PMID- 38377486 OWN - NLM STAT- Publisher LR - 20240507 IS - 1755-3245 (Electronic) IS - 0008-6363 (Linking) DP - 2024 Feb 20 TI - LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation. LID - cvae036 [pii] LID - 10.1093/cvr/cvae036 [doi] AB - AIMS: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signaling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and hematologic disorders including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are a major component of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. METHODS AND RESULTS: Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared to WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, proarrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodeling in vitro. Inhibition of soluble TNF-alpha prevented electrical remodeling and AF susceptibility, while IL-1beta inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. CONCLUSIONS: These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and in humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the proarrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodeling. CI - (c) The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Murphy, Matthew B AU - Murphy MB AUID- ORCID: 0000-0002-2297-2703 AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Yang, Zhenjiang AU - Yang Z AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Subati, Tuerdi AU - Subati T AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Farber-Eger, Eric AU - Farber-Eger E AD - Departments of Medicine, Pharmacology. FAU - Kim, Kyungsoo AU - Kim K AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Blackwell, Daniel J AU - Blackwell DJ AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Fleming, Matthew R AU - Fleming MR AD - Departments of Medicine, Pharmacology. FAU - Stark, Joshua M AU - Stark JM AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Van Amburg, Joseph C AU - Van Amburg JC AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Woodall, Kaylen K AU - Woodall KK AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Van Beusecum, Justin P AU - Van Beusecum JP AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Agrawal, Vineet AU - Agrawal V AD - Departments of Medicine, Pharmacology. FAU - Smart, Charles D AU - Smart CD AUID- ORCID: 0000-0003-0391-3916 AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Pitzer, Ashley AU - Pitzer A AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Atkinson, James B AU - Atkinson JB AD - Departments of Medicine, Biomedical Informatics. FAU - Fogo, Agnes B AU - Fogo AB AD - Departments of Medicine, Biomedical Informatics. FAU - Bastarache, Julie A AU - Bastarache JA AD - Departments of Medicine, Pharmacology. FAU - Kirabo, Annet AU - Kirabo A AUID- ORCID: 0000-0001-8580-9359 AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Wells, Quinn S AU - Wells QS AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. AD - Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN. FAU - Madhur, Meena S AU - Madhur MS AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Barnett, Joey V AU - Barnett JV AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. FAU - Murray, Katherine T AU - Murray KT AUID- ORCID: 0000-0002-1342-4457 AD - Departments of Medicine, Pharmacology. AD - Departments of Medicine, Pathology, Microbiology, and Immunology. LA - eng GR - R35 HL150783/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20240220 PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 SB - IM CIN - Cardiovasc Res. 2024 May 07;:. PMID: 38713542 EDAT- 2024/02/20 18:42 MHDA- 2024/02/20 18:42 CRDT- 2024/02/20 16:43 PHST- 2023/04/28 00:00 [received] PHST- 2023/08/31 00:00 [revised] PHST- 2023/10/07 00:00 [accepted] PHST- 2024/02/20 18:42 [medline] PHST- 2024/02/20 18:42 [pubmed] PHST- 2024/02/20 16:43 [entrez] AID - 7611672 [pii] AID - 10.1093/cvr/cvae036 [doi] PST - aheadofprint SO - Cardiovasc Res. 2024 Feb 20:cvae036. doi: 10.1093/cvr/cvae036.