A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4

Takehiro Yamaguchi, Ayano Watanabe, Masako Tanaka, Masayuki Shiota, Mayuko Osada-Oka, Soichi Sano, Minoru Yoshiyama, Katsuyuki Miura, Shojiro Kitajima, Shinji Matsunaga, Shuhei Tomita, Hiroshi Iwao, Yasukatsu Izumi

研究成果: Article

抄録

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.

元の言語English
ジャーナルJournal of Pharmacological Sciences
DOI
出版物ステータスAccepted/In press - 2019 1 1
外部発表Yes

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Dipeptidyl-Peptidase IV Inhibitors
Dipeptidyl Peptidase 4
Myocardial Infarction
Matrix Metalloproteinase 2
Transforming Growth Factors
Left Ventricular Function
Fibrosis
Macrophages
Myocardial Reperfusion Injury
Glucose Intolerance
Linagliptin
Inbred F344 Rats
Reperfusion Injury
Drinking Water
Myocardial Ischemia
Echocardiography
Proteins
Collagen
Fibroblasts
Hemodynamics

Keywords

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

    これを引用

    A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4. / Yamaguchi, Takehiro; Watanabe, Ayano; Tanaka, Masako; Shiota, Masayuki; Osada-Oka, Mayuko; Sano, Soichi; Yoshiyama, Minoru; Miura, Katsuyuki; Kitajima, Shojiro; Matsunaga, Shinji; Tomita, Shuhei; Iwao, Hiroshi; Izumi, Yasukatsu.

    :: Journal of Pharmacological Sciences, 01.01.2019.

    研究成果: Article

    Yamaguchi, T, Watanabe, A, Tanaka, M, Shiota, M, Osada-Oka, M, Sano, S, Yoshiyama, M, Miura, K, Kitajima, S, Matsunaga, S, Tomita, S, Iwao, H & Izumi, Y 2019, 'A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4' Journal of Pharmacological Sciences. https://doi.org/10.1016/j.jphs.2018.12.004
    Yamaguchi, Takehiro ; Watanabe, Ayano ; Tanaka, Masako ; Shiota, Masayuki ; Osada-Oka, Mayuko ; Sano, Soichi ; Yoshiyama, Minoru ; Miura, Katsuyuki ; Kitajima, Shojiro ; Matsunaga, Shinji ; Tomita, Shuhei ; Iwao, Hiroshi ; Izumi, Yasukatsu. / A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4. :: Journal of Pharmacological Sciences. 2019.
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    abstract = "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.",
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    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

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    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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