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

Yin M, Silljé HH, Meissner M, van Gilst WH, de Boer RA - Cardiovasc Diabetol (2011)

Bottom Line: Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: University Medical Center Groningen, University of Groningen, Department of Cardiology, Groningen, The Netherlands.

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.

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Related in: MedlinePlus

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.
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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.

Mentions: We measured the DPP-4 activity and active GLP-1 levels in plasma after 12 weeks of vildagliptin treatment to confirm that continuous administration of vildagliptin (supplied at 15 mg/kg in the drinking water) was indeed associated with suppression of plasma DPP-4 activity, and increase in the active GLP-1 levels. Plasma DPP-4 activity was significantly reduced by almost 70% in both treatment groups compared to non-treated groups. This was associated with a significant increase of active GLP-1 level in both vildagliptin groups (Figure 1).


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

Yin M, Silljé HH, Meissner M, van Gilst WH, de Boer RA - Cardiovasc Diabetol (2011)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198901&req=5

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.
Mentions: We measured the DPP-4 activity and active GLP-1 levels in plasma after 12 weeks of vildagliptin treatment to confirm that continuous administration of vildagliptin (supplied at 15 mg/kg in the drinking water) was indeed associated with suppression of plasma DPP-4 activity, and increase in the active GLP-1 levels. Plasma DPP-4 activity was significantly reduced by almost 70% in both treatment groups compared to non-treated groups. This was associated with a significant increase of active GLP-1 level in both vildagliptin groups (Figure 1).

Bottom Line: Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: University Medical Center Groningen, University of Groningen, Department of Cardiology, Groningen, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus