Journal article
A Catecholaldehyde Metabolite of Norepinephrine Induces Myofibroblast Activation and Toxicity via the Receptor for Advanced Glycation Endproducts: Mitigating Role of L-Carnosine
Chemical research in toxicology, Vol.34(10), pp.2194-2201
10/18/2021
DOI: 10.1021/acs.chemrestox.1c00262
PMCID: PMC8527521
PMID: 34609854
Appears in UI Libraries Support Open Access
Abstract
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 mu M) of DOPEGAL-modified albumin phenocopied many of the effects of norepinephrine and also induced an increase in RAGE expression. Higher doses (>10 mu M) 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.
Details
- Title: Subtitle
- A Catecholaldehyde Metabolite of Norepinephrine Induces Myofibroblast Activation and Toxicity via the Receptor for Advanced Glycation Endproducts: Mitigating Role of L-Carnosine
- Creators
- T. Blake Monroe - University of IowaEthan J Anderson - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.34(10), pp.2194-2201
- DOI
- 10.1021/acs.chemrestox.1c00262
- PMID
- 34609854
- PMCID
- PMC8527521
- NLM abbreviation
- Chem Res Toxicol
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Publisher
- American Chemical Society
- Number of pages
- 8
- Grant note
- R01HL122863; R21AG057006 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 20SFRN35200003 / American Heart Association Strategically Focused Research Network
- Language
- English
- Date published
- 10/18/2021
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology
- Record Identifier
- 9984230637702771
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