A Catecholaldehyde Metabolite of Norepinephrine Induces Myofibroblast Activation and Toxicity via the Receptor for Advanced Glycation Endproducts: Mitigating Role of l -Carnosine
| العنوان: | A Catecholaldehyde Metabolite of Norepinephrine Induces Myofibroblast Activation and Toxicity via the Receptor for Advanced Glycation Endproducts: Mitigating Role of |
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| المؤلفون: | Ethan J. Anderson, T. Blake Monroe |
| المصدر: | Chemical Research in Toxicology |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Monoamine Oxidase Inhibitors, Cardiac fibrosis, Receptor for Advanced Glycation End Products, Oxidative phosphorylation, Pharmacology, Toxicology, medicine.disease_cause, Article, RAGE (receptor), Norepinephrine (medication), Mice, Norepinephrine, medicine, Animals, Myofibroblasts, Receptor, Monoamine Oxidase, Cells, Cultured, chemistry.chemical_classification, Catecholaminergic, Reactive oxygen species, Molecular Structure, Chemistry, General Medicine, Fibroblasts, medicine.disease, Extracellular Matrix, Oxidative Stress, cardiovascular system, Reactive Oxygen Species, Oxidative stress, medicine.drug |
| الوصف: | Monoamine oxidase (MAO) is rapidly gaining appreciation for its pathophysiologic role in cardiac injury and failure. Oxidative deamination of norepinephrine by MAO generates H2O2 and the catecholaldehyde 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the latter of which is a highly potent and reactive electrophile that has been linked to cardiotoxicity. However, many questions remain as to whether catecholaldehydes regulate basic physiological processes in the myocardium and the pathways involved. Here, we examined the role of MAO-derived oxidative metabolites in mediating the activation of cardiac fibroblasts in response to norepinephrine. In neonatal murine cardiac fibroblasts, norepinephrine increased reactive oxygen species (ROS), accumulation of catechol-modified protein adducts, expression and secretion of collagens I/III, and other markers of profibrotic activation including STAT3 phosphorylation. These effects were attenuated with MAO inhibitors, the aldehyde-scavenging dipeptide l-carnosine, and FPS-ZM1, an antagonist for the receptor for advanced glycation endproducts (RAGE). Interestingly, treatment of cardiac fibroblasts with a low dose (1 μM) of DOPEGAL-modified albumin phenocopied many of the effects of norepinephrine and also induced an increase in RAGE expression. Higher doses (>10 μM) of DOPEGAL-modified albumin were determined to be toxic to cardiac fibroblasts in a RAGE-dependent manner, which was mitigated by l-carnosine. Collectively, these findings suggest that norepinephrine may influence extracellular matrix remodeling via an adrenergic-independent redox pathway in cardiac fibroblasts involving the MAO-mediated generation of ROS, catecholaldehydes, and RAGE. Furthermore, since elevations in the catecholaminergic tone and oxidative stress in heart disease are linked with cardiac fibrosis, this study illustrates novel drug targets that could potentially mitigate this serious disorder. |
| تدمد: | 1520-5010 0893-228X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d6eeb10a6c7a1108afe9a2e8a67fc51 https://doi.org/10.1021/acs.chemrestox.1c00262 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6d6eeb10a6c7a1108afe9a2e8a67fc51 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15205010 0893228X |
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