Hydrogen Sulfide Therapy Suppresses Cofilin-2 and Attenuates Ischemic Heart Failure in a Mouse Model of Myocardial Infarction
Khoa Nguyen, Vinh Q. Chau, Adolfo G Mauro, David Durrant, Stefano Toldo, Antonio Abbate, Anindita Das, Fadi N. Salloum
Abstract
Aims: Hydrogen sulfide (H 2 S) protects against ischemic and inflammatory injury following myocardial ischemia via induction of microRNA (miR)-21. We sought to determine whether H 2 S attenuates ischemic heart failure with reduced ejection fraction (HFrEF) and interrogate the role of cofilin-2, a target of miR-21, in this protective process. Methods and Results: Adult male mice underwent myocardial infarction (MI) by coronary artery ligation after baseline echocardiography. Following MI, mice were treated with Na 2 S (100 μg/kg/day; intraperitoneal [IP]) or saline up to 28 days. End-diastolic pressure, measured by Millar catheter, was significantly increased ( P < .05 vs sham) at 3 days post-MI in the saline group, which was attenuated with Na 2 S. Left ventricular (LV) fractional shortening decreased significantly at 28 days post-MI in the saline group but was preserved with Na 2 S and LV infarct scar size was smaller in Na 2 S group as compared to control. Apoptotic signaling, measured by Bcl-2/Bax ratio, was significantly increased in the saline group but was mitigated with Na 2 S. Survival rate was 2-fold higher in Na 2 S group compared to saline control ( P < .05). Proteomic analysis and Matrix-Assisted Laser Desorption/Ionization-Time of Flight (TOF)/TOF tandem mass spectrometry identified significant changes in proapoptotic cofilin-2 expression, a specific target of miR-21, between saline- and sodium sulfide -treated mice at 28 days post-MI. Western blot analysis confirmed a significant increase in cofilin-2 after MI, which was suppressed with Na 2 S treatment. Chronic Na 2 S treatment also attenuated inflammasome formation and activation leading to reduction of maladaptive signaling. Conclusion: Na 2 S treatment after MI preserves LV function and improves survival through attenuation of inflammasome-mediated adverse remodeling. We propose H 2 S donors as promising therapeutic tools for ischemic HFrEF.