Stefano Toldo1, Eleonora Mezzaroma2, Matthew D McGeough3, Carla A Peña3, Carlo Marchetti4, Chiara Sonnino4, Benjamin W Van Tassell5, Fadi N Salloum6, Norbert F Voelkel7, Hal M Hoffman3, Antonio Abbate4. 1. VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA stoldo2@vcu.edu. 2. VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA. 3. Division of Allergy, Immunology and Rheumatology, University of California at San Diego, La Jolla, CA, USA. 4. VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA. 5. Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA. 6. VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA. 7. School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
Abstract
AIMS: The NLRP3 inflammasome is activated in the ischaemic heart promoting caspase-1 activation, inflammation, and cell death. Ischaemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation). Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown. The aim of this study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in the absence of ischaemia or myocardial injury. METHODS AND RESULTS: We used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreT mice). The mice were treated for 10 days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome. Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V. The components of the inflammasome were significantly less expressed in the heart compared with the spleen. Subclinical low-dose lipopolysaccharide (LPS; 2 mg/kg) in Nlrp3-A350V/CreT mice induced the expression of the components of the inflammasome (priming), measured using real-time PCR and western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low-dose LPS was insufficient to induce LV systolic dysfunction in wild-type mice (all P < 0.01 for mutant vs. wild-type mice). CONCLUSION: The signalling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The NLRP3 inflammasome is activated in the ischaemic heart promoting caspase-1 activation, inflammation, and cell death. Ischaemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation). Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown. The aim of this study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in the absence of ischaemia or myocardial injury. METHODS AND RESULTS: We used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreTmice). The mice were treated for 10 days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome. Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V. The components of the inflammasome were significantly less expressed in the heart compared with the spleen. Subclinical low-dose lipopolysaccharide (LPS; 2 mg/kg) in Nlrp3-A350V/CreTmice induced the expression of the components of the inflammasome (priming), measured using real-time PCR and western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low-dose LPS was insufficient to induce LV systolic dysfunction in wild-type mice (all P < 0.01 for mutant vs. wild-type mice). CONCLUSION: The signalling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Eleonora Mezzaroma; Stefano Toldo; Daniela Farkas; Ignacio M Seropian; Benjamin W Van Tassell; Fadi N Salloum; Harsha R Kannan; Angela C Menna; Norbert F Voelkel; Antonio Abbate Journal: Proc Natl Acad Sci U S A Date: 2011-11-21 Impact factor: 11.205
Authors: D V Krysko; A Kaczmarek; O Krysko; L Heyndrickx; J Woznicki; P Bogaert; A Cauwels; N Takahashi; S Magez; C Bachert; P Vandenabeele Journal: Cell Death Differ Date: 2011-02-11 Impact factor: 15.828
Authors: Ignacio M Seropian; Antonio Abbate; Stefano Toldo; Jessica Harrington; Lisa Smithson; Ramzi Ockaili; Eleonora Mezzaroma; Federico Damilano; Emilio Hirsch; Benjamin W Van Tassell Journal: J Cardiovasc Pharmacol Date: 2010-12 Impact factor: 3.105
Authors: Benjamin W Van Tassell; Ross A Arena; Stefano Toldo; Eleonora Mezzaroma; Tania Azam; Ignacio M Seropian; Keyur Shah; Justin Canada; Norbert F Voelkel; Charles A Dinarello; Antonio Abbate Journal: PLoS One Date: 2012-03-16 Impact factor: 3.240
Authors: Sheri L Bonar; Susannah D Brydges; James L Mueller; Matthew D McGeough; Carla Pena; Debbie Chen; Susan K Grimston; Cynthia L Hickman-Brecks; Soumya Ravindran; Audrey McAlinden; Deborah V Novack; Daniel L Kastner; Roberto Civitelli; Hal M Hoffman; Gabriel Mbalaviele Journal: PLoS One Date: 2012-04-27 Impact factor: 3.240
Authors: Eleonora Mezzaroma; Ross B Mikkelsen; Stefano Toldo; Adolfo G Mauro; Khushboo Sharma; Carlo Marchetti; Asim Alam; Benjamin W Van Tassell; David A Gewirtz; Antonio Abbate Journal: Mol Med Date: 2015-03-26 Impact factor: 6.354
Authors: Paras K Mishra; Adriana Adameova; Joseph A Hill; Christopher P Baines; Peter M Kang; James M Downey; Jagat Narula; Masafumi Takahashi; Antonio Abbate; Hande C Piristine; Sumit Kar; Shi Su; Jason K Higa; Nicholas K Kawasaki; Takashi Matsui Journal: Am J Physiol Heart Circ Physiol Date: 2019-08-16 Impact factor: 4.733
Authors: Antonio Abbate; Stefano Toldo; Carlo Marchetti; Jordana Kron; Benjamin W Van Tassell; Charles A Dinarello Journal: Circ Res Date: 2020-04-23 Impact factor: 17.367
Authors: Larry Scott; Anke C Fender; Arnela Saljic; Luge Li; Xiaohui Chen; Xiaolei Wang; Dominik Linz; Jilu Lang; Mathias Hohl; Darragh Twomey; Thuy T Pham; Rodrigo Diaz-Lankenau; Mihail G Chelu; Markus Kamler; Mark L Entman; George E Taffet; Prashanthan Sanders; Dobromir Dobrev; Na Li Journal: Cardiovasc Res Date: 2021-06-16 Impact factor: 10.787