The flavonoid phloretin suppresses stimulated expression of endothelial adhesion molecules and reduces activation of human platelets.
Atherosclerosis is a chronic inflammatory disease accompanied by the expression of endothelial adhesion molecules. Phloretin is a plant-derived phytochemical that is mainly present in apples. Because phloretin is reported to promote antioxidative activities, we investigated the effects of phloretin on cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) in human umbilical vein endothelial cells (HUVECs). Phloretin prevented TNF-alpha-stimulated upregulation of VCAM-1, ICAM-1, and E-selectin expression in a concentration-dependent manner. To the same extent as for TNF-alpha, phloretin also inhibited IL-1beta-induced upregulation in expression of all 3 adhesion molecules. Inhibition of cytokine-induced adhesion molecule expression for VCAM-1, ICAM-1, and E-selectin was detected already at the level of mRNA. Preincubation with phloretin dose-dependently attenuated TNF-alpha-stimulated adhesion of monocytic THP-1 cells to HUVECs and human aortic endothelial cells. Phloretin did not affect TNF-alpha-stimulated activation of nuclear factor kappaB (NF-kappaB) but inhibited activation of interferon regulatory factor 1, a transcription factor involved in the regulation of endothelial cell adhesion molecule expression. In human platelets, phloretin diminished adenosine diphosphate (ADP) and thrombin receptor-activating peptide-stimulated expression of the activated form of the GPIIb/IIIa complex and reduced platelet aggregation stimulated by ADP. Thus phloretin may have beneficial effects in the onset and progression of cardiovascular diseases.
Stangl
Verena
V
Medizinische Klinik und Poliklinik, Schwerpunkt Kardiologie, Angiologie, Pneumologie, Charité der Humboldt-Universität, Campus Mitte, Berlin, Germany. verena.stangl@charite.de
Lorenz
Mario
M
Ludwig
Antje
A
Grimbo
Nicole
N
Guether
Carola
C
Sanad
Wasiem
W
Ziemer
Sabine
S
Martus
Peter
P
Baumann
Gert
G
Stangl
Karl
K
D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019040:E-Selectin / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D010693:Phloretin / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D005419:Flavonoids; D007375:Interleukin-1; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D010693:Phloretin