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Published on: February 3, 2017
Antiapoptotic effects of GLP-1 in murine HL-1 cardiomyocytes
Susana Ravassa1, Amaia Zudaire, Richard D Carr
1Division of Cardiovascular Sciences, Center for Applied Medical Research, University Clinic, School of Medicine, University of Navarra, Pamplona, Spain. sravassa@unav.es
Abstract:
Activation of apoptosis contributes to cardiomyocyte dysfunction and death in diabetic cardiomyopathy. The peptide glucagon-like peptide-1 (GLP-1), a hormone that is the basis of emerging therapy for type 2 diabetic patients, has cytoprotective actions in different cellular models. We investigated whether GLP-1 inhibits apoptosis in HL-1 cardiomyocytes stimulated with staurosporine, palmitate, and ceramide. Studies were performed in HL-1 cardiomyocytes. Apoptosis was induced by incubating HL-1 cells with staurosporine (175 nM), palmitate (135 μM), or ceramide (15 μM) for 24 h. In staurosporine-stimulated HL-1 cardiomyocytes, phosphatidylserine exposure, Bax-to-Bcl-2 ratio, Bad phosphorylation (Ser(136)), BNIP3 expression, mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, DNA fragmentation, and mammalian target of rapamycin (mTOR)/p70S6K phosphorylation (Ser(2448) and Thr(389), respectively) were assessed. Apoptotic hallmarks were also measured in the absence or presence of low (5 mM) and high (10 mM) concentrations of glucose. In addition, phosphatidylserine exposure and DNA fragmentation were analyzed in palmitate- and ceramide-stimulated cells. Staurosporine increased apoptosis in HL-1 cardiomyocytes. GLP-1 (100 nM) partially inhibited staurosporine-induced mitochondrial membrane depolarization and completely blocked the rest of the staurosporine-induced apoptotic changes. This cytoprotective effect was mainly mediated by phosphatidylinositol 3-kinase (PI3K) and partially dependent on ERK1/2. Increasing concentrations of glucose did not influence GLP-1-induced protection against staurosporine. Furthermore, GLP-1 inhibited palmitate- and ceramide-induced phosphatidylserine exposure and DNA fragmentation. Incretin GLP-1 protects HL-1 cardiomyocytes against activation of apoptosis. This cytoprotective ability is mediated mainly by the PI3K pathway and partially by the ERK1/2 pathway and seems to be glucose independent. It is proposed that therapies based on GLP-1 may contribute to prevent cardiomyocyte apoptosis.
Insights
Glucagon-like peptide-1 (GLP-1) protects heart cells from apoptosis, a key factor in diabetic cardiomyopathy. This protective effect, mediated by PI3K and ERK1/2 pathways, is independent of glucose levels and may offer therapeutic benefits.
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Cellular Physiology
Background:
- Diabetic cardiomyopathy is characterized by cardiomyocyte dysfunction and death due to apoptosis.
- Glucagon-like peptide-1 (GLP-1), an incretin hormone, exhibits cytoprotective properties in various cell models.
- Emerging therapies for type 2 diabetes utilize GLP-1.
Purpose of the Study:
- To investigate the potential of GLP-1 to inhibit apoptosis in HL-1 cardiomyocytes.
- To determine the mechanisms underlying GLP-1's cytoprotective effects against apoptotic stimuli.
- To assess the influence of glucose concentration on GLP-1's protective actions.
Main Methods:
- HL-1 cardiomyocytes were treated with apoptotic inducers: staurosporine, palmitate, or ceramide.
- Apoptosis was assessed by measuring phosphatidylserine exposure, Bax-to-Bcl-2 ratio, caspase-3 activation, and DNA fragmentation.
- GLP-1's effects were evaluated in the presence or absence of glucose, and involvement of PI3K and ERK1/2 pathways was investigated.
Main Results:
- GLP-1 significantly inhibited staurosporine-induced apoptosis, including mitochondrial depolarization and caspase-3 activation.
- The cytoprotective effect of GLP-1 was primarily mediated by the phosphatidylinositol 3-kinase (PI3K) pathway and partially by ERK1/2.
- GLP-1 also reduced apoptosis induced by palmitate and ceramide, independent of glucose concentration.
Conclusions:
- GLP-1 demonstrates significant cytoprotective effects against apoptosis in cardiomyocytes.
- This protection is mediated by PI3K and ERK1/2 signaling pathways and is not affected by glucose levels.
- GLP-1-based therapies hold promise for preventing cardiomyocyte apoptosis in conditions like diabetic cardiomyopathy.
