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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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Effect of Sitagliptin pre-treatment on in vivo myocardial infarct size. (A) Myocardial infarct size is expressed as a percentage of the risk zone. Sitagliptin pre-treatment reduced myocardial infarct to area at risk ratio (I/R%) in middle aged Wistar and GK rats. There was no difference in myocardial infarct to area at risk ratio in SD or Wistar rats. * P < 0.05:N ≥ 6/group. (B) Representative short axis slices of control and treated hearts depicting non-ischemic zone (blue), area of myocardial infarction (white), and non-infarcted viable myocardium in the area at risk (red).
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Figure 5: Effect of Sitagliptin pre-treatment on in vivo myocardial infarct size. (A) Myocardial infarct size is expressed as a percentage of the risk zone. Sitagliptin pre-treatment reduced myocardial infarct to area at risk ratio (I/R%) in middle aged Wistar and GK rats. There was no difference in myocardial infarct to area at risk ratio in SD or Wistar rats. * P < 0.05:N ≥ 6/group. (B) Representative short axis slices of control and treated hearts depicting non-ischemic zone (blue), area of myocardial infarction (white), and non-infarcted viable myocardium in the area at risk (red).

Mentions: In the in vivo LAD occlusion/reperfusion studies, Sitagliptin pre-treatment was found to reduce myocardial infarct size in both middle aged Wistar and GK rats (15.4 ± 2.4% with Sitagliptin versus 44.8 ± 4.0% with control in Wistars; and 29.10 ± 5.3% with Sitagliptin versus 60.9 ± 5.5% with control in GKs. P < 0.05:N ≥ 6/group). However, in the SD or Wistar groups there were no differences in MI size (42.1 ± 7.4% and 34.5 ± 5.9% with Sitagliptin versus 46.6 ± 5.7% and 33.8 ± 3.1% with control, respectively for SD and Wistar) (Figure 5 A,B).


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)

Effect of Sitagliptin pre-treatment on in vivo myocardial infarct size. (A) Myocardial infarct size is expressed as a percentage of the risk zone. Sitagliptin pre-treatment reduced myocardial infarct to area at risk ratio (I/R%) in middle aged Wistar and GK rats. There was no difference in myocardial infarct to area at risk ratio in SD or Wistar rats. * P < 0.05:N ≥ 6/group. (B) Representative short axis slices of control and treated hearts depicting non-ischemic zone (blue), area of myocardial infarction (white), and non-infarcted viable myocardium in the area at risk (red).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Effect of Sitagliptin pre-treatment on in vivo myocardial infarct size. (A) Myocardial infarct size is expressed as a percentage of the risk zone. Sitagliptin pre-treatment reduced myocardial infarct to area at risk ratio (I/R%) in middle aged Wistar and GK rats. There was no difference in myocardial infarct to area at risk ratio in SD or Wistar rats. * P < 0.05:N ≥ 6/group. (B) Representative short axis slices of control and treated hearts depicting non-ischemic zone (blue), area of myocardial infarction (white), and non-infarcted viable myocardium in the area at risk (red).
Mentions: In the in vivo LAD occlusion/reperfusion studies, Sitagliptin pre-treatment was found to reduce myocardial infarct size in both middle aged Wistar and GK rats (15.4 ± 2.4% with Sitagliptin versus 44.8 ± 4.0% with control in Wistars; and 29.10 ± 5.3% with Sitagliptin versus 60.9 ± 5.5% with control in GKs. P < 0.05:N ≥ 6/group). However, in the SD or Wistar groups there were no differences in MI size (42.1 ± 7.4% and 34.5 ± 5.9% with Sitagliptin versus 46.6 ± 5.7% and 33.8 ± 3.1% with control, respectively for SD and Wistar) (Figure 5 A,B).

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