Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation
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- Chunxia Yao
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Tina Veleva
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen (T.V., I.A.-T., S.G., S.N., D.D.).
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- Larry Scott
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Shuyi Cao
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Luge Li
- Departments of Medicine (Cardiovascular Research) (C.Y., L.S. L.L., G.C., P.J., N.L.), Baylor College of Medicine, Houston, TX.
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- Gong Chen
- Departments of Medicine (Cardiovascular Research) (C.Y., L.S. L.L., G.C., P.J., N.L.), Baylor College of Medicine, Houston, TX.
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- Prince Jeyabal
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Xiaolu Pan
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Katherina M. Alsina
- Integrative Molecular Biomedical Sciences Program (K.M.A.), Baylor College of Medicine, Houston, TX.
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- Issam Abu-Taha
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen (T.V., I.A.-T., S.G., S.N., D.D.).
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- Shokoufeh Ghezelbash
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen (T.V., I.A.-T., S.G., S.N., D.D.).
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- Corey L. Reynolds
- Molecular Physiology and Biophysics (L.S., S.C., X.P., C.L.R., C.B., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Ying H. Shen
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Scott A. LeMaire
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Wilhelm Schmitz
- Department of Pharmacology and Toxicology, University of Münster, Germany (W.S., F.U.M.).
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- Frank U. Müller
- Department of Pharmacology and Toxicology, University of Münster, Germany (W.S., F.U.M.).
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- Ali El-Armouche
- Department of Pharmacology and Toxicology, Dresden University of Technology, Germany (AE.-A.).
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- N. Tony Eissa
- Medicine (Pulmonary) (N.T.E.), Baylor College of Medicine, Houston, TX.
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- Christine Beeton
- Molecular Physiology and Biophysics (L.S., S.C., X.P., C.L.R., C.B., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Stanley Nattel
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen (T.V., I.A.-T., S.G., S.N., D.D.).
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- Xander H.T. Wehrens
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
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- Dobromir Dobrev
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen (T.V., I.A.-T., S.G., S.N., D.D.).
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- Na Li
- Cardiovascular Research Institute (C.Y., L.S., S.C., P.J., X.P., Y.H.S., S.A.L., X.H.T.W., N.L.), Baylor College of Medicine, Houston, TX.
抄録
<jats:sec> <jats:title>Background:</jats:title> <jats:p>Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The NLRP3 (NACHT, LRR, and PYD domain containing protein 3) inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3 inflammasome in AF.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal AF or long-standing persistent (chronic) AF. To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knockin mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electric activation pattern, Ca <jats:sup>2+</jats:sup> spark frequency, atrial effective refractory period, and morphology of atria were evaluated in CM-KI mice and wild-type littermates. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> NLRP3 inflammasome activity was increased in the atrial CMs of patients with paroxysmal AF and chronic AF. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3 inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> release, atrial effective refractory period shortening, and atrial hypertrophy. Adeno-associated virus subtype-9–mediated CM-specific knockdown of <jats:italic>Nlrp3</jats:italic> suppressed AF development in CM-KI mice. Finally, genetic inhibition of <jats:italic>Nlrp3</jats:italic> prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Our study establishes a novel pathophysiological role for CM NLRP3 inflammasome signaling, with a mechanistic link to the pathogenesis of AF, and establishes the inhibition of NLRP3 as a potential novel AF therapy approach.</jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 138 (20), 2227-2242, 2018-11-13
Ovid Technologies (Wolters Kluwer Health)