Hydrogen Sulfide Therapy Suppresses Cofilin-2 and Attenuates Ischemic Heart Failure in a Mouse Model of Myocardial Infarction.

AIMS

Hydrogen sulfide (HS) protects against ischemic and inflammatory injury following myocardial ischemia via induction of microRNA (miR)-21. We sought to determine whether HS 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 NaS (100 μg/kg/day; intraperitoneal [IP]) or saline up to 28 days. End-diastolic pressure, measured by Millar catheter, was significantly increased ( < .05 vs sham) at 3 days post-MI in the saline group, which was attenuated with NaS. Left ventricular (LV) fractional shortening decreased significantly at 28 days post-MI in the saline group but was preserved with NaS and LV infarct scar size was smaller in NaS group as compared to control. Apoptotic signaling, measured by Bcl-2/Bax ratio, was significantly increased in the saline group but was mitigated with NaS. Survival rate was 2-fold higher in NaS group compared to saline control ( < .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 NaS treatment. Chronic NaS treatment also attenuated inflammasome formation and activation leading to reduction of maladaptive signaling.

CONCLUSION

NaS treatment after MI preserves LV function and improves survival through attenuation of inflammasome-mediated adverse remodeling. We propose HS donors as promising therapeutic tools for ischemic HFrEF.