its management places a huge burden on healthcare systems through hospitalisation and treatment. Atherosclerosis is a chronic inflammatory disease of the arterial wall resulting in the formation of lipid-rich, fibrotic plaques under the subendothelium and is a key contributor to the development of CVD. As such, a detailed understanding of the mechanisms involved in the development of atherosclerosis is urgently required for more effective disease treatment and prevention strategies.

The pleiotropic effects of high-density lipoproteins and apolipoprotein A-I.

The high density lipoprotein (HDL) fraction of human plasma consists of multiple subpopulations of spherical particles that are structurally uniform, but heterogeneous in terms of size, composition and function. Numerous epidemiological studies have established that an elevated high density lipoprotein cholesterol (HDL-C) level is associated with decreased cardiovascular risk. However, with several recent randomised clinical trials of HDL-C raising agents failing to reduce cardiovascular events, contemporary research is transitioning towards clinical development of the cardioprotective functions of HDLs and the identification of functions that can be exploited for treatment of other diseases.

Periodontitis induces endothelial dysfunction in mice.

The treatment of periodontitis has numerous positive effects on established chronic health conditions, including cardiovascular disease and diabetes. However, ethical considerations do limit the establishment of human trials to investigate whether periodontitis promotes the early stages of chronic conditions. Therefore, the aim of this study was to investigate whether periodontitis induces endothelial dysfunction in hyperlipidemic apolipoprotein E gene-deficient (ApoE) mice.

Polyamine-Conjugated Nitroxides Are Efficacious Inhibitors of Oxidative Reactions Catalyzed by Endothelial-Localized Myeloperoxidase.

The heme enzyme myeloperoxidase (MPO) is a key mediator of endothelial dysfunction and a therapeutic target in cardiovascular disease. During inflammation, MPO released by circulating leukocytes is internalized by endothelial cells and transcytosed into the subendothelial extracellular matrix of diseased vessels. At this site, MPO mediates endothelial dysfunction by catalytically consuming nitric oxide (NO) and producing reactive oxidants, hypochlorous acid (HOCl) and the nitrogen dioxide radical (NO).

Endothelial-transcytosed myeloperoxidase activates endothelial nitric oxide synthase via a phospholipase C-dependent calcium signaling pathway.

During vascular inflammation, the leukocyte-derived enzyme myeloperoxidase (MPO) is transcytosed across the endothelium and into the sub-endothelial extracellular matrix, where it promotes endothelial dysfunction by catalytically consuming nitric oxide (NO) produced by endothelial NO synthase (eNOS). In the presence of chloride ions and hydrogen peroxide (HO), MPO forms the oxidant hypochlorous acid (HOCl). Here we examined the short-term implications of HOCl produced by endothelial-transcytosed MPO for eNOS activity.

Novel Antioxidant Therapy with the Immediate Precursor to Glutathione, γ-Glutamylcysteine (GGC), Ameliorates LPS-Induced Cellular Stress in In Vitro 3D-Differentiated Airway Model from Primary Cystic Fibrosis Human Bronchial Cells.

Systemic glutathione deficiency, inflammation, and oxidative stress are hallmarks of cystic fibrosis (CF), an inherited disease that causes persistent lung infections and severe damage to the respiratory system and many of the body organs. Improvements to current antioxidant therapeutic strategies are needed. The dietary supplement, γ-glutamylcysteine (GGC), which is the immediate precursor to glutathione, rapidly boosts cellular glutathione levels following a single dose in healthy individuals.

Myeloperoxidase: A versatile mediator of endothelial dysfunction and therapeutic target during cardiovascular disease.

Myeloperoxidase (MPO) is a prominent mammalian heme peroxidase and a fundamental component of the innate immune response against microbial pathogens. In recent times, MPO has received considerable attention as a key oxidative enzyme capable of impairing the bioactivity of nitric oxide (NO) and promoting endothelial dysfunction; a clinically relevant event that manifests throughout the development of inflammatory cardiovascular disease. Increasing evidence indicates that during cardiovascular disease, MPO is released intravascularly by activated leukocytes resulting in its transport and sequestration within the vascular endothelium.

Neutrophil-Mediated Cardiac Damage After Acute Myocardial Infarction: Significance of Defining a New Target Cell Type for Developing Cardioprotective Drugs.

Acute myocardial infarction (AMI) is a leading cause of death worldwide. Post-AMI survival rates have increased with the introduction of angioplasty as a primary coronary intervention. However, reperfusion after angioplasty represents a clinical paradox, restoring blood flow to the ischemic myocardium while simultaneously inducing ion and metabolic imbalances that stimulate immune cell recruitment and activation, mitochondrial dysfunction and damaging oxidant production.

