Ning Bing-Bing, Zhang Yong, Wu Dan-Dan, Cui Jin-Gang, Liu Li, Wang Pei-Wei, Wang Wen-Jian, Zhu Wei-Liang, Chen Yu, Zhang Teng
Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharmacol Sin. 2017 Mar;38(3):331-341. doi: 10.1038/aps.2016.142. Epub 2017 Jan 23.
Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg·d, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg·d, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGFβ-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.
心肌损伤及随之而来的纤维化改变会损害正常心脏结构并导致心脏功能障碍。氧化应激已被认为是心脏损伤发病机制、心脏功能障碍进展及促进纤维化过程中的关键因素。在本研究中，我们探究了食用植物中天然存在的抗氧化剂木犀草素 -7- 二葡萄糖醛酸苷（L7DG）是否能减轻异丙肾上腺素（ISO）诱导的小鼠心肌损伤和纤维化及其潜在机制。通过腹腔注射ISO（5 mg·kg·d）持续5天或10天诱导小鼠发生心肌损伤和纤维化。采用两种治疗方案（预处理和后处理）将L7DG（5 - 40 mg·kg·d，腹腔注射）给予小鼠。小鼠安乐死后，对心脏切片进行形态学检查发现，L7DG预处理和后处理方案均能显著减轻ISO诱导的心肌损伤和纤维化。但预处理方案对ISO诱导的心肌纤维化的保护作用优于后处理方案。此外，L7DG预处理可阻断ISO刺激的编码NADPH氧化酶酶亚基的基因（Cyba、Cybb、Ncf1、Ncf4和Rac2）的表达，NADPH氧化酶是哺乳动物细胞中氧化剂产生的主要来源。此外，L7DG预处理显著抑制了ISO刺激的胶原蛋白基因Col1a1、Col1a2、Col3a1和Col12a1以及非胶原蛋白细胞外基质基因原纤维蛋白 -1、弹性蛋白、含胶原蛋白三螺旋重复序列1和结缔组织生长因子的表达。此外，L7DG预处理几乎逆转了ISO改变的与TGFβ介导的纤维化相互作用的微小RNA的表达，包括miR - 29c - 3p、miR - 29c - 5p、miR - 30c - 3p、miR - 30c - 5p和miR - 21。本研究首次证明L7DG在药理上可有效保护心脏免受ISO诱导的损伤和纤维化，这为进一步评估L7DG作为治疗相关心血管疾病的心脏保护剂提供了依据。
