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Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner.

Hausenloy DJ, Whittington HJ, Wynne AM, Begum SS, Theodorou L, Riksen N, Mocanu MM, Yellon DM - Cardiovasc Diabetol (2013)

Bottom Line: This effect was abolished by Exendin 9-39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist).We find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner.Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Hatter Cardiovascular Institute, UCL Institute of Cardiovascular Science and NIHR University College London Hospitals Biomedical Research Centre, 67 Chenies Mews, London WC1E 6HX, UK. d.yellon@ucl.ac.uk.

ABSTRACT

Background: The dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which also confers cardioprotection. As such, we hypothesized that treatment with DPP-4 inhibitors are also cardioprotective.

Methods: In ex vivo experiments: Male Sprague-Dawley rats were randomized to receive by oral gavage either Vildagliptin (20 mg/kg/day), Sitagliptin (100 mg/kg/day), or water for 2 weeks. Excised hearts were Langendorff-perfused with buffer containing either 5 mmol/L or 11 mmol/L glucose and subjected to 35 minutes ischaemia/120 minutes reperfusion. In in vivo experiments: Male young Wistar and Sprague-Dawley rats, middle aged Wistar and Goto-Kakizaki diabetic rats were randomized to receive by oral gavage either Sitagliptin (100 mg/kg/day), or water for 2 weeks. Rats were then subjected to 30 minutes ischaemia/120 minutes reperfusion and infarct size ascertained.

Results: Two weeks pre-treatment with either Vildagliptin or Sitagliptin reduced ex vivo myocardial infarction (MI) size in hearts perfused with buffer containing 11 mmol/L glucose but not 5 mmol/L glucose. This effect was abolished by Exendin 9-39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist). Treatment of perfused hearts with native GLP-1 was also glucose-sensitive, reducing MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L. Finally, Sitagliptin reduced in vivo MI size in middle aged Wistar (7-8 mmol/L glucose) and Goto-Kakizaki (9-10 mmol/L glucose) rats where blood glucose was elevated, but not in young Wistar (5 mmol/L glucose) or Sprague-Dawley (5 mmol/L glucose) rats, where blood glucose was normal.

Conclusions: We find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner. Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.

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Ex vivo myocardial infarct size expressed as a percentage of the risk zone. The reduction in myocardial infarct to area at risk ratio (I/R%) induced by pre-treatment with Vildagliptin (Vilda) was abolished by treatment with either Exendin 9–39 (Exendin), a GLP-1 receptor antagonist, or H-89 (a PKA antagonist). *P < 0.05. N ≥ 6/group.
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Figure 3: Ex vivo myocardial infarct size expressed as a percentage of the risk zone. The reduction in myocardial infarct to area at risk ratio (I/R%) induced by pre-treatment with Vildagliptin (Vilda) was abolished by treatment with either Exendin 9–39 (Exendin), a GLP-1 receptor antagonist, or H-89 (a PKA antagonist). *P < 0.05. N ≥ 6/group.

Mentions: There was no difference in the area at risk or haemodynamic variables between the treatment groups. The infarct-limiting effects of Sitaglipitin at 11 mmol/L glucose were abolished by Exendin 9–39 (a GLP-1 receptor antagonist) (63.6 ± 5.5% with Sitagliptin + Exendin 9–39 versus 61.4 ± 3.0% with Control + Exendin 9–39: P > 0.05:N > 7/group)(Figure 2A) and the cardioprotective effects of Vildagliptin were abolished in the presence of Exendin 9–39 and H-89 (a PKA inhibitor) (61.5 ± 3.3% with Vildagliptin + Exendin 9–39 and 59.4 ± 2.1% with Vildagliptin + H-89 versus 35.0 ± 5.0% with Vildagliptin + vehicle: P < 0.05:N ≥ 6/group)(Figure 3). Importantly, the pharmacological inhibitors themselves did not influence infarct size significantly (61.4 ± 3.0% with control + Exendin 9–39 and 53.0 ± 4.9% with control + H-89 versus 53.1 ± 3.1% with control + vehicle: P > 0.05: N ≥ 6/group) (Figure 3).


Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner.

