Highly Reactive Isolevuglandins Promote Atrial Fibrillation Caused by Hypertension

Joseph K Prinsen; Prince J Kannankeril; Tatiana N Sidorova; Liudmila V Yermalitskaya; Olivier Boutaud; Irene Zagol-Ikapitte; Joey V Barnett; Matthew B Murphy; Tuerdi Subati; Joshua M Stark; Isis L Christopher; Scott R Jafarian-Kerman; Mohamed A Saleh; Allison E Norlander; Roxana Loperena; James B Atkinson; Agnes B Fogo; James M Luther; Venkataraman Amarnath; Sean S Davies; Annet Kirabo; Meena S Madhur; David G Harrison; Katherine T Murray

doi:10.1016/j.jacbts.2020.04.004

Highly Reactive Isolevuglandins Promote Atrial Fibrillation Caused by Hypertension

JACC Basic Transl Sci. 2020 May 27;5(6):602-615. doi: 10.1016/j.jacbts.2020.04.004. eCollection 2020 Jun.

Authors

Joseph K Prinsen^{1

2}, Prince J Kannankeril³, Tatiana N Sidorova^{1

2}, Liudmila V Yermalitskaya^{1

2}, Olivier Boutaud^{1

2}, Irene Zagol-Ikapitte^{1

2}, Joey V Barnett^{1

2}, Matthew B Murphy^{1

2}, Tuerdi Subati^{1

2}, Joshua M Stark^{1

2}, Isis L Christopher^{1

2}, Scott R Jafarian-Kerman^{1

2}, Mohamed A Saleh^{1

2}, Allison E Norlander^{1

2}, Roxana Loperena^{1

2}, James B Atkinson⁴, Agnes B Fogo⁴, James M Luther^{1

2}, Venkataraman Amarnath^{1

2}, Sean S Davies^{1

2}, Annet Kirabo^{1

2}, Meena S Madhur^{1

2}, David G Harrison^{1

2}, Katherine T Murray^{1

2}

Affiliations

¹ Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
² Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
³ Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
⁴ Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Abstract

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.

Keywords: 2-HOBA, 2-hydroxylbenzylamine; 4-HOBA, 4-hydroxylbenzylamine; AF, atrial fibrillation; ANP, atrial natriuretic peptide; B-type natriuretic peptide; BNP, B-type natriuretic peptide; BP, blood pressure; ECG, electrocardiogram; G/R, green/red ratio; IsoLG, isolevuglandin; PAO, preamyloid oligomer; PBS, phosphate-buffered saline; ROS, reactive oxygen species; ang II, angiotensin II; atrial fibrillation; atrial natriuretic peptide; hypertension; isolevuglandins; oxidative stress; preamyloid oligomers.

Abstract

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