Jin Bu, Ji Fangfang, Zuo Anjun, Liu Huiting, Qi Lin, He Yun, Wang Qingyao, Zhao Peng
Department of Pathology, the Affiliated Hospital of Qingdao University.
Department of Forensic Medicine, School of Basic Medicine, Qingdao University.
Int Heart J. 2020 Mar 28;61(2):355-363. doi: 10.1536/ihj.19-372. Epub 2020 Mar 14.
Heart failure (HF) is a disease with high morbidity and mortality. In patients with HF, decreased cardiac output and blood redistribution results in decreased intestinal perfusion and destruction of intestinal barrier. Microorganisms and endotoxins can migrate into the blood circulation, aggravating systemic inflammation and HF. Trimethylamine N-oxide (TMAO) is highly closed to the occurrence of HF. However, the exact mechanism between TMAO and HF remains unclear.To investigate the role of TMAO in transverse-tubule (T-tubule) in the cultured cardiomyocytes.T-tubule imaging and analysis detected T-tubule network in cardiomyocytes. Ca handling dysfunction was identified by confocal Ca imaging. Tubulin densification and polymerization were assessed by western blot and immunofluorescent staining of cardiomyocytes.TMAO induced T-tubule network damage in cardiomyocytes and Ca handling dysfunction in cardiomyocytes under the TMAO stress via promoting tubulin densification and polymerization and therefore Junctophilin-2 (JPH2) redistribution. Mice treated with TMAO represented cardiac dysfunction and T-tubule network disorganization.TMAO impairs cardiac function via the promotion of tubulin polymerization, subsequent translocation of JPH2, and T-tubule remodeling, which provides a novel mechanism for the relationship between HF and elevated TMAO.
心力衰竭（HF）是一种发病率和死亡率都很高的疾病。在HF患者中，心输出量降低和血液重新分布导致肠道灌注减少和肠屏障破坏。微生物和内毒素可迁移至血液循环，加重全身炎症和HF。氧化三甲胺（TMAO）与HF的发生密切相关。然而，TMAO与HF之间的确切机制仍不清楚。为了研究TMAO在培养心肌细胞横管（T管）中的作用。T管成像和分析检测心肌细胞中的T管网络。通过共聚焦钙成像确定钙处理功能障碍。通过蛋白质免疫印迹法和心肌细胞免疫荧光染色评估微管蛋白致密化和聚合。TMAO通过促进微管蛋白致密化和聚合，进而导致连接蛋白2（JPH2）重新分布，在TMAO应激下诱导心肌细胞T管网络损伤和钙处理功能障碍。用TMAO处理的小鼠表现出心脏功能障碍和T管网络紊乱。TMAO通过促进微管蛋白聚合、随后的JPH2易位和T管重塑来损害心脏功能，这为HF与TMAO升高之间的关系提供了一种新机制。
