Shiheido-Watanabe Yuka, Maejima Yasuhiro, Kasama Takeshi, Tamura Natsuko, Nakagama Shun, Ito Yusuke, Hirao Kenzo, Isobe Mitsuaki, Sasano Tetsuo
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Research Center for Medical and Dental Sciences, Tokyo Medical Dental University, Tokyo, Japan.
JACC Basic Transl Sci. 2021 Jun 9;6(6):527-542. doi: 10.1016/j.jacbts.2021.04.006. eCollection 2021 Jun.
This study sought to show the mechanism of how to ameliorate experimental autoimmune myocarditis (EAM) by administering dipeptidyl peptidase (DPP)-4 inhibitor linagliptin. The number of RAR-related orphan nuclear receptor gamma-positive Th17 cells infiltrated to the EAM myocardium was significantly attenuated by linagliptin treatment. Tandem mass spectrometry-based analysis demonstrated that DPP-4 binds to cathepsin G in EAM hearts, thereby protecting cathepsin G activity through inhibiting SerpinA3N activity. Linagliptin suppresses oxidative stress in EAM hearts as well. Thus, we found that DPP-4 plays a detrimental role in the progression of EAM by interacting with cathepsin G, which, in turn, suppresses SerpinA3N activity.
本研究旨在揭示通过给予二肽基肽酶（DPP）-4抑制剂利那格列汀改善实验性自身免疫性心肌炎（EAM）的机制。利那格列汀治疗可显著减少浸润至EAM心肌的视黄酸相关孤儿核受体γ阳性Th17细胞数量。基于串联质谱的分析表明，DPP-4在EAM心脏中与组织蛋白酶G结合，从而通过抑制丝氨酸蛋白酶抑制剂A3N（SerpinA3N）的活性来保护组织蛋白酶G的活性。利那格列汀还可抑制EAM心脏中的氧化应激。因此，我们发现DPP-4通过与组织蛋白酶G相互作用在EAM进展中发挥有害作用，而组织蛋白酶G反过来又抑制SerpinA3N的活性。
