Abstract 14911: Dipeptidyl Peptidase-4 Deteriorates Cardiac Function During Autoimmune Myocarditis by Facilitating Cathepsin-G Activity
Post-myocarditis dilated cardiomyopathy is the most common cause of non-hereditary heart failure developing at a young age. Our colleagues have shown previously that dipeptidyl peptidase-4 (DPP-4) worsens the development of experimental autoimmune myocarditis (EAM) by promoting expression of inflammatory cytokines and cardiac fibrosis in mice. In order to clarify how DPP-4 mediates this detrimental effect in the EAM heart, mouse EAM model generated by immunizing with α-MHC peptide in BALB/c mice were given a diet mixed with linagliptin, a selective DPP-4 inhibitor (83 mg/kg chow corresponding to around 3 mg/kg oral dosing) (LINA group, N = 6), or normal diet (CONT group, N = 6). After 21 days of EAM induction, lung weight / body weight were significantly smaller in LINA group than in CONT group (7.7 ± 0.1 mg/g* vs. 8.3 ± 0.1 mg/g, *P < 0.05). Left ventricular ejection fraction after induction of EAM was significantly higher in LINA group than in CONT group (72.6 ± 6.6%* vs. 60.1 ± 9.2%, *P < 0.05). Immunostaining demonstrated that the number of RORγt-positive Th17 cells infiltrated to inflamed myocardium was significantly smaller in LINA group than in CONT group. Consistent with this result and the previous finding that Th17 cells express high level of enzymatically active DPP-4, the DPP-4 activity in inflamed myocardium was significantly lower in LINA group than in CONT group (46.9 ± 2.4 RFU* vs. 116.8 ± 8.6 RFU, *P < 0.05). Mass spectrometry analysis using lysates from inflamed myocardium co-immunoprecipitated with Flag-DPP-4 recombinant protein revealed that DPP-4 bound to cathepsin-G (CTSG), a plasma membrane-bound serine protease, in the EAM heart. Co-immunoprecipitation - western blot analysis verified the physical interaction between DPP-4 and CTSG. The activity of CTSG in inflamed myocardium was significantly higher in EAM mice compared to those in untreated mice, and CTSG activity in the EAM heart was significantly lower in LINA group than in CONT group. The amount of angiotensin II, a major product catalyzed by CTSG, in the EAM heart was also significantly lower in LINA group than in CONT group. Collectively, these results suggest that DPP-4 derived from Th17 cells aggravates cardiac dysfunction during EAM, possibly through enhancing CTSG activity in the heart.
Author Disclosures: Y. Maejima: None. Y. Ito: None. N. Tamura: None. R. Watanabe: None. M. Isobe: None.
- © 2015 by American Heart Association, Inc.