Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart.
Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart.
复制标题
DOI：
10.1371/journal.pone.0257280
复制
发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Tang Y;Kline KT;Zhong XS;Xiao Y;Lian H;Peng J;Liu X;Powell DW;Tang G;Li Q
溃疡性结肠炎和克罗恩病被归类为具有已知肠外表现的慢性炎症性肠病（IBD）。先前已经注意到IBD中心脏和肠道之间的相互作用，但其机制仍然难以捉摸。我们的目的是鉴定在结肠炎大鼠模型中介导分子重塑和导致心脏损害的microRNA。为了诱导慢性结肠炎，给予成年大鼠葡聚糖硫酸钠（DSS）5天，然后9天，正常饮用水，8周内共4个周期。进行超声心动图检查以评估心脏功能。DSS诱导的结肠炎导致射血分数显著降低，左心室质量和大小增加，B型利钠蛋白升高。MicroRNA分析显示，结肠炎导致心脏中总共有56种miRNA显著增加，其中8种预测靶向脑源性神经营养因子（BDNF）。RT-qPCR验证了miR-1b、Let-7 d和miR-155的增加。瞬时转染显示miR-155显著抑制H9 c2细胞中的BDNF。重要的是，DSS结肠炎显著降低心肌和血清中的BDNF。对心脏稳态至关重要的各种蛋白质的水平也发生了变化。功能研究表明，BDNF增加细胞活力，减轻H9 c2细胞中H2 O2诱导的氧化损伤，证明其在成人心脏中的保护作用。从机制上讲，细胞实验将IL-1β鉴定为上调心脏miR-155的炎症介质;这种作用在成年大鼠中得到证实。此外，IL-1β中和抗体改善了DSS诱导的成年心脏中miR-155的增加和BDNF的同时减少，显示出治疗潜力。我们的研究结果表明，慢性结肠炎通过IL-1β→miR-155→BDNF信号轴损害心脏功能。
Ulcerative colitis and Crohn’s disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1β as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1β neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1β→miR-155→BDNF signaling axis.
登录
查看更多内容
炎症性肠病患者发生急性心肌梗死和心力衰竭的风险增加。
DOI：
10.1016/j.cgh.2018.04.031
发表时间：
2018-10
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
--
作者：
Aniwan S;Pardi DS;Tremaine WJ;Loftus EV Jr
通讯作者：
Loftus EV Jr
影响因子：
2
作者：
Håkansson A;Bränning C;Molin G;Adawi D;Hagslätt ML;Nyman M;Jeppsson B;Ahrné S
通讯作者：
Ahrné S
影响因子：
7.6
作者：
Choi, Yoon Jin;Lee, Dong Ho;Kim, Nayoung
通讯作者：
Kim, Nayoung
影响因子：
6.4
作者：
Ertem, Furkan U.;Zhang, Wenqian;Dashwood, Roderick H.
通讯作者：
Dashwood, Roderick H.
影响因子：
4.9
作者：
Keppner, Anna;Malsure, Sumedha;Hummler, Edith
通讯作者：
Hummler, Edith