Department of Internal Medicine II, University Hospital Bonn, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
Department of Internal Medicine II, University Hospital Bonn, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
Int J Cardiol. 2018 Jan 1;250:21-28. doi: 10.1016/j.ijcard.2017.09.017.
The peptide hormone relaxin-2 (RLX) exerts beneficial effects during myocardial ischemia, but functional data on lower-dose RLX in myocardial infarction (MI) is lacking. Therefore, we investigated the impact of 75μg/kg/d RLX treatment on electrical vulnerability and left ventricular function in a mouse model of MI.
Standardized cryoinfarction of the left anterior ventricular wall was performed in mice. A two week treatment period with vehicle or RLX via subcutaneously implanted osmotic minipumps was started immediately after MI. The relaxin receptor RXFP1 was expressed on ventricular/atrial cardiomyocytes, myofibroblasts, macrophages and endothelial but not vascular smooth muscle cells of small coronary vessels. RLX treatment resulted in a significant reduction of ventricular tachycardia inducibility (vehicle: 91%, RLX: 18%, p<0.0001) and increased epicardial conduction velocity in the left ventricle and borderzone. Furthermore, left ventricular function following MI was improved in RLX treated mice (left ventricular ejection fraction; vehicle: 41.1±1.9%, RLX: 50.5±3.5%, p=0.04). Interestingly, scar formation was attenuated by RLX with decreased transcript expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1β were upregulated in hearts of vehicle treated animals compared to mice without MI. Application of RLX attenuated this inflammatory response. In addition, macrophage infiltration was reduced in the borderzone of RLX treated mice.
Treatment with lower-dose RLX in mice prevents post-infarction ventricular tachycardia due to attenuation of scar formation and cardiac inflammation. Therefore, RLX could be evaluated as new therapeutic option in the treatment of MI.
肽激素松弛素-2（RLX）在心肌缺血时发挥有益作用，但缺乏关于心肌梗死（MI）中低剂量 RLX 的功能数据。因此，我们研究了 75μg/kg/d RLX 治疗对 MI 小鼠模型中心电易损性和左心室功能的影响。
在小鼠中进行标准的左前壁冷冻梗死。MI 后立即通过皮下植入的渗透微型泵开始为期两周的药物或 RLX 治疗。松弛素受体 RXFP1 在心室/心房心肌细胞、肌成纤维细胞、巨噬细胞和内皮细胞上表达，但不在小冠状动脉的血管平滑肌细胞上表达。RLX 治疗可显著降低室性心动过速的诱发性（载体：91%，RLX：18%，p<0.0001）和增加左心室和边缘区的心外膜传导速度。此外，RLX 治疗可改善 MI 后左心室功能（左心室射血分数；载体：41.1±1.9%，RLX：50.5±3.5%，p=0.04）。有趣的是，RLX 可通过降低结缔组织生长因子的转录表达来减轻疤痕形成。与没有 MI 的小鼠相比，载体处理的动物心脏中促炎细胞因子白细胞介素-6 和白细胞介素-1β 的转录水平上调。RLX 的应用减弱了这种炎症反应。此外，RLX 治疗小鼠的边缘区巨噬细胞浸润减少。
在小鼠中用低剂量 RLX 治疗可预防梗死后室性心动过速，这是由于疤痕形成和心脏炎症的减弱。因此，RLX 可作为 MI 治疗的新治疗选择进行评估。
