Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

Abstract

Background: Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI.

Methods: Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed.

Results: Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p < 0.05 vs. non-treated groups). Cardiac function (ejection fraction) was decreased in all 3 MI groups compared with Sham group (p < 0.05); treatment with vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model.

Conclusion: Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.

Figures

Figure 1

Effects of Vildagliptin on DPP-4 activity and active GLP-1 levels. A:Vildagliptin increases active plasma GLP-1 levels after 12 weeks treatment. B: Vildagliptin reduces DPP-4 activity after 12 weeks treatment.Data are presented as means ± SEM. N = 8-10 for all groups. *P < 0.05 vs. sham group; $P < 0.05 vs. MI group.

Figure 2

Effects of Vildagliptin on infarct size. A: Sirius red and fast green staining of rat myocardium shows the infarcted area with the red color in all groups. B:Graphic representation of infarct size expressed as percentage of the scar length to the total LV circumference. Data are presented as means ±SEM. N = 8-10 for all groups.

Figure 3

Effects of vildagliptin on capillary density in cardiomyocyte cross-sectional area. A: Graphic representation of capillary density expresses as the number of capillaries/mm2 field. B: Typical examples of capillary density in the experimental groups at ×40 magnification. Data are presented as means ± SEM. N = 8-10 for all groups. **P < 0.01 vs. sham group.

Figure 4

Cardiomyocyte size was measured by gomori staining in cross-sectional areas. A: Graphic representation of cardiomyocyte size in all experimental groups. B: Typical examples of cardiomyocyte size in the experimental groups at ×40 magnification. Data are presented as means ± SEM. N = 8-10 for all groups. **P < 0.01 vs. sham group.

Figure 5

Quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) was conducted and expression was measured of myocardial atrial natriuretic peptide (ANP; A), brain natriuretic peptide (BNP; B), collagen I (C), and matrix metalloproteinase-9 (MMP-9; D), respectively (mRNA corrected for 36B4 mRNA level). The relative corrected values are shown for each group. Data are presented as means ± SEM. N = 8-10 for all groups.*P < 0.05 vs. sham group.