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Cardioprotection Resulting from Glucagon-Like Peptide-1 Administration Involves Shifting Metabolic Substrate Utilization to Increase Energy Efficiency in the Rat Heart.

Aravindhan K, Bao W, Harpel MR, Willette RN, Lepore JJ, Jucker BM - PLoS ONE (2015)

Bottom Line: Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding.Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury.In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

View Article: PubMed Central - PubMed

Affiliation: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.

ABSTRACT
Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

No MeSH data available.


Related in: MedlinePlus

Infarct assessment following cardiac ischemia-reperfusion injury in rat.Sprague-Dawley rats (n = 5-6) were subjected to a 30 min LAD coronary artery occlusion followed by 24 hr period of reperfusion. Hearts were harvested for assessment of area at risk and infarct size. Representative photographs of heart sections stained with TTC and Evans Blue dye are shown for both Vehicle (A) and GLP-1 (B) groups. The areas of myocardial infarct are white, areas at risk (AAR) are the combined white and red regions, and area not at risk (ANAR) are dark blue. Infarct size and area at risk are presented as percentage of AAR and left ventricle, respectively (C). Data are presented as mean±SEM. *p<0.05 vs Vehicle.
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pone.0130894.g001: Infarct assessment following cardiac ischemia-reperfusion injury in rat.Sprague-Dawley rats (n = 5-6) were subjected to a 30 min LAD coronary artery occlusion followed by 24 hr period of reperfusion. Hearts were harvested for assessment of area at risk and infarct size. Representative photographs of heart sections stained with TTC and Evans Blue dye are shown for both Vehicle (A) and GLP-1 (B) groups. The areas of myocardial infarct are white, areas at risk (AAR) are the combined white and red regions, and area not at risk (ANAR) are dark blue. Infarct size and area at risk are presented as percentage of AAR and left ventricle, respectively (C). Data are presented as mean±SEM. *p<0.05 vs Vehicle.

Mentions: Differential staining of LV with TTC and Evans Blue dyes was used at the end of the reperfusion period to delineate the affected areas and determine the extent of myocardial damage. Representative photographs of heart sections are shown in (Fig 1A and 1B). The area of myocardial infarction appears white; AAR, white and red; ANAR, dark blue. As quantified in (Fig 1C), AAR was similar between vehicle and GLP-1 treatment groups, suggesting that both groups underwent similar ischemic insults. The infarct size in the vehicle group of 58.6±2.0% of AAR was reduced significantly with GLP-1 treatment to 42.1±5.0% of AAR.


Cardioprotection Resulting from Glucagon-Like Peptide-1 Administration Involves Shifting Metabolic Substrate Utilization to Increase Energy Efficiency in the Rat Heart.

Aravindhan K, Bao W, Harpel MR, Willette RN, Lepore JJ, Jucker BM - PLoS ONE (2015)

Infarct assessment following cardiac ischemia-reperfusion injury in rat.Sprague-Dawley rats (n = 5-6) were subjected to a 30 min LAD coronary artery occlusion followed by 24 hr period of reperfusion. Hearts were harvested for assessment of area at risk and infarct size. Representative photographs of heart sections stained with TTC and Evans Blue dye are shown for both Vehicle (A) and GLP-1 (B) groups. The areas of myocardial infarct are white, areas at risk (AAR) are the combined white and red regions, and area not at risk (ANAR) are dark blue. Infarct size and area at risk are presented as percentage of AAR and left ventricle, respectively (C). Data are presented as mean±SEM. *p<0.05 vs Vehicle.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476748&req=5

pone.0130894.g001: Infarct assessment following cardiac ischemia-reperfusion injury in rat.Sprague-Dawley rats (n = 5-6) were subjected to a 30 min LAD coronary artery occlusion followed by 24 hr period of reperfusion. Hearts were harvested for assessment of area at risk and infarct size. Representative photographs of heart sections stained with TTC and Evans Blue dye are shown for both Vehicle (A) and GLP-1 (B) groups. The areas of myocardial infarct are white, areas at risk (AAR) are the combined white and red regions, and area not at risk (ANAR) are dark blue. Infarct size and area at risk are presented as percentage of AAR and left ventricle, respectively (C). Data are presented as mean±SEM. *p<0.05 vs Vehicle.
Mentions: Differential staining of LV with TTC and Evans Blue dyes was used at the end of the reperfusion period to delineate the affected areas and determine the extent of myocardial damage. Representative photographs of heart sections are shown in (Fig 1A and 1B). The area of myocardial infarction appears white; AAR, white and red; ANAR, dark blue. As quantified in (Fig 1C), AAR was similar between vehicle and GLP-1 treatment groups, suggesting that both groups underwent similar ischemic insults. The infarct size in the vehicle group of 58.6±2.0% of AAR was reduced significantly with GLP-1 treatment to 42.1±5.0% of AAR.

Bottom Line: Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding.Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury.In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

View Article: PubMed Central - PubMed

Affiliation: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.

ABSTRACT
Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

No MeSH data available.


Related in: MedlinePlus