Xiao Chi, Chen Meng-Yuan, Han Yu-Peng, Liu Li-Juan, Yan Jia-Lin, Qian Ling-Bo
School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China.
Food Funct. 2023 Mar 20;14(6):2740-2749. doi: 10.1039/d2fo03871d.
Increasing evidence has shown that impaired autophagy dramatically causes myocardial hypertrophy and fibrosis in the diabetic heart, ultimately leading to diabetic cardiomyopathy (DCM). Luteolin has been reported to effectively attenuate diabetic cardiovascular injury by inhibiting oxidative stress and alleviate sepsis-induced myocardial injury by enhancing autophagy. However, whether luteolin can reduce DCM through activating autophagy and the underlying mechanism remain unclear. Here, reversing the c-Jun N-terminal kinase (JNK)-suppressed autophagy pathway by which luteolin attenuates DCM was explored. Male Sprague-Dawley rats were injected with streptozotocin to induce diabetes. After 6 weeks of diabetes, rats were treated with luteolin (50, 100 and 200 mg kg, i.g.) for 4 weeks. Histological and functional alterations in the diabetic heart were determined using HE staining, Masson staining and echocardiography. The expressions of myocardial miR-221, JNK, and c-Jun and autophagic vesicles in diabetes were evaluated by quantitative PCR, Western blotting and electron microscopy. Luteolin significantly improved cardiac function and attenuated myocardial disorganization and fibrosis in the diabetic rat accompanying the dose-dependent down-regulation of JNK, c-Jun, miR-221 and p62, increase of LC3-II/I and autophagic vesicles, and decrease of mitochondrial swelling in the diabetic heart. These data suggest that the protection of luteolin against DCM, at least, is related to suppressing JNK/c-Jun-regulated miR-221 and the subsequent blockage of autophagy.
越来越多的证据表明，自噬受损会显著导致糖尿病心脏的心肌肥大和纤维化，最终导致糖尿病性心肌病（DCM）。据报道，木犀草素可通过抑制氧化应激有效减轻糖尿病心血管损伤，并通过增强自噬减轻脓毒症诱导的心肌损伤。然而，木犀草素是否能通过激活自噬来减轻DCM及其潜在机制仍不清楚。在此，我们探讨了木犀草素通过逆转c-Jun氨基末端激酶（JNK）抑制的自噬途径来减轻DCM的机制。雄性Sprague-Dawley大鼠注射链脲佐菌素诱导糖尿病。糖尿病6周后，大鼠接受木犀草素（50、100和200mg/kg，腹腔注射）治疗4周。使用HE染色、Masson染色和超声心动图测定糖尿病心脏的组织学和功能改变。通过定量PCR、蛋白质印迹和电子显微镜评估糖尿病心肌中miR-221、JNK和c-Jun的表达以及自噬小泡。木犀草素显著改善了糖尿病大鼠的心脏功能，减轻了心肌紊乱和纤维化，同时伴随JNK、c-Jun、miR-221和p62的剂量依赖性下调，LC3-II/I和自噬小泡增加，以及糖尿病心脏线粒体肿胀减少。这些数据表明，木犀草素对DCM的保护作用至少与抑制JNK/c-Jun调节的miR-221以及随后的自噬阻断有关。
