TY - JOUR
T1 - A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4
AU - Yamaguchi, Takehiro
AU - Watanabe, Ayano
AU - Tanaka, Masako
AU - Shiota, Masayuki
AU - Osada-Oka, Mayuko
AU - Sano, Soichi
AU - Yoshiyama, Minoru
AU - Miura, Katsuyuki
AU - Kitajima, Shojiro
AU - Matsunaga, Shinji
AU - Tomita, Shuhei
AU - Iwao, Hiroshi
AU - Izumi, Yasukatsu
N1 - Funding Information:
This work was partially supported by a grant from Boehringer Ingelheim .
Publisher Copyright:
© 2018 The Authors
PY - 2019/2
Y1 - 2019/2
N2 - Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats. After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg −1 ·day −1 ), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-β1 (TGF-β1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-β1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts. Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.
AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats. After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg −1 ·day −1 ), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-β1 (TGF-β1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-β1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts. Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.
KW - Dipeptidyl peptidase-4
KW - Fibrosis
KW - Left ventricular diastolic function
KW - Macrophage
KW - Myocardial infarction
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U2 - 10.1016/j.jphs.2018.12.004
DO - 10.1016/j.jphs.2018.12.004
M3 - Article
C2 - 30638989
AN - SCOPUS:85059777404
SN - 1347-8613
VL - 139
SP - 112
EP - 119
JO - Journal of Pharmacological Sciences
JF - Journal of Pharmacological Sciences
IS - 2
ER -
