Adolfo G Mauro1, Eleonora Mezzaroma, Juan Torrado, Priyanka Kundur, Priyashma Joshi, Kelsey Stroud, Federico Quaini, Costanza A Lagrasta, Antonio Abbate, Stefano Toldo. 1. *VCU Pauley Heart Center, Virginia Comonwealth University, Richmond, VA;†VCU Johnson Research Center, Virginia Comonwealth University, Richmond, VA;‡Department of Biomedical, Biotechnological, and Translational Sciences, University of Parma, Parma, Italy;§Department of Pharmacotherapy and Outcome Sciences, School of Pharmacy, Virginia Comonwealth University, Richmond, VA;¶Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy; and‖Department of Surgery, Virginia Commonwealth University, Richmond, VA.
Abstract
BACKGROUND: Interleukin-1α (IL-1α) released by dying cells is an alarmin that activates the innate immunity. We hypothesized that after myocardial ischemia-reperfusion (I/R) injury, IL-1α amplifies the myocardial damage by activating the inflammasome and caspase-1. METHODS: Adult male CD1 mice were used. The left anterior descending coronary artery was ligated for 30 minutes, after 24 hours of reperfusion. An IL-1α blocking antibody (15 μg/kg intraperitoneally) or matching vehicle was given after reperfusion. A subgroup of mice underwent sham surgery. We assessed the effects of IL-1α blockade on caspase-1 activity, infarct size, cardiac troponin I serum levels, and left ventricular fractional shortening, 24 hours after I/R. RESULTS: I/R led to inflammasome formation, and IL-1α blockade significantly reduced inflammasome formation, reflected by a >50% reduction in caspase-1 activity versus vehicle (P = 0.03). IL-1α blockade also reduced the infarct size (-52% infarct expressed as percentage of area at risk, and -79% for cardiac troponin I serum levels, P < 0.001 vs. vehicle) and preserved the left ventricular fractional shortening (31 ± 3% vs. 25 ± 2%, P < 0.001 vs. vehicle). CONCLUSION: IL-1α blockade after I/R reduces the inflammasome activation, decreases the infarct size, and preserves the left ventricular function. IL-1α blockade may therefore represent a novel therapeutic strategy to reduce I/R injury.
BACKGROUND: Interleukin-1α (IL-1α) released by dying cells is an alarmin that activates the innate immunity. We hypothesized that after myocardial ischemia-reperfusion (I/R) injury, IL-1α amplifies the myocardial damage by activating the inflammasome and caspase-1. METHODS: Adult male CD1mice were used. The left anterior descending coronary artery was ligated for 30 minutes, after 24 hours of reperfusion. An IL-1α blocking antibody (15 μg/kg intraperitoneally) or matching vehicle was given after reperfusion. A subgroup of mice underwent sham surgery. We assessed the effects of IL-1α blockade on caspase-1 activity, infarct size, cardiac troponin I serum levels, and left ventricular fractional shortening, 24 hours after I/R. RESULTS: I/R led to inflammasome formation, and IL-1α blockade significantly reduced inflammasome formation, reflected by a >50% reduction in caspase-1 activity versus vehicle (P = 0.03). IL-1α blockade also reduced the infarct size (-52% infarct expressed as percentage of area at risk, and -79% for cardiac troponin I serum levels, P < 0.001 vs. vehicle) and preserved the left ventricular fractional shortening (31 ± 3% vs. 25 ± 2%, P < 0.001 vs. vehicle). CONCLUSION: IL-1α blockade after I/R reduces the inflammasome activation, decreases the infarct size, and preserves the left ventricular function. IL-1α blockade may therefore represent a novel therapeutic strategy to reduce I/R injury.
Authors: Stefano Toldo; Eleonora Mezzaroma; Leo F Buckley; Nicola Potere; Marcello Di Nisio; Giuseppe Biondi-Zoccai; Benjamin W Van Tassell; Antonio Abbate Journal: Pharmacol Ther Date: 2021-12-11 Impact factor: 13.400
Authors: Benjamin W Van Tassell; Michael J Lipinski; Darryn Appleton; Charlotte S Roberts; Michael C Kontos; Nayef Abouzaki; Ryan Melchior; George Mueller; James Garnett; Justin Canada; Salvatore Carbone; Leo F Buckley; George Wohlford; Dinesh Kadariya; Cory R Trankle; Claudia Oddi Erdle; Robin Sculthorpe; Laura Puckett; Christine DeWilde; Keyur Shah; Dominick J Angiolillo; George Vetrovec; Giuseppe Biondi-Zoccai; Ross Arena; Antonio Abbate Journal: Clin Cardiol Date: 2018-08-17 Impact factor: 2.882
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: Sumia A Bageghni; Karen E Hemmings; Nadira Y Yuldasheva; Azhar Maqbool; Filomena O Gamboa-Esteves; Neil E Humphreys; Maj Simonsen Jackson; Christopher P Denton; Sheila Francis; Karen E Porter; Justin Fx Ainscough; Emmanuel Pinteaux; Mark J Drinkhill; Neil A Turner Journal: JCI Insight Date: 2019-08-08