Hausenloy DJ, Whittington HJ, Wynne AM, Begum SS, Theodorou L, Riksen N, Mocanu MM, Yellon DM - Cardiovasc Diabetol (2013)

Ex vivo myocardial infarct size expressed as a percentage of the risk zone. The reduction in myocardial infarct to area at risk ratio (I/R%) induced by pre-treatment with Vildagliptin (Vilda) was abolished by treatment with either Exendin 9–39 (Exendin), a GLP-1 receptor antagonist, or H-89 (a PKA antagonist). *P < 0.05. N ≥ 6/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3815626&req=5

Figure 3: Ex vivo myocardial infarct size expressed as a percentage of the risk zone. The reduction in myocardial infarct to area at risk ratio (I/R%) induced by pre-treatment with Vildagliptin (Vilda) was abolished by treatment with either Exendin 9–39 (Exendin), a GLP-1 receptor antagonist, or H-89 (a PKA antagonist). *P < 0.05. N ≥ 6/group.
Mentions: There was no difference in the area at risk or haemodynamic variables between the treatment groups. The infarct-limiting effects of Sitaglipitin at 11 mmol/L glucose were abolished by Exendin 9–39 (a GLP-1 receptor antagonist) (63.6 ± 5.5% with Sitagliptin + Exendin 9–39 versus 61.4 ± 3.0% with Control + Exendin 9–39: P > 0.05:N > 7/group)(Figure 2A) and the cardioprotective effects of Vildagliptin were abolished in the presence of Exendin 9–39 and H-89 (a PKA inhibitor) (61.5 ± 3.3% with Vildagliptin + Exendin 9–39 and 59.4 ± 2.1% with Vildagliptin + H-89 versus 35.0 ± 5.0% with Vildagliptin + vehicle: P < 0.05:N ≥ 6/group)(Figure 3). Importantly, the pharmacological inhibitors themselves did not influence infarct size significantly (61.4 ± 3.0% with control + Exendin 9–39 and 53.0 ± 4.9% with control + H-89 versus 53.1 ± 3.1% with control + vehicle: P > 0.05: N ≥ 6/group) (Figure 3).

Bottom Line: This effect was abolished by Exendin 9-39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist).We find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner.Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Hatter Cardiovascular Institute, UCL Institute of Cardiovascular Science and NIHR University College London Hospitals Biomedical Research Centre, 67 Chenies Mews, London WC1E 6HX, UK. d.yellon@ucl.ac.uk.

ABSTRACT

Background: The dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which also confers cardioprotection. As such, we hypothesized that treatment with DPP-4 inhibitors are also cardioprotective.

Methods: In ex vivo experiments: Male Sprague-Dawley rats were randomized to receive by oral gavage either Vildagliptin (20 mg/kg/day), Sitagliptin (100 mg/kg/day), or water for 2 weeks. Excised hearts were Langendorff-perfused with buffer containing either 5 mmol/L or 11 mmol/L glucose and subjected to 35 minutes ischaemia/120 minutes reperfusion. In in vivo experiments: Male young Wistar and Sprague-Dawley rats, middle aged Wistar and Goto-Kakizaki diabetic rats were randomized to receive by oral gavage either Sitagliptin (100 mg/kg/day), or water for 2 weeks. Rats were then subjected to 30 minutes ischaemia/120 minutes reperfusion and infarct size ascertained.

Results: Two weeks pre-treatment with either Vildagliptin or Sitagliptin reduced ex vivo myocardial infarction (MI) size in hearts perfused with buffer containing 11 mmol/L glucose but not 5 mmol/L glucose. This effect was abolished by Exendin 9-39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist). Treatment of perfused hearts with native GLP-1 was also glucose-sensitive, reducing MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L. Finally, Sitagliptin reduced in vivo MI size in middle aged Wistar (7-8 mmol/L glucose) and Goto-Kakizaki (9-10 mmol/L glucose) rats where blood glucose was elevated, but not in young Wistar (5 mmol/L glucose) or Sprague-Dawley (5 mmol/L glucose) rats, where blood glucose was normal.

Conclusions: We find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner. Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.

Show MeSH
Related in: MedlinePlus