Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α

Cardioprotective effects of GLP‐1(28‐36a): A degraded metabolite or GLP‐1’s better half?

“…Recently, Siraj et al 14 . provided intriguing results that explain how GLP‐1 might exert its cardioprotective effects in a GLP‐1R‐independent manner (Figure 2).…”

“…The authors found that a NEP24.11‐generated metabolite of GLP‐1, GLP‐1(28‐36a), reduced myocardial infarct size, prevented cardiac dysfunction and protected coronary vascular cells from oxidative stress injury in both in vivo and ex vivo models of IRI 14 . Their rigorous work showed that GLP‐1(28‐36a) enters coronary artery endothelial cells through macropinocytosis and binds to mitochondrial trifunctional protein‐α (MTPα), shifting substrate utilization from oxygen‐consuming fatty acid metabolism toward oxygen‐sparing glycolysis and glucose oxidation to increase adenosine triphosphate (ATP) production 14 . The increased intracellular ATP then modulates the ATP‐sensor ,soluble adenylyl cyclase, thereby producing cyclic adenosine monophosphate and activating protein kinase A to exert cytoprotection from oxidative injury 14 .…”

“…Further studies are required to determine whether the findings by Siraj et al 14 can explain the differing cardioprotective effects of DPP-4 inhibitors and GLP-1R agonists in diabetes, and whether GLP-1(28-36a) can be utilized as a new anti-CVD therapy with lesser adverse effects than those associated with GLP-1R agonists (e.g., elevated heart rate), which the authors mention. The findings by Siraj et al 14 shed light on the effects of GLP-1 in other tissues and cell types. Previous studies showed benefits of GLP-1 and some GLP-1R agonists on non-alcoholic fatty liver disease in mice and humans, although the liver lacks expression of conventional GLP-1R 2 .…”

“…Recently, Siraj et al 14 provided intriguing results that explain how GLP-1 might exert its cardioprotective effects in a GLP-1R-independent manner ( Figure 2). The authors found that a NEP24.11-generated metabolite of GLP-1, GLP-1(28-36a), reduced myocardial infarct size, prevented cardiac dysfunction and protected coronary vascular cells from oxidative stress injury in both in vivo and ex vivo models of IRI 14 . Their rigorous work showed that GLP-1(28-36a) enters coronary artery endothelial cells through macropinocytosis and binds to mitochondrial trifunctional protein-a (MTPa), shifting substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation to increase adenosine triphosphate (ATP) production 14 .…”

“…Questions include the relevance of the findings by Siraj et al 14 shift substrate utilization. Exendin-4based GLP-1R agonists (e.g., exenatide and lixisenatide) that failed to show cardioprotective effects in CVOTs 3,15 are resistant to cleavage by NEP21.11.…”