Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
J Cardiovasc Pharmacol Ther. 2020 Sep;25(5):472-483. doi: 10.1177/1074248420923542. Epub 2020 May 11.
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.
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.
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.
硫化氢（HS）通过诱导 microRNA（miR）-21 来保护心肌缺血后的缺血性和炎症性损伤。我们试图确定 HS 是否减轻射血分数降低的心力衰竭（HFrEF），并探讨 miR-21 的靶标肌动蛋白丝解聚因子 2（cofilin-2）在这一保护过程中的作用。
成年雄性小鼠在基线超声心动图检查后通过冠状动脉结扎术发生心肌梗死（MI）。MI 后，小鼠用 NaS（100μg/kg/天；腹腔内[IP]）或生理盐水治疗至 28 天。Millar 导管测量的舒张末期压在盐水组 MI 后 3 天显著升高（<0.05 与假手术组相比），而 NaS 可减轻这种升高。盐水组 MI 后 28 天左心室（LV）缩短分数显著降低，但 NaS 可保留该分数，且 NaS 组 LV 梗死瘢痕面积小于对照组。盐水组凋亡信号通过 Bcl-2/Bax 比值显著增加，但 NaS 可减轻这种增加。与盐水对照组相比，NaS 组的存活率提高了 2 倍（<0.05）。蛋白质组分析和基质辅助激光解吸/电离飞行时间（TOF）/TOF 串联质谱分析发现，在 MI 后 28 天，NaS 治疗和盐水治疗的小鼠之间，促凋亡肌动蛋白丝解聚因子 2（miR-21 的特定靶标）的表达有显著变化。Western blot 分析证实，MI 后肌动蛋白丝解聚因子 2 显著增加，NaS 治疗可抑制其增加。慢性 NaS 治疗还可减轻炎症小体的形成和激活，从而减少适应性不良信号。
MI 后 NaS 治疗通过抑制炎症小体介导的不良重构来保护 LV 功能并提高存活率。我们提出 HS 供体是治疗缺血性 HFrEF 的有前途的治疗工具。
