Chunxia Yao1,2,3, Tina Veleva4, Larry Scott1,2,5, Shuyi Cao1,5, Luge Li2, Gong Chen2, Prince Jeyabal1,2, Xiaolu Pan1,5, Katherina M Alsina6, Issam Abu-Taha4, Shokoufeh Ghezelbash4, Corey L Reynolds5,7, Ying H Shen1,8, Scott A LeMaire1,8, Wilhelm Schmitz9, Frank U Müller9, Ali El-Armouche10, N Tony Eissa11, Christine Beeton5, Stanley Nattel4,12, Xander H T Wehrens1,5,13,14,15, Dobromir Dobrev4, Na Li1,2,5. 1. 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. 2. Departments of Medicine (Cardiovascular Research) (C.Y., L.S. L.L., G.C., P.J., N.L.), Baylor College of Medicine, Houston, TX. 3. Affiliated Hospital, College of Medicine, Hebei University of Engineering, Handan, China (C.Y.). 4. Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen (T.V., I.A.-T., S.G., S.N., D.D.). 5. 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. 6. Integrative Molecular Biomedical Sciences Program (K.M.A.), Baylor College of Medicine, Houston, TX. 7. Mouse Phenotyping Core (C.L.R.), Baylor College of Medicine, Houston, TX. 8. Surgery (Y.H.S., S.A.L.), Baylor College of Medicine, Houston, TX. 9. Department of Pharmacology and Toxicology, University of Münster, Germany (W.S., F.U.M.). 10. Department of Pharmacology and Toxicology, Dresden University of Technology, Germany (AE.-A.). 11. Medicine (Pulmonary) (N.T.E.), Baylor College of Medicine, Houston, TX. 12. Department of Medicine, Montreal Heart Institute and Université de Montréal, Québec, Canada (S.N.). 13. Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX. 14. Pediatrics (X.H.T.W.), Baylor College of Medicine, Houston, TX. 15. Center for Space Medicine (X.H.T.W.), Baylor College of Medicine, Houston, TX.
Abstract
BACKGROUND: 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. METHODS: 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, Ca2+ spark frequency, atrial effective refractory period, and morphology of atria were evaluated in CM-KI mice and wild-type littermates. RESULTS: 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 Ca2+ release, atrial effective refractory period shortening, and atrial hypertrophy. Adeno-associated virus subtype-9-mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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, Ca2+ spark frequency, atrial effective refractory period, and morphology of atria were evaluated in CM-KI mice and wild-type littermates. RESULTS: 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 Ca2+ release, atrial effective refractory period shortening, and atrial hypertrophy. Adeno-associated virus subtype-9-mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. CONCLUSIONS: 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.
Authors: Alvin Lu; Venkat Giri Magupalli; Jianbin Ruan; Qian Yin; Maninjay K Atianand; Matthijn R Vos; Gunnar F Schröder; Katherine A Fitzgerald; Hao Wu; Edward H Egelman Journal: Cell Date: 2014-03-13 Impact factor: 41.582
Authors: Na Li; Tiannan Wang; Wei Wang; Michael J Cutler; Qiongling Wang; Niels Voigt; David S Rosenbaum; Dobromir Dobrev; Xander H T Wehrens Journal: Circ Res Date: 2011-12-08 Impact factor: 17.367
Authors: Richard Y Kim; James W Pinkerton; Ama T Essilfie; Avril A B Robertson; Katherine J Baines; Alexandra C Brown; Jemma R Mayall; M Khadem Ali; Malcolm R Starkey; Nicole G Hansbro; Jeremy A Hirota; Lisa G Wood; Jodie L Simpson; Darryl A Knight; Peter A Wark; Peter G Gibson; Luke A J O'Neill; Matthew A Cooper; Jay C Horvat; Philip M Hansbro Journal: Am J Respir Crit Care Med Date: 2017-08-01 Impact factor: 21.405
Authors: Baris Gungor; Ahmet Ekmekci; Ahmet Arman; Kazim S Ozcan; Ekrem Ucer; Ahmet T Alper; Nazmi Calik; Hale Yilmaz; Tuna Tezel; Ajda Coker; Osman Bolca Journal: Pacing Clin Electrophysiol Date: 2013-05-28 Impact factor: 1.976
Authors: Toru Oka; Marjorie Maillet; Alistair J Watt; Robert J Schwartz; Bruce J Aronow; Stephen A Duncan; Jeffery D Molkentin Journal: Circ Res Date: 2006-03-02 Impact factor: 17.367
Authors: David L Beavers; Wei Wang; Sameer Ather; Niels Voigt; Alejandro Garbino; Sayali S Dixit; Andrew P Landstrom; Na Li; Qiongling Wang; Iacopo Olivotto; Dobromir Dobrev; Michael J Ackerman; Xander H T Wehrens Journal: J Am Coll Cardiol Date: 2013-08-21 Impact factor: 24.094
Authors: Rebecca C Coll; Avril A B Robertson; Jae Jin Chae; Sarah C Higgins; Raúl Muñoz-Planillo; Marco C Inserra; Irina Vetter; Lara S Dungan; Brian G Monks; Andrea Stutz; Daniel E Croker; Mark S Butler; Moritz Haneklaus; Caroline E Sutton; Gabriel Núñez; Eicke Latz; Daniel L Kastner; Kingston H G Mills; Seth L Masters; Kate Schroder; Matthew A Cooper; Luke A J O'Neill Journal: Nat Med Date: 2015-02-16 Impact factor: 53.440
Authors: Rossana G Iannitti; Valerio Napolioni; Vasilis Oikonomou; Antonella De Luca; Claudia Galosi; Marilena Pariano; Cristina Massi-Benedetti; Monica Borghi; Matteo Puccetti; Vincenzina Lucidi; Carla Colombo; Ersilia Fiscarelli; Cornelia Lass-Flörl; Fabio Majo; Lisa Cariani; Maria Russo; Luigi Porcaro; Gabriella Ricciotti; Helmut Ellemunter; Luigi Ratclif; Fernando Maria De Benedictis; Vincenzo Nicola Talesa; Charles A Dinarello; Frank L van de Veerdonk; Luigina Romani Journal: Nat Commun Date: 2016-03-14 Impact factor: 14.919
Authors: Maarten Hulsmans; Aaron D Aguirre; Matthew D Bonner; Aneesh Bapat; Sebastian Cremer; Yoshiko Iwamoto; Kevin R King; Filip K Swirski; David J Milan; Ralph Weissleder; Matthias Nahrendorf Journal: Circ Res Date: 2018-11-09 Impact factor: 17.367