Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, PR China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China.
Department of Laboratory Medicine and Central Laboratories, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, PR China.
Pharmacol Res. 2020 Mar;153:104655. doi: 10.1016/j.phrs.2020.104655. Epub 2020 Jan 26.
Ischemia/reperfusion (IR) induces additional damage during the restoration of blood flow to ischemic myocardium. Urolithin B (UB) is one of the gut metabolites of ellagitannins, a class of antioxidant polyphenols, which was found to be protective against oxidative stress in multiple organs. However, the role of UB in cardiovascular disease remains elusive. Adult Sprague Dawley rats were subjected to left anterior descending artery ligation for 30 min followed by 120 min of reperfusion, with or without UB treatment. In vitro, the H9c2 cardiomyocytes were subjected to hypoxia (94 %N/5 %CO/1 %O) for 3 h, followed by reoxygenation (74 %N/5 %CO/21 %O) for 3 h (HR). UB was found to decrease myocardial infarct size and attenuate the cardiac dysfunction in the rats after IR, and protect against HR injury in H9c2 cardiomyocytes. Mechanistically, UB inhibited autophagy by activating Akt/mTOR/ULK1 pathway and protected against oxidative stress and caspase 3-dependent cell apoptosis. In particular, UB induced accumulation of p62 and its interaction with Keap1, which promoted Nrf2 nuclear translocation during HR insult. Of note, the protection of UB against superoxide production and apoptotic cell death was compromised with Nrf2 gene silencing. Taken together, our findings suggested that UB protected against myocardial IR injury at least partially via the p62/Keap1/Nrf2 signaling pathway, which highlights the potential of UB as a novel therapy for ischemic heart disease.
缺血/再灌注（IR）在恢复缺血心肌血流时会引起额外的损伤。尿石素 B（UB）是鞣花单宁的一种肠道代谢物，属于抗氧化多酚类，已被发现可防止多种器官的氧化应激。然而，UB 在心血管疾病中的作用仍不清楚。将成年 Sprague Dawley 大鼠进行左前降支结扎 30 分钟，随后再灌注 120 分钟，同时给予或不给予 UB 治疗。在体外，将 H9c2 心肌细胞进行缺氧（94%N/5%CO/1%O）3 小时，随后进行复氧（74%N/5%CO/21%O）3 小时（HR）。UB 可减少 IR 后大鼠的心肌梗死面积和心脏功能障碍，并保护 H9c2 心肌细胞免受 HR 损伤。在机制上，UB 通过激活 Akt/mTOR/ULK1 通路抑制自噬，从而防止氧化应激和 caspase 3 依赖性细胞凋亡。特别是，UB 在 HR 损伤时诱导 p62 的积累及其与 Keap1 的相互作用，促进 Nrf2 核转位。值得注意的是，UB 对超氧化物产生和凋亡细胞死亡的保护作用在 Nrf2 基因沉默后受到损害。综上所述，我们的研究结果表明，UB 通过 p62/Keap1/Nrf2 信号通路至少部分保护心肌 IR 损伤，这突出了 UB 作为缺血性心脏病新疗法的潜力。
