Resveratrol reverses ET-1-evoked mitogenic effects in human coronary arterial cells by activating the kinase-G to inhibit ERK-enzymes.
In human coronary smooth muscle cells (HCSMC), treatment with the vascular mitogen; endothelin-1 (ET-1), induced cell proliferation and stimulated ERK-1/2 phosphorylation at active sites. Pretreatment with the MEK-ERK inhibitor (PD98059) appreciably reversed the mitogenic effects of ET-1. On the other hand, pretreatment with the polyphenolic stilbene resveratrol (RSVL, 1-100 microM) triggered more prominent inhibition of ET-1-evoked cell proliferation and ERK1/2 activation. Besides, RSVL also markedly (2-3 fold) and rapidly enhanced cGMP formation, but had no effect on cAMP levels. This RSVL-evoked upregulation of cGMP was insensitive to pretreatment with the soluble guanylyl cyclase (sGC)-inhibitor (ODQ, 10 microM), but was ablated with an inhibitor of pGC (PMA, 0.1 microM). Further, pretreatment with the specific cGMP-phosphodiesterase inhibitor, zaprinast (10 microM) appreciably augmented RSVL-evoked cGMP formation, ERK inhibition, and cytostatic response. Moreover, the RSVL-induced ERK-inhibitory effects were significantly reversed by the kinase-G inhibitor, KT-5823 (10 microM; 69%), but not by the kinase-A inhibitor (KT-5720). These results demonstrate a novel signaling pathway for RSVL that leads from activation of the pGC/kinase-G system to inhibition of ERK1/2 and their downstream nuclear targets. This pathway functions to counteract the atherogenic signaling induced by vascular mitogens.
El-Mowafy
A M
AM
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt. aelmowafy@yahoo.com
Alkhalaf
M
M
Nassar
N N
NN
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D002227:Carbazoles; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D008934:Mitogens; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013267:Stilbenes; C073601:KT 5823; C057416:KT 5720; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006162:Guanylate Cyclase; D000077185:Resveratrol