Human Indoleamine 2,3-Dioxygenase 1 Is an Efficient Mammalian Nitrite Reductase.

The heme enzyme indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the first reaction of l-tryptophan oxidation along the kynurenine pathway. IDO1 is a central immunoregulatory enzyme with important implications for inflammation, infectious disease, autoimmune disorders, and cancer. Here we demonstrate that IDO1 is a mammalian nitrite reductase capable of chemically reducing nitrite to nitric oxide (NO) under hypoxia.

TRAIL protects against endothelial dysfunction in vivo and inhibits angiotensin-II-induced oxidative stress in vascular endothelial cells in vitro.

The vascular endothelium is critical for maintenance of cardiovascular homeostasis. Endothelial dysfunction is a key event of atherosclerosis, with oxidative stress mediated by reactive oxygen species (ROS) playing a major role. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is increasingly recognised to play a protective role in atherosclerosis, however the molecular mechanisms by which it exerts its beneficial effects are unclear.

Identification of Native and Posttranslationally Modified HLA-B*57:01-Restricted HIV Envelope Derived Epitopes Using Immunoproteomics.

The recognition of pathogen-derived peptides by T lymphocytes is the cornerstone of adaptive immunity, whereby intracellular antigens are degraded in the cytosol and short peptides assemble with class I human leukocyte antigen (HLA) molecules in the ER. These peptide-HLA complexes egress to the cell surface and are scrutinized by cytotoxic CD8+ T-cells leading to the eradication of the infected cell. Here, naturally presented HLA-B*57:01 bound peptides derived from the envelope protein of the human immunodeficiency virus (HIVenv) are identified.

Non-alcoholic fatty liver disease, vascular inflammation and insulin resistance are exacerbated by TRAIL deletion in mice.

Non-alcoholic fatty liver disease (NAFLD) incorporates steatosis, non-alcoholic steato-hepatitis (NASH) and liver cirrhosis, associating with diabetes and cardiovascular disease (CVD). TNF-related apoptosis-inducing ligand (TRAIL) is protective of CVD. We aimed to determine whether TRAIL protects against insulin resistance, NAFLD and vascular injury.

Regulation of the nitric oxide oxidase activity of myeloperoxidase by pharmacological agents.

The leukocyte-derived heme enzyme myeloperoxidase (MPO) is released extracellularly during inflammation and impairs nitric oxide (NO) bioavailability by directly oxidizing NO or producing NO-consuming substrate radicals. Here, structurally diverse pharmacological agents with activities as MPO substrates/inhibitors or antioxidants were screened for their effects on MPO NO oxidase activity in human plasma and physiological model systems containing endogenous MPO substrates/antioxidants (tyrosine, urate, ascorbate). Hydrazide-based irreversible/reversible MPO inhibitors (4-ABAH, isoniazid) or the sickle cell anaemia drug, hydroxyurea, all promoted MPO NO oxidase activity.

Activation of Endothelial Nitric Oxide (eNOS) Occurs through Different Membrane Domains in Endothelial Cells.

Endothelial cells respond to a large range of stimuli including circulating lipoproteins, growth factors and changes in haemodynamic mechanical forces to regulate the activity of endothelial nitric oxide synthase (eNOS) and maintain blood pressure. While many signalling pathways have been mapped, the identities of membrane domains through which these signals are transmitted are less well characterized. Here, we manipulated bovine aortic endothelial cells (BAEC) with cholesterol and the oxysterol 7-ketocholesterol (7KC).

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia-Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide-Dependent Mechanisms.

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to inhibit angiogenesis by inducing endothelial cell death, as well as being able to promote pro-angiogenic activity in vitro. These seemingly opposite effects make its role in ischemic disease unclear. Using Trail(-/-) and wildtype mice, we sought to determine the role of TRAIL in angiogenesis and neovascularization following hindlimb ischemia.

Role of indoleamine 2,3-dioxygenase in health and disease.

IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised.

Endoglin potentiates nitric oxide synthesis to enhance definitive hematopoiesis.

During embryonic development, hematopoietic cells develop by a process of endothelial-to hematopoietic transition of a specialized population of endothelial cells. These hemogenic endothelium (HE) cells in turn develop from a primitive population of FLK1(+) mesodermal cells. Endoglin (ENG) is an accessory TGF-β receptor that is enriched on the surface of endothelial and hematopoietic stem cells and is also required for the normal development of hemogenic precursors.

Using cell-substrate impedance and live cell imaging to measure real-time changes in cellular adhesion and de-adhesion induced by matrix modification.

Cell-matrix adhesion plays a key role in controlling cell morphology and signaling. Stimuli that disrupt cell-matrix adhesion (e.g.