DPP-4 Inhibitors and GLP-1 Reduce Myocardial Infarct Size
DPP-4 Inhibitors and GLP-1 Reduce Myocardial Infarct Size
There was no difference in the area at risk or haemodynamic variables between the treatment groups. The blood glucose levels after 2 week of treatment averaged 5.5 ± 0.3 mmol/L, 5.7 ± 0.2 mmol/L and 5.7 ± 0.4 mmol/L for Sitagliptin, Vildagliptin and control, respectively.
Sitagliptin pre-treatment was found to reduce myocardial infarct size in hearts perfused with buffer containing 11 mmol/L of glucose (30.7 ± 3.4% with Sitagliptin versus 57.9 ± 5.0% with control: P < 0.05:N ≥ 6/group) but not 5 mmol/L glucose (51.4 ± 7.6% with Sitagliptin versus 53.1 ± 5.4% with control: P > 0.05:N ≥ 6/group) (Figure 2A). Similarly, Vildagliptin pre-treatment reduced myocardial infarct size in hearts perfused with buffer containing 11 mmol/L of glucose (34.4 ± 4.1% with Vildagliptin versus 52.9 ± 5.2% with control: P < 0.05:N ≥ 6/group) but not 5 mmol/L glucose (53.2 ± 4.8% with Vildagliptin versus 52.6 ± 7.2% with control: P > 0.05:N ≥ 6/group) (Figure 2B). Interestingly, ischaemic preconditioning (IPC) (used as a positive control in this setting) reduced myocardial infarct size in perfused rat hearts at both 5 mmol/L glucose (18.8 ± 2.7% with IPC versus 38.8 ± 4.3% with control: P < 0.05: N > 6/group) and 11 mmol/L glucose (21.7 ± 4.8% with IPC versus 41.6 ± 3.9% with control: P < 0.05: N ≥ 6/group) (Figure 2C).
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Figure 2.
Ex-vivo myocardial infarct size following Sitagliptin or Vildagliptin pre-treatment. (A) Ex vivo myocardial infarct size expressed as a percentage of the risk zone. A. Pre-treatment with Sitagliptin (Sita) reduced the myocardial infarct to area at risk ratio (I/R%) in isolated rat hearts perfused with buffer containing 11 but not 5 mmol/L glucose. This infarct-limiting effect was abolished in hearts Langendorff-perfused with Exendin 9–39 (Exendin), a GLP-1 receptor antagonist. *P < 0.05. N ≥ 6/group. (B) Pre-treatment with Vildagliptin (Vilda) reduced the myocardial infarct to area at risk ratio (I/R%) in isolated rat hearts perfused with buffer containing 11 but not 5 mmol/L glucose. *P < 0.05. N ≥ 6/group. (C) Ischaemic preconditioning (IPC) reduces the myocardial infarct to area at risk ratio (I/R%) in isolated rat hearts perfused with buffer containing either 5 or 11 mmol/L glucose. *P < 0.05. N ≥ 6/group.
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).
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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.
There was no difference in the area at risk or haemodynamic variables between the treatment groups. The perfusion of hearts with buffer containing GLP-1 reduced MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L (30.8 ± 0.6% at 7 mmol, 29.3 ± 0.6% at 9 mmol/L, 39.1 ± 2.5% at 11 mmol/Lpretreatment did not reduce blood glucose levels in any of the groups. versus 55.6 ± 1.2% at 5 mmol/L:P < 0.05:N ≥ 6/group) (Figure 4A). There was no difference in MI size in control hearts perfused at the different glucose concentrations (57.1 ± 0.7% at 5 mmol/L, 52.7 ± 1.2% at 7 mmol/L, 55.6 ± 1.5% at 9 mmol/L, 50.1 ± 2.9% at 11 mmol/L:P > 0.05:N ≥ 6/group)(Figure 4B).
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Figure 4.
Ex-vivo myocardial infarct size expressed as a percentage of the risk zone. (A) There was no difference in myocardial infarct to area at risk ratio (I/R%) in hearts perfused with buffer containing glucose at either 5, 7, 9, or 11 mmol/L. *P < 0.05. N ≥ 6/group. (B) Perfusion of isolated rat hearts with buffer containing GLP-1 reduced myocardial infarct to area at risk ratio (I/R%) in hearts perfused with buffer containing glucose at 7, 9, or 11 mmol/L but not at 5 mmol/L. *P < 0.05. N ≥ 6/group.
Blood glucose levels were not significantly different between SD and Wistar rats, but were significantly different between these groups and middle aged Wistar and GK rats (in mmol/L: 5.5 ± 0.3, 5.6 ± 0.2, 7.5 ± 0.3 and 9.3 ± 1.5, respectively. P < 0.05:N ≥ 6/group). Sitagliptin pre-treatment did not reduce blood glucose levels in any of the groups.
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).
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Figure 5.
Effect of Sitagliptin pre-treatment onin vivomyocardial 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).
