The Crataegus extract WS 1442 inhibits balloon catheter-induced intimal hyperplasia in the rat carotid artery by directly influencing PDGFR-beta.
OBJECTIVE
Effective systemic drugs against restenosis upon percutaneous transluminal coronary angioplasty (PTCA) are largely lacking. Polyphenols have been suggested to ameliorate post-angioplasty restenosis. Hawthorn (Crataegus spp.) extracts, which are among the most frequently used herbal medicinal products against mild forms of congestive heart failure, contain polyphenols, but have not been investigated in this context. We aimed to assess the potential of the hawthorn extract WS 1442 to prevent balloon catheter-induced intimal hyperplasia and to elucidate the underlying mechanisms.


METHODS
We analyzed the effects of WS 1442 on serum-induced vascular smooth muscle cell (VSMC) and endothelial cell (EC) growth and migration, growth factor-induced proliferation, growth factor receptor activity, and neointima formation in the rat carotid artery model.


RESULTS
WS 1442 (100 microg/ml) decreased VSMC migration by 38% and proliferation by 44%, whereas EC migration and proliferation were unaltered. The extract inhibited VSMC DNA synthesis induced by platelet-derived growth factor (PDGF) (IC(50): 47 microg/ml), but not that of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Along this line, WS 1442 blocked recombinant human PDGF receptor (PDGFR)-beta kinase activity (IC(50): 1.4 microg/ml) and decreased PDGFR-beta activation and extracellular signal-regulated kinase (ERK) activation in VSMCs. In rats, orally administered WS 1442 significantly reduced neointima formation after balloon catheter dilatation of the carotid artery.


CONCLUSIONS
WS 1442 inhibits migration and proliferation of VSMCs, but not of ECs, and reduces balloon catheter-evoked neointima formation probably through inhibition of PDGFR-beta. Thus, the present study suggests a novel adjunct pharmacological strategy to prevent angioplasty-related restenosis.
Fürst
Robert
R
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstr. 5-13, 81377 Munich, Germany. robert.fuerst@cup.uni-muenchen.de
Zirrgiebel
Ute
U
Totzke
Frank
F
Zahler
Stefan
S
Vollmar
Angelika M
AM
Koch
Egon
E
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D002339:Carotid Arteries / Q000473:pathology*; D002404:Catheterization / Q000009:adverse effects*; D042783:Endothelial Cells / Q000166:cytology; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D041681:NIH 3T3 Cells; D028321:Plant Preparations / Q000494:pharmacology; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D014945:Wound Healing
D005419:Flavonoids; D036341:Intercellular Signaling Peptides and Proteins; D028321:Plant Preparations; C421782:WS 1442; D020797:Receptor, Platelet-Derived Growth Factor beta