Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4.
OBJECTIVE
Exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However, their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall, one of the earliest steps in atherosclerogenesis.


METHODS
After continuous infusion of low (300 pmol . kg(-1) . day(-1)) or high (24 nmol . kg(-1) . day(-1)) dose of exendin-4 in C57BL/6 or apolipoprotein E-deficient mice (apoE(-/-)), we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes.


RESULTS
Treatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE(-/-) mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1, and suppressed nuclear translocation of p65, a component of nuclear factor-kappaB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI(14-22), a protein kinase A-specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b.


CONCLUSIONS
Our data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.
Arakawa
Masayuki
M
Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Mita
Tomoya
T
Azuma
Kosuke
K
Ebato
Chie
C
Goto
Hiromasa
H
Nomiyama
Takashi
T
Fujitani
Yoshio
Y
Hirose
Takahisa
T
Kawamori
Ryuzo
R
Watada
Hirotaka
H
D000818:Animals; D001011:Aorta / Q000502:physiology; D050197:Atherosclerosis / Q000188:drug therapy / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D000077270:Exenatide; D005434:Flow Cytometry; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide