Resveratrol reverses hydrogen peroxide-induced proliferative effects in human coronary smooth muscle cells: a novel signaling mechanism.
BACKGROUND
In human coronary smooth muscle cells (HCSMCs), we tested the proatherogenic/proliferative potential of the reactive oxygen species (ROS), hydrogen peroxide (HP), and the ability of the polyphenol stilbene resveratrol (RSVL) to protect against such effects.


METHODS
Activity for ERK1/2 and the kinase-G cascade were determined and correlated with HCSMC count before and after treatment with HP and/or RSVL.


RESULTS
HP evoked concentration-dependent cell proliferation and stimulated ERK1/2 phosphorylation at active sites. Pretreatment with the MEK-ERK inhibitor (PD98059) reversed these effects of HP. RSVL (1-100 microM) elicited more prominent inhibition of HP-evoked cell proliferation and ERK1/2 activation. In addition, RSVL markedly enhanced cGMP formation, a response that was insensitive to the soluble guanylyl-cyclase (sGC) inhibitor (ODQ, 10 microM) but was obliterated with the phorbol ester, (PMA, 0.1 microM), a desensitizer of the pGC enzyme. Likewise, the RSVL-evoked cytostatic and ERK inhibitory effects were significantly reversed by the kinase-G-inhibitor, KT-5823 (10 microM).


CONCLUSIONS
Collectively, RSVL activates the kinase-G system to counteract HP-induced ERK1/2 activation and coronary arterial proliferation. These effects for RSVL remain functional in endothelium-disrupted arteries, scenarios that commonly occur in advanced coronary heart disease.
El-Mowafy
Abdalla M
AM
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. aelmowafy@yahoo.com
Alkhalaf
Moussa
M
El-Kashef
Hassan A
HA
D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000166:cytology / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology*; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
D000975:Antioxidants; D005419:Flavonoids; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D013267:Stilbenes; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077185:Resveratrol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one