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Published on: March 12, 2013
LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation
Matthew B Murphy1,2, Zhenjiang Yang1,2, Tuerdi Subati1,2
1Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA.
Insights
Loss of the lymphocyte adaptor protein (LNK) promotes atrial fibrillation (AF) in mice and humans. Reactive lipid dicarbonyls drive this inflammatory AF substrate by causing electrical remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics of Arrhythmias
Background:
- Lymphocyte adaptor protein (LNK) negatively regulates cytokine and growth factor signaling.
- A variant (rs3184504) in SH2B3 reduces LNK function, linked to cardiovascular and inflammatory diseases.
- LNK deficiency in mice causes inflammation and oxidative stress, suggesting a role in atrial fibrillation (AF).
Purpose of the Study:
- To investigate if LNK-deficient mice are susceptible to AF.
- To determine if the rs3184504 variant is associated with human AF and stroke.
- To explore the role of reactive lipid dicarbonyls in AF pathogenesis in LNK-deficient mice.
Main Methods:
- LNK-deficient (Lnk-/-) and wild-type (WT) mice were treated with a dicarbonyl scavenger (2-hydroxybenzylamine, 2-HOBA).
- Electrophysiological studies, mitochondrial function assays, and cytokine level measurements were performed.
- Human genetic data for rs3184504 association with AF and stroke were analyzed.
Main Results:
- Lnk-/- mice exhibited increased AF duration, which was prevented by 2-HOBA.
- Lnk-/- atria showed prolonged action potentials, altered ion currents, and mitochondrial dysfunction (Complex I), all ameliorated by 2-HOBA.
- Elevated TNF-α and IL-1β in Lnk-/- mice contributed to electrical and bioenergetic remodeling; rs3184504 was associated with human AF and stroke.
Conclusions:
- LNK plays a critical role in the pathophysiology of atrial fibrillation.
- Reactive lipid dicarbonyls are key mediators of the inflammatory AF substrate in LNK deficiency.
- These findings link LNK function, oxidative stress, inflammation, and AF susceptibility in both mice and humans.
Aims:
The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic 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 the major components 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 with 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, pro-arrhythmic 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. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-α prevented electrical remodelling and AF susceptibility, while IL-1β 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.
Conclusion:
These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling.
