AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings
AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings
复制标题
AdipoRon 是第一个口服活性脂联素受体激活剂，通过 AMPK 介导和 AMPK 独立信号传导减弱缺血后心肌细胞凋亡。
DOI：
10.1152/ajpendo.00577.2014
复制
发表时间：
2015-08-01
影响因子：
5.1
通讯作者：
Wang, Ya-Jing
中科院分区：
文献类型：
--
作者：
Zhang, Yanqing;Zhao, Jianli;Wang, Ya-Jing
脂联素（APN）是一种心脏保护分子。其在糖尿病中的减少加剧了心肌缺血/再灌注（MI/R）损伤。虽然APN在动物中的施用减轻了MI/R损伤，但多种因素限制了其临床应用。目前的研究调查了AdipoRon，第一个结合APN受体的口服活性分子，是否可以保护心脏免受MI/R损伤，如果是的话，描述了相关的机制。野生型（WT）、APN敲除（APN-KO）和心肌细胞特异性AMPK显性阴性（AMPK-DN）小鼠用媒介物或AdipoRon（50 mg/kg，MI前10 min）处理并经受MI/R（30 min/3-24 h）。与溶剂组相比，AdipoRon口服给药可显著改善WT小鼠的心功能，减少缺血后心肌细胞凋亡（均P < 0.01）。MI/R诱导的凋亡性细胞死亡在APN（APN-KO）或AMPK（AMPK-DN）缺陷的小鼠中显著增强。在APN-KO小鼠中，AdipoRon减轻MI/R损伤的程度与WT小鼠相同。在AMPK-DN小鼠中，AdipoRon的抗凋亡作用被部分抑制，但没有丧失。最后，AdipoRon显著减弱缺血后氧化应激，如通过减少NADPH氧化酶表达和超氧化物产生所证明的。总的来说，这些结果首次证明，AdipoRon，一种口服活性APN受体激活剂，有效地减轻了缺血后心脏损伤，支持APN受体激动剂作为治疗肥胖相关疾病（如2型糖尿病）引起的心血管并发症的有前途的新治疗方法。
Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT mice significantly improved cardiac function and attenuated postischemic cardiomyocyte apoptosis, determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (all P < 0.01). MI/R-induced apoptotic cell death was significantly enhanced in mice deficient in either APN (APN-KO) or AMPK (AMPK-DN). In APN-KO mice, AdipoRon attenuated MI/R injury to the same degree as observed in WT mice. In AMPK-DN mice, AdipoRon's antiapoptotic action was partially inhibited but not lost. Finally, AdipoRon significantly attenuated postischemic oxidative stress, as evidenced by reduced NADPH oxidase expression and superoxide production. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated postischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes.