Teixeira Rayane Brinck, Albro Jane H, Sabra Mohamed, Abedin Taslova, Tucker Aja N, Sidharth Raj, Sellke Frank W, Wipf Peter, Abid M Ruhul
Department of Surgery, Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2025 Apr 24;20(4):e0320703. doi: 10.1371/journal.pone.0320703. eCollection 2025.
This study aimed at evaluating the effects of JP4-039, a mitochondria-specific reactive oxygen species (mito-ROS) scavenger, on coronary angiogenesis and cardiac function in a post-myocardial infarction (MI) animal model.
Mice underwent ligation of the left anterior descending (LAD) artery to induce MI and received intraperitoneal (i.p.) injections of JP4-039 or vehicle (n=8 animals/group) three times/week for four weeks. Echocardiography for cardiac function and immunohistochemistry for Infarction area and capillary density were carried out. Angiogenic potential of endothelial cells (EC) was assessed by ex vivo tube formation using mouse heart EC (MHEC) and by aortic and atrial sprouting. Western blots were conducted using mouse cardiac tissue and lysates from HCAECs that were treated with or without JP4-039.
Cardiac function including ejection fraction, fractional shortening, and fractional area change were improved significantly in JP4-039-treated animals compared to the vehicle group. JP4-039-treated hearts demonstrated significant reduction in infarction size and increased capillary density in the ischemic area. These findings were consistent with increased ex vivo endothelial sprouting of the aortae and atrial tissue from the mice treated with JP4-039. Western blots using cardiac tissue lysates from JP4-039-treated animals showed decrease in phosphorylation of AMPKα at the Threonine 172, suggesting a plausible increase in the ATP:AMP ratio. Interestingly, JP4-039 increased expression of mitochondrial complexes I and IV and increased ATP synthesis in EC.
JP4-039-mediated reduction in mito-ROS results in significantly increased coronary vascular density in ischemic myocardium, improved ATP synthesis, and recovery of post-MI cardiac function. Together, these results suggest that nitroxide nanodrug-mediated reduction in mito-ROS may help recover post-MI cardiac function.
本研究旨在评估线粒体特异性活性氧（mito-ROS）清除剂JP4-039对心肌梗死（MI）后动物模型冠状动脉血管生成和心脏功能的影响。
小鼠接受左前降支（LAD）动脉结扎以诱导MI，并每周3次腹腔内（i.p.）注射JP4-039或赋形剂（每组n = 8只动物），持续4周。进行心脏功能的超声心动图检查以及梗死面积和毛细血管密度的免疫组织化学检查。使用小鼠心脏内皮细胞（MHEC）通过体外管形成以及主动脉和心房发芽来评估内皮细胞（EC）的血管生成潜力。使用小鼠心脏组织以及用或不用JP4-039处理的人冠状动脉内皮细胞（HCAEC）裂解物进行蛋白质免疫印迹分析。
与赋形剂组相比，接受JP4-039治疗的动物的心脏功能，包括射血分数、缩短分数和面积变化分数均有显著改善。接受JP4-039治疗的心脏梗死面积显著减小，缺血区域的毛细血管密度增加。这些发现与JP4-039处理的小鼠主动脉和心房组织的体外内皮发芽增加一致。使用接受JP4-039治疗的动物的心脏组织裂解物进行的蛋白质免疫印迹分析显示，苏氨酸172处的AMPKα磷酸化水平降低，提示ATP：AMP比值可能升高。有趣的是，JP4-039增加了线粒体复合物I和IV的表达，并增加了EC中的ATP合成。
JP4-039介导的mito-ROS减少导致缺血心肌中冠状动脉血管密度显著增加、ATP合成改善以及MI后心脏功能恢复。总之，这些结果表明氮氧化物纳米药物介导的mito-ROS减少可能有助于恢复MI后心脏功能。