Results
Both Sitagliptin and Vildagliptin Pre-treatment Reduced Myocardial Infarct Size ex vivo in a Glucose-dependent Manner
There was no difference in the area at risk or haemodynamic variables between the treatment groups. The blood glucose levels after 2 week of treatment averaged 5.5 ± 0.3 mmol/L, 5.7 ± 0.2 mmol/L and 5.7 ± 0.4 mmol/L for Sitagliptin, Vildagliptin and control, respectively.
Sitagliptin pre-treatment was found to reduce myocardial infarct size in hearts perfused with buffer containing 11 mmol/L of glucose (30.7 ± 3.4% with Sitagliptin versus 57.9 ± 5.0% with control: P < 0.05:N ≥ 6/group) but not 5 mmol/L glucose (51.4 ± 7.6% with Sitagliptin versus 53.1 ± 5.4% with control: P > 0.05:N ≥ 6/group) (Figure 2A). Similarly, Vildagliptin pre-treatment reduced myocardial infarct size in hearts perfused with buffer containing 11 mmol/L of glucose (34.4 ± 4.1% with Vildagliptin versus 52.9 ± 5.2% with control: P < 0.05:N ≥ 6/group) but not 5 mmol/L glucose (53.2 ± 4.8% with Vildagliptin versus 52.6 ± 7.2% with control: P > 0.05:N ≥ 6/group) (Figure 2B). Interestingly, ischaemic preconditioning (IPC) (used as a positive control in this setting) reduced myocardial infarct size in perfused rat hearts at both 5 mmol/L glucose (18.8 ± 2.7% with IPC versus 38.8 ± 4.3% with control: P < 0.05: N > 6/group) and 11 mmol/L glucose (21.7 ± 4.8% with IPC versus 41.6 ± 3.9% with control: P < 0.05: N ≥ 6/group) (Figure 2C).
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Figure 2.
Ex-vivo myocardial infarct size following Sitagliptin or Vildagliptin pre-treatment. (A) Ex vivo myocardial infarct size expressed as a percentage of the risk zone. A. Pre-treatment with Sitagliptin (Sita) reduced the myocardial infarct to area at risk ratio (I/R%) in isolated rat hearts perfused with buffer containing 11 but not 5 mmol/L glucose. This infarct-limiting effect was abolished in hearts Langendorff-perfused with Exendin 9–39 (Exendin), a GLP-1 receptor antagonist. *P < 0.05. N ≥ 6/group. (B) Pre-treatment with Vildagliptin (Vilda) reduced the myocardial infarct to area at risk ratio (I/R%) in isolated rat hearts perfused with buffer containing 11 but not 5 mmol/L glucose. *P < 0.05. N ≥ 6/group. (C) Ischaemic preconditioning (IPC) reduces the myocardial infarct to area at risk ratio (I/R%) in isolated rat hearts perfused with buffer containing either 5 or 11 mmol/L glucose. *P < 0.05. N ≥ 6/group.
Pharmacological Inhibition of the GLP-1 Receptor and the PKA Signalling Pathway Abrogated Both Sitagliptin and Vildagliptin-induced Cardioprotection
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).
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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.
The Infarct-limiting Effects of GLP-1 Treatment Are Also Glucose-sensitive
There was no difference in the area at risk or haemodynamic variables between the treatment groups. The perfusion of hearts with buffer containing GLP-1 reduced MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L (30.8 ± 0.6% at 7 mmol, 29.3 ± 0.6% at 9 mmol/L, 39.1 ± 2.5% at 11 mmol/Lpretreatment did not reduce blood glucose levels in any of the groups. versus 55.6 ± 1.2% at 5 mmol/L:P < 0.05:N ≥ 6/group) (Figure 4A). There was no difference in MI size in control hearts perfused at the different glucose concentrations (57.1 ± 0.7% at 5 mmol/L, 52.7 ± 1.2% at 7 mmol/L, 55.6 ± 1.5% at 9 mmol/L, 50.1 ± 2.9% at 11 mmol/L:P > 0.05:N ≥ 6/group)(Figure 4B).
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Figure 4.
Ex-vivo myocardial infarct size expressed as a percentage of the risk zone. (A) There was no difference in myocardial infarct to area at risk ratio (I/R%) in hearts perfused with buffer containing glucose at either 5, 7, 9, or 11 mmol/L. *P < 0.05. N ≥ 6/group. (B) Perfusion of isolated rat hearts with buffer containing GLP-1 reduced myocardial infarct to area at risk ratio (I/R%) in hearts perfused with buffer containing glucose at 7, 9, or 11 mmol/L but not at 5 mmol/L. *P < 0.05. N ≥ 6/group.
Sitagliptin Pre-treatment Reduced Myocardial Infarct Size in vivo in a Glucose-dependent Manner
Blood glucose levels were not significantly different between SD and Wistar rats, but were significantly different between these groups and middle aged Wistar and GK rats (in mmol/L: 5.5 ± 0.3, 5.6 ± 0.2, 7.5 ± 0.3 and 9.3 ± 1.5, respectively. P < 0.05:N ≥ 6/group). Sitagliptin pre-treatment did not reduce blood glucose levels in any of the groups.
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).
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Figure 5.
Effect of Sitagliptin pre-treatment onin vivomyocardial 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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