PMID- 23343509
OWN - NLM
STAT- MEDLINE
DCOM- 20130808
LR  - 20181202
IS  - 1479-6813 (Electronic)
IS  - 0952-5041 (Linking)
VI  - 50
IP  - 2
DP  - 2013 Apr
TI  - Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 
      MAPK, and JNK pathways.
PG  - 229-41
LID - 10.1530/JME-12-0166 [doi]
AB  - Experimental studies have indicated that endothelial cells play an important role 
      in maintaining vascular homeostasis. We previously reported that human coronary 
      artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) 
      receptor and that the stable GLP1 mimetic exendin-4 is able to activate the 
      receptor, leading to increased cell proliferation. Here, we have studied the 
      effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying 
      mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 
      activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive 
      oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, 
      eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of 
      transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated 
      cells to release NO and ROS, concomitant with upregulation of eNOS, which 
      required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between 
      NO and ROS production in which ROS production decreased and NO production was 
      further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs 
      against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 
      MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the 
      anti-apoptotic effect afforded by exendin-4. Our results support the notion that 
      GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity 
      and that such agonists protect against lipoapoptosis through 
      PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent 
      mechanism.
FAU - Erdogdu, Ozlem
AU  - Erdogdu O
AD  - Department of Clinical Science and Education, Karolinska Institutet, Stockholm, 
      Sweden.
FAU - Eriksson, Linnea
AU  - Eriksson L
FAU - Xu, Hua
AU  - Xu H
FAU - Sjoholm, Ake
AU  - Sjoholm A
FAU - Zhang, Qimin
AU  - Zhang Q
FAU - Nystrom, Thomas
AU  - Nystrom T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130318
PL  - England
TA  - J Mol Endocrinol
JT  - Journal of molecular endocrinology
JID - 8902617
RN  - 0 (GLP1R protein, human)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Palmitates)
RN  - 0 (Peptides)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Glucagon)
RN  - 0 (Venoms)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9P1872D4OL (Exenatide)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Caspase 3/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - DNA Fragmentation/drug effects
MH  - Endothelial Cells/*drug effects/*metabolism
MH  - Enzyme Activation/drug effects
MH  - Exenatide
MH  - Glucagon-Like Peptide 1/pharmacology
MH  - Glucagon-Like Peptide-1 Receptor
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Palmitates/pharmacology
MH  - Peptides/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation/drug effects
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, Glucagon/metabolism
MH  - Signal Transduction/*drug effects
MH  - Venoms/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2013/01/25 06:00
MHDA- 2013/08/09 06:00
CRDT- 2013/01/25 06:00
PHST- 2013/01/25 06:00 [entrez]
PHST- 2013/01/25 06:00 [pubmed]
PHST- 2013/08/09 06:00 [medline]
AID - JME-12-0166 [pii]
AID - 10.1530/JME-12-0166 [doi]
PST - epublish
SO  - J Mol Endocrinol. 2013 Mar 18;50(2):229-41. doi: 10.1530/JME-12-0166. Print 2013 
      Apr.