Caffeic acid phenethyl ester inhibits PDGF-induced proliferation of vascular smooth muscle cells via activation of p38 MAPK, HIF-1α, and heme oxygenase-1.
Hyperproliferation of vascular smooth muscle cells (VSMCs) is critically involved in the onset of atherosclerosis and restenosis. Although caffeic acid phenethyl ester (CAPE, 1), one of the main constituents of honeybee propolis, has been shown to exert a beneficial effect in models of vascular injury in vivo, detailed mechanistic investigations in vascular cells are scarce. This study has examined the antiproliferative activity of 1 in platelet-derived growth factor (PDGF)-stimulated primary rat aortic VSMCs and aimed to shed light on underlying molecular mechanisms. Compound 1 inhibited the proliferation of VSMCs upon exposure to PDGF in a dose-dependent manner by interfering with cell cycle progression from the G0/1- to the S-phase. Enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) as well as stabilization of hypoxia-inducible factor (HIF)-1α and subsequent induction of heme oxygenase-1 (HO-1) could be identified as molecular events contributing to the observed growth arrest in PDGF-activated VSMCs upon exposure to 1.
Department of Pharmacy, Center of Drug Research, University of Munich, 81377 Munich, Germany.
Thomas U
TU
Roos
Elke H
EH
Heiss
Andrea V
AV
Schwaiberger
Daniel
D
Schachner
Irene M
IM
Sroka
Tina
T
Oberan
Angelika M
AM
Vollmar
Verena M
VM
Dirsch
D000818:Animals; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000187:drug effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D011429:Propolis / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects*
D002109:Caffeic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D011429:Propolis; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol