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  • DPP also known as CD is a

    2020-08-04

    DPP-4 (also known as CD26) is a novel therapeutic target for T2DM. DPP-4 is a membrane-bound X-prolyl dipeptidyl peptidase, which involves the degradation of chemokines, such as stromal-cell derived factor 1 (SDF-1) and macrophage derived chemokine, and incretins, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).4, 5, 6 Therefore, it is thought that DPP-4 inhibitors not only improve impaired sennoside australia tolerance but also have anti-inflammatory effect and other pleiotropic extra-pancreatic effects. It has been known that both GLP-1 and SDF-1 have cardioprotective effect for ischemic myocardium,7, 8, 9 and several papers experimentally demonstrated that DPP-4 inhibitors attenuate cardiac remodeling after MI via the upregulation of their substrates.10, 11 However, it remains unclear whether cardioprotective effect of DPP-4 inhibitors depends only on blockage of degradation of DPP-4 substrates. Therefore, we investigated whether DPP-4 inhibitors have a cardioprotective effect independently of DPP-4. 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
    Results
    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 sennoside australia GLP-1, blood glucose level (Fig. 1B, D), and the protein expression 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.