Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor, ameliorates experimental autoimmune myocarditis by suppressing cathepsin-G activity [post]

Yuka Shiheido-Watanabe, Yasuhiro Maejima, Shun Nakagama, Natsuko Tamura, Takeshi Kasama, Tetsuo Sasano
2020 unpublished
Background There is a compelling need for establishing effective therapy for autoimmune myocarditis which primarily manifest as chest pain, heart failure or sudden death. Although our group have previously shown that dipeptidyl peptidase-4 (DPP-4) aggravates experimental autoimmune myocarditis (EAM), the detailed underlying mechanism remains to be unelucidated. Methods The effects of linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor, on cardiac function were investigated by
more » ... stigated by treating mouse EAM models and elucidated the role of DPP-4 on EAM using proteomic approaches. Results Immunohistochemical analyses demonstrated that the number of Th17 cells expressing high level of DPP-4 infiltrated to EAM myocardium was significantly attenuated by linagliptin treatment. MS/MS-based analyses demonstrated that DPP-4 binds to cathepsin-G in EAM hearts. DPP-4 also protects cathepsin-G activity by inhibiting the activity of SerpinA3N, a protease inhibitor that catalyzes cathepsin-G. The activity of cathepsin-G and the level of Angiotensin II were markedly elevated in EAM myocardium; this effect was reversed by linagliptin treatment. Furthermore, we found that linagliptin suppresses oxidative stress in EAM hearts. Conclusions DPP-4 physically interacts with cathepsin-G, which, in turn, suppresses SerpinA3N; this promotes angiotensin II accumulation in EAM hearts. Thus, DPP-4 derived from Th17 cells could aggravate cardiac dysfunction during EAM.
doi:10.21203/rs.3.rs-70009/v1 fatcat:yhi32jzgpvc7faqiywhfssea7e