Activation of mitogen-activated protein kinase pathways by cyclic GMP and cyclic GMP-dependent protein kinase in contractile vascular smooth muscle cells.

Komalavilas P, Shah PK, Jo H, Lincoln TM
J Biol Chem. 1999 274 (48): 34301-9

PMID: 10567406 · DOI:10.1074/jbc.274.48.34301

Vascular smooth muscle cells (VSMC) exist in either a contractile or a synthetic phenotype in vitro and in vivo. The molecular mechanisms regulating phenotypic modulation are unknown. Previous studies have suggested that the serine/threonine protein kinase mediator of nitric oxide (NO) and cyclic GMP (cGMP) signaling, the cGMP-dependent protein kinase (PKG) promotes modulation to the contractile phenotype in cultured rat aortic smooth muscle cells (RASMC). Because of the potential importance of the mitogen-activated protein kinase (MAP kinase) pathways in VSMC proliferation and phenotypic modulation, the effects of PKG expression in PKG-deficient and PKG-expressing adult RASMC on MAP kinases were examined. In PKG-expressing adult RASMC, 8-para-chlorophenylthio-cGMP activated extracellular signal- regulated kinases (ERK1/2) and c-Jun N-terminal kinase (JNK). The major effect of PKG activation was increased activation by MAP kinase kinase (MEK). The cAMP analog, 8-Br-cAMP inhibited ERK1/2 activation in PKG-deficient and PKG-expressing RASMC but had no effect on JNK activity. The effects of PKG on ERK and JNK activity were additive with those of platelet-derived growth factor (PDGF), suggesting that PKG activates MEK through a pathway not used by PDGF. The stimulatory effects of cGMP on ERK and JNK activation were also observed in low-passaged, contractile RASMC still expressing endogenous PKG, suggesting that the effects of PKG expression were not artifacts of cell transfections. These results suggest that in contractile adult RASMC, NO-cGMP signaling increases MAP kinase activity. Increased activation of these MAP kinase pathways may be one mechanism by which cGMP and PKG activation mediate c-fos induction and increased proliferation of contractile adult RASMC.

MeSH Terms (32)

8-Bromo Cyclic Adenosine Monophosphate Alkaloids Animals Aorta Carbazoles Cells, Cultured Cyclic GMP Cyclic GMP-Dependent Protein Kinases Enzyme Activation Enzyme Inhibitors Gene Expression Indoles JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase 4 MAP Kinase Kinase Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Muscle, Smooth, Vascular Muscle Contraction p38 Mitogen-Activated Protein Kinases Platelet-Derived Growth Factor Protein-Serine-Threonine Kinases Pyrroles Rats Rats, Sprague-Dawley Recombinant Fusion Proteins Thionucleotides Time Factors Transfection Tumor Necrosis Factor-alpha

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