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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Pharmacological Sciences
DOIs
Publication statusAccepted/In press - 2019 Jan 1
Externally publishedYes

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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

  • Dipeptidyl peptidase-4
  • Fibrosis
  • Left ventricular diastolic function
  • Macrophage
  • Myocardial infarction

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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.

In: Journal of Pharmacological Sciences, 01.01.2019.

Research output: Contribution to journalArticle

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. In: Journal of Pharmacological Sciences. 2019.
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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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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.

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KW - Macrophage

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