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Pivot Concepts:
Gene/Protein
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Target Concepts:
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Query: EC:2.7.11.12 (
PKG
)
2,515
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The
glucagon-like peptide-1 receptor
(
GLP-1R
) agonist exendin-4 is a long-acting analog of GLP-1, which stimulates insulin secretion and is clinically used in the treatment of type 2 diabetes. Previous studies have demonstrated that GLP-1 agonists and analogs serve as cardioprotective factors in various conditions. Disturbances in calcium cycling are characteristic of heart failure (HF); therefore, the aim of this study was to investigate the effect of exendin-4 (a GLP-1 mimetic) on the regulation of calcium handling and to identify the underlying mechanisms in an HF rat model after myocardial infarction (MI). Rats underwent surgical ligation of the left anterior descending coronary artery or sham surgery prior to infusion with vehicle, exendin-4, or exendin-4 and exendin9-39 for 4 weeks. Exendin-4 treatment decreased MI size, suppressed chamber dilation, myocyte hypertrophy, and fibrosis and improved in vivo heart function in the rats subjected to MI. Exendin-4 resulted in an increase in circulating GLP-1 and
GLP-1R
in ventricular tissues. Additionally, exendin-4 activated the eNOS/cGMP/
PKG
signaling pathway and inhibited the Ca
2+
/calmodulin-dependent kinase II (CaMKII) pathways. Myocytes isolated from exendin-4-treated hearts displayed higher Ca
2+
transients, higher sarcoplasmic reticulum Ca
2+
content, and higher l-type Ca
2+
current densities than MI hearts. Exendin-4 treatment restored the protein expression of sarcoplasmic reticulum Ca
2+
uptake ATPase (SERCA2a), phosphorylated phospholamban (PLB) and Cav1.2 and decreased the levels of phosphorylated ryanodine receptor (RyR). Moreover, the favorable effects of exendin-4 were significantly inhibited by exendin9-39 (a
GLP-1 receptor
antagonist). Exendin-4 treatment of an HF rat model after MI inhibited cardiac and cardiomyocytes progressive remodeling. In addition, Ca
2+
handling and its molecular modulation were also improved by exendin-4 treatment. The beneficial effects of exendin-4 on cardiac remodeling may be mediated through activation of the eNOS/cGMP/
PKG
pathway.
...
PMID:Exendin-4 inhibits structural remodeling and improves Ca
2+
homeostasis in rats with heart failure via the GLP-1 receptor through the eNOS/cGMP/PKG pathway. 2824 57
Glucagon-like peptide 1 (GLP-1) is object of intensive investigation for not only its metabolic effects but also the protective vascular actions. Since platelets exert a primary role in the pathogenesis of atherosclerosis, inflammation and vascular complications, we investigated whether GLP-1 directly influences platelet reactivity. For this purpose, in platelets from 72 healthy volunteers we evaluated
GLP-1 receptor
(
GLP-1R
) expression and the effects of a 15-minute incubation with the native form GLP-1(7-36), the N-terminally truncated form GLP-1(9-36) and the GLP-1 analogue Liraglutide (100 nmol/l) on: i) aggregation induced by collagen or arachidonic acid (AA); ii) platelet function under shear stress; iii) cGMP and cAMP synthesis and
cGMP-dependent protein kinase
(
PKG
)-induced Vasodilator-Stimulated-Phosphoprotein (VASP) phosphorylation; iv) activation of the signalling molecules Phosphatidylinositol 3-Kinase (PI3-K)/Akt and Mitogen Activated Protein Kinase (MAPK)/ERK-1/2; and v) oxidative stress. Experiments were repeated in the presence of the nitric oxide donor Na-nitroprusside. We found that platelets constitutively express
GLP-1R
and that, independently of
GLP-1R
, GLP-1(7-36), GLP-1(9-36) and Liraglutide exert platelet inhibitory effects as shown by: a) increased NO-antiaggregating effects, b) increased the activation of the cGMP/
PKG
/VASP pathway, c) reduced the activation of PI3-K/Akt and MAPK/ERK-2 pathways, d) reduced the AA-induced oxidative stress. When the experiments were repeated in the presence of the antagonist of
GLP-1R
Exendin(9-39), the platelet inhibitory effects were maintained, thus indicating a mechanism independent of
GLP-1R
. In conclusion, GLP-1(7-36), its degradation product GLP-1(9-36) and Liraglutide exert similar inhibitory effects on platelet activation, suggesting a potential protective effect on the cardiovascular system.
...
PMID:Glucagon-like peptide 1-related peptides increase nitric oxide effects to reduce platelet activation. 2840 72
