Highly Reactive Isolevuglandins Promote Atrial Fibrillation Caused by Hypertension
| Autor: | Sean S. Davies, Prince J. Kannankeril, Joshua M. Stark, James M. Luther, Annet Kirabo, Isis L Christopher, Meena S. Madhur, James B. Atkinson, Irene Zagol-Ikapitte, Liudmila V. Yermalitskaya, Scott R. Jafarian-Kerman, Matthew B Murphy, Agnes B. Fogo, David G. Harrison, Katherine T. Murray, Mohamed A. Saleh, Joey V. Barnett, Olivier Boutaud, Roxana Loperena, Joseph K. Prinsen, Venkataraman Amarnath, Tatiana N. Sidorova, Allison E. Norlander, Tuerdi Subati |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
BP blood pressure hypertension AF atrial fibrillation PAO preamyloid oligomer oxidation PBS phosphate-buffered saline ang II angiotensin II 030204 cardiovascular system & hematology Pharmacology medicine.disease_cause preamyloid oligomers Oxidative damage 03 medical and health sciences PRECLINICAL RESEARCH 0302 clinical medicine ROS reactive oxygen species Atrial natriuretic peptide atrial natriuretic peptide medicine Cytotoxic T cell oxidative stress atrial fibrillation ANP atrial natriuretic peptide isolevuglandins BNP B-type natriuretic peptide AF - Atrial fibrillation 2-HOBA 2-hydroxylbenzylamine Chemistry Atrial fibrillation G/R green/red ratio medicine.disease 4-HOBA 4-hydroxylbenzylamine 030104 developmental biology Minimal effect Murine model B-type natriuretic peptide ECG electrocardiogram IsoLG isolevuglandin Cardiology and Cardiovascular Medicine Editorial Comment Oxidative stress |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| Popis: | Visual Abstract Highlights • IsoLGs are highly reactive lipid dicarbonyl metabolites that constitute a major component of oxidative stress-related injury, and they promote the formation of amyloid. • In a hypertensive murine model, IsoLG adducts and PAOs developed in the atria, along with inducible AF. • IsoLG and PAO accumulation and AF were prevented by the dicarbonyl scavenger 2-HOBA, but not by an inactive analog 4-hydroxybenzylamine. • Mechanically stretched atrial cells generated cytosolic IsoLG adducts and PAOs that were prevented by 2-HOBA. • Natriuretic peptides generated cytotoxic oligomers, a process accelerated by IsoLGs, contributing to atrial PAO formation. • These findings identify a novel pathway during oxidative stress to increase AF susceptibility, and they support the concept of preemptively scavenging reactive downstream mediators as a potential therapeutic approach to prevent AF. Summary Oxidative damage is implicated in atrial fibrillation (AF), but antioxidants are ineffective therapeutically. The authors tested the hypothesis that highly reactive lipid dicarbonyl metabolites, or isolevuglandins (IsoLGs), are principal drivers of AF during hypertension. In a hypertensive murine model and stretched atriomyocytes, the dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) prevented IsoLG adducts and preamyloid oligomers (PAOs), and AF susceptibility, whereas the ineffective analog 4-hydroxybenzylamine (4-HOBA) had minimal effect. Natriuretic peptides generated cytotoxic oligomers, a process accelerated by IsoLGs, contributing to atrial PAO formation. These findings support the concept of pre-emptively scavenging reactive downstream oxidative stress mediators as a potential therapeutic approach to prevent AF. |
| Databáze: | OpenAIRE |
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