The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase‐4 (DPP‐4) levels, we investigated whether the clinically approved DPP‐4 inhibitor linagliptin reduces left ventricular stiffness in MetS‐induced cardiac disease. Sixteen‐week‐old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin‐supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (F_passive). The reduced F_passive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP‐4 directly cleaved titin in vitro, resulting in an increased F_passive, which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4‐mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS‐induced early diastolic dysfunction in human.

中文翻译：

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利格列汀通过减少肌联蛋白裂解和低磷酸化来预防左心室僵硬


代谢综合征 (MetS) 是一个世界范围内不断升级的问题，会导致左心室僵硬，这是舒张功能障碍的早期特征，目前尚无治疗方法。由于 MetS 患者的舒张功能障碍和僵硬与循环二肽基肽酶 4 (DPP-4) 水平升高相关，因此我们研究了临床批准的 DPP-4 抑制剂利格列汀是否可以降低 MetS 诱发的心脏病中的左心室僵硬度。 16 周大的肥胖 ZSF1 大鼠表现出 MetS 和左心室僵硬，接受利格列汀补充剂或安慰剂饮食 4 周。利格列汀显着降低肥胖、高脂血症和高血糖，并改善左心室舒张。这种放松的改善与心脏纤维化和心肌细胞被动硬度（ F_被动）的减少有关。 F_被动减少是肌联蛋白亚型从刚性 N2B 转换为更灵活的 N2BA 以及总肌联蛋白尤其是其 N2Bus 区域（S4080 和 S3391）磷酸化增加的结果。重要的是，DPP-4 在体外直接裂解肌联蛋白，导致F_被动增加，而同时服用利格列汀可以防止这种情况发生。总之，利格列汀通过防止直接 DPP4 介导的肌联蛋白裂解以及调节肌联蛋白亚型水平和磷酸化来改善肥胖 ZSF1 大鼠的左心室僵硬度。通过服用利格列汀降低左心室硬度可能会预防 MetS 引起的人类早期舒张功能障碍。