Coupling factor 6 downregulates platelet endothelial cell adhesion molecule-1 via c-Src activation and acts as a proatherogenic molecule.
Coupling factor 6 (CF6), a component of ATP synthase, suppresses the generation of prostacyclin and nitric oxide (NO). Platelet endothelial cell adhesion molecule-1 (PECAM-1) is involved in shear-induced NO production. To investigate the linkage between the actions of CF6 and PECAM-1, we examined the effects of CF6 on PECAM-1 expression and shear-mediated NO release, comparatively with those of angiotensin II (AngII). Treatment of human umbilical vein endothelial cells (HUVEC) and aortic endothelial cells (HAEC) with CF6 at 10(-7)M or AngII at 10(-7)M for 24h suppressed PECAM-1 gene and protein expression. CF6 or AngII activated c-Src at 15 min in HUVEC, and blockade of c-Src with PP1, its specific inhibitor, restored them. Efrapeptin, an inhibitor of ATPase, attenuated CF6-induced suppression of PECAM-1 gene expression by blockade of acidification, whereas superoxide dismutase or apocinin, an inhibitor of NADPH oxidase, blocked AngII-induced suppression of PECAM-1. Exposure of the cells to shear stress at 25 dynes/cm(2) for 30 min enhanced phosphorylation of eNOS at Ser(1177) and NO release. Pretreatment with CF6 or AngII for 24h attenuated them in HUVEC and HAEC. These suggest that CF6 downregulates PECAM-1 expression via c-Src activation and attenuates shear-induced NO release presumably by suppressing eNOS phosphorylation.
Kumagai
Akiko
A
Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Osanai
Tomohiro
T
Katoh
Chisato
C
Tanaka
Makoto
M
Tomita
Hirofumi
H
Morimoto
Takeshi
T
Murakami
Reiichi
R
Magota
Koji
K
Okumura
Ken
K
D000804:Angiotensin II / Q000502:physiology; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D025261:Mitochondrial Proton-Translocating ATPases / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010086:Oxidative Phosphorylation Coupling Factors / Q000502:physiology*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology; D019061:src-Family Kinases
D010086:Oxidative Phosphorylation Coupling Factors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000804:Angiotensin II; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases