Youn Seock-Won, Li Yang, Kim Young-Mee, Sudhahar Varadarajan, Abdelsaid Kareem, Kim Ha Won, Liu Yutao, Fulton David J R, Ashraf Muhammad, Tang Yaoliang, Fukai Tohru, Ushio-Fukai Masuko
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Department of Cellular Biology & Anatomy, Augusta University, Augusta, GA 30912, USA.
Antioxidants (Basel). 2019 Jan 10;8(1):18. doi: 10.3390/antiox8010018.
Myocardial infarction (MI) is the primary cause of cardiovascular mortality, and therapeutic strategies to prevent or mitigate the consequences of MI are a high priority. Cardiac progenitor cells (CPCs) have been used to treat cardiac injury post-MI, and despite poor engraftment, they have been shown to inhibit apoptosis and to promote angiogenesis through poorly understood paracrine effects. We previously reported that the direct injection of exosomes derived from CPCs (CPCexo) into mouse hearts provides protection against apoptosis in a model of acute ischemia/reperfusion injury. Moreover, we and others have reported that reactive oxygen species (ROS) derived from NADPH oxidase (NOX) can enhance angiogenesis in endothelial cells (ECs). Here we examined whether bioengineered CPCexo transfected with a pro-angiogenic miR-322 (CPCexo-322) can improve therapeutic efficacy in a mouse model of MI as compared to CPCexo. Systemic administration of CPCexo-322 in mice after ischemic injury provided greater protection post-MI than control CPCexo, in part, through enhanced angiogenesis in the border zones of infarcted hearts. Mechanistically, the treatment of cultured human ECs with CPCexo-322 resulted in a greater angiogenic response, as determined by increased EC migration and capillary tube formation via increased Nox2-derived ROS. Our study reveals that the engineering of CPCexo via microRNA (miR) programing can enhance angiogenesis, and this may be an effective therapeutic strategy for the treatment of ischemic cardiovascular diseases.
心肌梗死（MI）是心血管疾病死亡的主要原因，预防或减轻MI后果的治疗策略是当务之急。心脏祖细胞（CPCs）已被用于治疗MI后的心脏损伤，尽管其植入效果不佳，但已显示它们可抑制细胞凋亡，并通过尚未完全了解的旁分泌作用促进血管生成。我们之前报道过，将源自CPCs的外泌体（CPCexo）直接注射到小鼠心脏中，可在急性缺血/再灌注损伤模型中提供抗细胞凋亡保护。此外，我们和其他人报道过，源自NADPH氧化酶（NOX）的活性氧（ROS）可增强内皮细胞（ECs）的血管生成。在这里，我们研究了与CPCexo相比，用促血管生成的miR-322转染的生物工程化CPCexo（CPCexo-322）是否能提高MI小鼠模型中的治疗效果。缺血性损伤后对小鼠进行CPCexo-322全身给药，与对照CPCexo相比，MI后提供了更大的保护，部分原因是梗死心脏边缘区的血管生成增强。从机制上讲，用CPCexo-322处理培养的人ECs会导致更大的血管生成反应，这是通过增加Nox2衍生的ROS来增加EC迁移和毛细血管管形成来确定的。我们的研究表明，通过微小RNA（miR）编程对CPCexo进行工程改造可增强血管生成，这可能是治疗缺血性心血管疾病的一种有效治疗策略。
