• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • In the present study we used


    In the present study, we used linagliptin, one of the commercially available DPP-4 inhibitors, because it has more long-lasting inhibition of DPP-4 activity than other drugs of this class. We hypothesized that linagliptin may interact with intercellular components, not only with DPP-4 on the plasma membrane, and may have beneficial effects independently of DPP-4. From this study, we obtained the evidence that linagliptin has beneficial effect of improving cardiac remodeling in LV diastolic dysfunction after MI.
    Materials and methods
    Discussion Accumulating evidence suggests that DPP-4 inhibitors have the protective effect on cardiovascular remodeling such as MI, diabetes and pressure overload, in a DPP-4-dependent manner.10, 11, 24, 25, 26, 27 However, to our knowledge, there is no report that demonstrates DPP-4-independent cardioprotection of DPP-4 inhibitors at all. We used linagliptin in this class in the present study due to the following two reasons: First, it has more long-lasting inhibitory effect of DPP-4. Second, it is a sole lipid-soluble drug and may have off-target effect by interacting intracellular components directly. Therefore, we examined whether linagliptin has a cardioprotective effect in an experimental MI model of DPP-4-deficient rats. Linagliptin does not affect serum concentration of GLP-1, blood glucose level (Fig. 1B, D), and the protein Deferasirox of SDF-1α in DPP-4-deficient rats (Fig. 1C), as expected. Thus, we could clearly evaluate the effect of linagliptin independently of DPP-4. Although the influences of secondary factors affecting cardiac remodeling, such as hemodynamic status and MI size were similar in all MI-induced rats (Fig. 2B–D), linagliptin administration surprisingly attenuated the progression of diastolic dysfunction and cardiac fibrosis due to MI (Fig. 3, Fig. 4). Whereas, LV contractile dysfunction and levels of cardiomyocyte apoptosis (Fig. 4A,D) were comparable in all MI-induced rats. We preliminarily compared DPP-4-independent anti-remodeling effect of linagliptin to that of sitagliptin to elucidate whether anti-remodeling effect of linagliptin is due to drug effect or class effect. Interestingly, linagliptin, but not sitagliptin, significantly improved MI-induced cardiac dysfunction in Fischer 344 rats (data not shown). As previous study reported, linagliptin may have the stronger anti-remodeling effect than sitagliptin. Cardiac remodeling after MI is caused by activated myofibroblasts. They are attracted to the infarct region by various chemotactic factors, including TGF-β1, which is mainly produced by fibroblasts. TGF-β1 promotes trans-differentiation from fibroblasts to myofibroblasts, and upregulates biosynthesis of collagen type I and matrix metalloproteinases by activated myofibroblasts. Therefore, TGF-β1 is essential in normal tissue repair after MI. However, excessive production of TGF-β1 causes cardiac fibrosis extremely not only in the infarct area but also in sites distant from the infarction. Our data show that linagliptin attenuates the MI-induced elevation of TGF-β1 expression in the marginal area (Fig. 5C). Therefore, we examined whether linagliptin can attenuate TGF-β1 expression in CFs independently of DPP-4. Surprisingly, linagliptin treatment downregulated TGF-β1 level in CFs from DPP-4-deficient rats in a dose-dependent manner (Fig. 6A). This finding suggests that linagliptin may suppress TGF-β1 production in CFs, independently of DPP-4. However, the detail mechanism how linagliptin suppresses TGF-β1 signaling remains unclear. Transcription factor GATA6 is a critical repressor of TGF-β1 expression. In our data, although linagliptin didn\'t affect GATA6 level in the all MI-induced rats (Fig. 6E), TGF-β1 was significantly suppressed (Fig. 6B,D). Linagliptin may reverse epigenetic modification which enhances TGF-β1 expression due to MI. However, further investigation is required to explore the precise mechanism and to identify the novel target of linagliptin.