Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
Cardiovasc Res. 2017 May 1;113(6):609-619. doi: 10.1093/cvr/cvw246.
The preconditioning-like infarct-sparing and anti-inflammatory effects of the peptide hormone relaxin following ischemic injury have been studied in the heart. Whether reperfusion therapy with recombinant human relaxin-2, serelaxin, reduces myocardial infarct size and attenuates the subsequent NLRP3 inflammasome activation leading to further loss of functional myocardium following ischemia/reperfusion (I/R) injury is unknown.
After baseline echocardiography, adult male wild-type C57BL or eNOS knockout mice underwent myocardial infarction (MI) by coronary artery ligation for 30 min followed by 24 h reperfusion. Mice were treated with either serelaxin (10 µg/kg; sc) or saline 1 h prior to ischemia or 5 min before reperfusion. In both pre-treatment and reperfusion therapy arms, serelaxin improved survival at 24 h post MI in wild-type mice (79% and 82%) as compared with controls (46% and 50%, P = 0.01), whereas there was no difference in survival between serelaxin- and saline-treated eNOS knockout mice. Moreover, serelaxin significantly reduced infarct size (64% and 67% reduction, P < 0.05), measured with TTC staining, and preserved LV fractional shortening (FS) and end-systolic diameter (LVESD) in wild-type mice as compared with controls (P < 0.05). Interestingly, caspase-1 activity in the heart tissue, a measure of inflammasome formation, was markedly reduced in serelaxin-treated wild-type mice compared with controls at 24 h post-MI in both treatment modalities (P < 0.05). Genetic deletion of eNOS abolished the infarct-sparing and anti-inflammatory effects of serelaxin as well as functional preservation. Serelaxin plasma levels assessed at 5 min and 1 h after treatment, using ELISA, approximated physiologic relaxin levels during pregnancy in mice and parallels that in humans.
Serelaxin attenuates myocardial I/R injury and the subsequent caspase-1 activation via eNOS-dependent mechanism.
在心脏中，已经研究了肽激素松弛素在缺血损伤后的预处理样梗死保护和抗炎作用。在缺血/再灌注（I / R）损伤后，用重组人松弛素-2（serelaxin）进行再灌注治疗是否可以减少心肌梗死面积并减轻随后的 NLRP3 炎性小体激活，从而导致功能心肌的进一步丧失尚不清楚。
在基线超声心动图检查后，成年雄性野生型 C57BL 或 eNOS 敲除小鼠通过冠状动脉结扎进行心肌梗死（MI）30 分钟，然后再灌注 24 小时。在缺血前 1 小时或再灌注前 5 分钟，用 serelaxin（10 µg / kg; sc）或盐水对小鼠进行治疗。在预处理和再灌注治疗臂中，与对照组相比（46％和 50％），serelaxin 在 24 小时后增加了野生型小鼠的存活率（79％和 82％）（P = 0.01），而在 eNOS 敲除小鼠中，serelaxin 与盐水治疗之间的存活率没有差异。此外，serelaxin 可显着减少 TTC 染色测量的梗死面积（64％和 67％的减少，P < 0.05），并保留野生型小鼠的左室短轴缩短率（FS）和左室收缩末期直径（LVESD）与对照组相比（P < 0.05）。有趣的是，与对照组相比，在两种治疗方式下，在 MI 后 24 小时，心肌组织中半胱天冬酶-1 活性（炎性小体形成的一种衡量标准）在接受 serelaxin 治疗的野生型小鼠中明显降低（P < 0.05）。eNOS 的基因缺失消除了 serelaxin 的梗死保护和抗炎作用以及功能保存。使用 ELISA 在治疗后 5 分钟和 1 小时评估的 serelaxin 血浆水平接近妊娠期间小鼠的生理性松弛素水平，并与人类的水平平行。
Serelaxin 通过 eNOS 依赖性机制减轻心肌 I / R 损伤和随后的半胱天冬酶-1 激活。
