Author + information
- Received January 2, 2020
- Revision received March 31, 2020
- Accepted April 2, 2020
- Published online June 22, 2020.
- Joseph K. Prinsen, DO, PhDa,b,
- Prince J. Kannankeril, MD, MScic,
- Tatiana N. Sidorova, PhDa,b,
- Liudmila V. Yermalitskaya, MSa,b,
- Olivier Boutaud, PhDa,b,
- Irene Zagol-Ikapitte, PhDa,b,
- Joey V. Barnett, PhDa,b,
- Matthew B. Murphy, PharmDa,b,
- Tuerdi Subati, MD, PhDa,b,
- Joshua M. Stark, BAa,b,
- Isis L. Christopher, BSa,b,
- Scott R. Jafarian-Kerman, MD, MSCIa,b,
- Mohamed A. Saleh, PhDa,b,
- Allison E. Norlander, PhDa,b,
- Roxana Loperena, PhDa,b,
- James B. Atkinson, MD, PhDd,
- Agnes B. Fogo, MDd,
- James M. Luther, MDa,b,
- Venkataraman Amarnath, PhDa,b,
- Sean S. Davies, PhDa,b,
- Annet Kirabo, PhDa,b,
- Meena S. Madhur, MD, PhDa,b,
- David G. Harrison, MDa,b and
- Katherine T. Murray, MDa,b,∗ ()
- aDepartment of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
- bDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee
- cDepartment of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
- dDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
- ↵∗Address for correspondence:
Dr. Katherine T. Murray, Division of Clinical Pharmacology, Room 559 Preston Research Building, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232-6602.
• 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.
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.
- atrial fibrillation
- atrial natriuretic peptide
- B-type natriuretic peptide
- oxidative stress
- preamyloid oligomers
This work was supported by National Heart, Lung, and Blood Institute grants HL096844 and HL133127 to Dr. Murray and K01HL130497 to Dr. Kirabo, the National Institute of Aging grant 5R44AG005184 to Dr. Boutaud, the National Institute of General Medical Sciences grant T32 GM007569 to Dr. Prinsen at the National Institutes of Health, the American Heart Association, Southeast Affiliate grant 2160035 to Dr. Murray, and National Center grant 18SFRN34230125 to Dr. Dan Roden (Dr. Murray is the Basic Project PI). Drs. Prinsen and Murray are supported by the National Center for Advancing Translational Sciences of the National Institute of Health under Award Number UL1 TR000445. Drs. Amarnath and Murray have a pending patent application with Metabolic Technologies, Inc., and Vanderbilt University. Dr. Davies is a patent holder for use of 2-HOBA, an isolevuglandin scavenger. Drs. Kirabo and Harrison are coinventors on U.S. Patent # 14/232,615. Confocal microscopy and image analysis were performed through the Vanderbilt Cell Imaging Shared Resource (also supported by the National Institutes of Health [CA68485, DK20593, DK58404, DK59637 and EY08126]). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Stark is currently affiliated with the College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee. Dr. Jafarian-Kerman is currently affiliated with the Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. Dr. Saleh is currently affiliated with the Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received January 2, 2020.
- Revision received March 31, 2020.
- Accepted April 2, 2020.
- 2020 The Authors