Dipeptidyl Peptidase-4 Suppression Leads to Attenuation of Cardiac Dysfunction Caused by Autoimmune Myocarditis Through Inhibiting Cathepsin-G Activity

Abstract

We have shown previously that dipeptidyl peptidase-4 (DPP-4) plays a critical role in the development of experimental autoimmune myocarditis(EAM). Here we show that the mechanism how DPP-4 promotes the progression of EAM in mice. Mouse EAM model were given a diet mixed with linagliptin, a DPP-4 inhibitor (3mg/kg/day)(LINA-group), or normal diet (CONT-group). Left ventricular ejection fraction after 21 days of EAM induction was significantly higher in LINAgroup than in CONT group. Immunostaining showed that the number of Th17 cells infiltrated to the EAM heart was significantly smaller in LINA-group than in CONT-group. Consistent with this finding and the fact that Th17 cells express high level of active DPP-4, the activity of DPP-4 in the EAM heart was significantly lower in LINA-group than in CONT-group. Mass spectrometry and co-immunoprecipitation-western blot analyses revealed that DPP-4 physically interacts with cathepsin-G(CTSG) in inflamed myocardium. The CTSG activity in the EAM heart was significantly higher in EAM mice compared to those in untreated mice, and the activity of CTSG in inflamed myocardium was significantly lower in LINA-group than in CONT-group. The amount of angiotensin II, a product catalyzed by CTSG, in inflamed myocardium was also significantly lower in LINA-group than in CONT-group. In conclusion, suppression of DPP-4 causes a salutary effect in the cardiac function during EAM by inhibiting CTSG activity in the heart.