PMID- 21278133
OWN - NLM
STAT- MEDLINE
DCOM- 20110620
LR  - 20220410
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 300
IP  - 4
DP  - 2011 Apr
TI  - Antiapoptotic effects of GLP-1 in murine HL-1 cardiomyocytes.
PG  - H1361-72
LID - 10.1152/ajpheart.00885.2010 [doi]
AB  - 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 
      muM), or ceramide (15 muM) 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.
FAU - Ravassa, Susana
AU  - Ravassa S
AD  - Division of Cardiovascular Sciences, Center for Applied Medical Research, 
      University Clinic, School of Medicine, University of Navarra, Pamplona, Spain. 
      sravassa@unav.es
FAU - Zudaire, Amaia
AU  - Zudaire A
FAU - Carr, Richard D
AU  - Carr RD
FAU - Diez, Javier
AU  - Diez J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110128
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (BNip3 protein, mouse)
RN  - 0 (Ceramides)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Incretins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Palmitates)
RN  - 0 (Phosphatidylserines)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - H88EPA0A3N (Staurosporine)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Caspase 3/biosynthesis
MH  - Cell Line
MH  - Ceramides/pharmacology
MH  - Cytochromes c/metabolism
MH  - DNA Fragmentation
MH  - Enzyme Inhibitors/pharmacology
MH  - Glucagon-Like Peptide 1/*pharmacology
MH  - Glucose/pharmacology
MH  - Incretins/*pharmacology
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Membrane Proteins/biosynthesis
MH  - Mice
MH  - Mitochondrial Proteins/biosynthesis
MH  - Myocytes, Cardiac/*drug effects
MH  - Palmitates/pharmacology
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Phosphatidylserines/pharmacology
MH  - Proto-Oncogene Proteins c-bcl-2/biosynthesis
MH  - Staurosporine/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2011/02/01 06:00
MHDA- 2011/06/21 06:00
CRDT- 2011/02/01 06:00
PHST- 2011/02/01 06:00 [entrez]
PHST- 2011/02/01 06:00 [pubmed]
PHST- 2011/06/21 06:00 [medline]
AID - ajpheart.00885.2010 [pii]
AID - 10.1152/ajpheart.00885.2010 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1361-72. doi: 
      10.1152/ajpheart.00885.2010. Epub 2011 Jan 28.