Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myeloperoxidase (MPO) is a vital component of the innate immune system, which produces the potent oxidant hypochlorous acid (HOCl) to kill invading pathogens. However, an overproduction of HOCl during chronic inflammatory conditions causes damage to host cells, which promotes disease, including atherosclerosis. As such, there is increasing interest in the use of thiocyanate (SCN-) therapeutically to decrease inflammatory disease, as SCN- is the favoured substrate for MPO, and a potent competitive inhibitor of HOCl formation. Use of SCN- by MPO forms hypothiocyanous acid (HOSCN), which can be less damaging to mammalian cells. In this study, we examined the ability of SCN- to modulate damage to macrophages induced by HOCl, which is relevant to lesion formation in atherosclerosis. Addition of SCN- prevented HOCl-mediated cell death, altered the extent and nature of thiol oxidation and the phosphorylation of mitogen activated protein kinases. These changes were dependent on the concentration of SCN- and were observed in some cases, at a sub-stoichiometric ratio of SCN-: HOCl. Co-treatment with SCN- also modulated HOCl-induced perturbations in the expression of various antioxidant and inflammatory genes. In general, the data reflect the conversion of HOCl to HOSCN, which can induce reversible modifications that are repairable by cells. However, our data also highlight the ability of HOSCN to increase pro-inflammatory gene expression and cytokine/chemokine release, which may be relevant to the use of SCN- therapeutically in atherosclerosis. Overall, this study provides further insight into the cellular pathways by which SCN- could exert protective effects on supplementation to decrease the development of chronic inflammatory diseases, such as atherosclerosis.
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PMID:Role of thiocyanate in the modulation of myeloperoxidase-derived oxidant induced damage to macrophages. 3278 24

Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.
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PMID:Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase. 3300 47

Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets.
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PMID:The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms. 3308 76


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