THE MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY CAN MEDIATE GROWTH-INHIBITION AND PROLIFERATION IN SMOOTH-MUSCLE CELLS - DEPENDENCE ON THE AVAILABILITY OF DOWNSTREAM TARGETS

Activation of the classical mitogen-activated protein kinase (MAPK) pa thway leads to proliferation of many cell types. Accordingly, an inhib itor of MAPK kinase, PD 098059, inhibits PDGF-induced proliferation of human arterial smooth muscle cells (SMCs) that do not secrete growth- inhibitory PGs such as PGE(2). In striking contrast, in SMCs that expr ess the inducible form of cyclooxygenase (COX-2), activation of MAPK s erves as a negative regulator of proliferation. In these cells, PDGF-i nduced MAPK activation leads to cytosolic phospholipase A(2) activatio n, PGE(2) release, and subsequent activation of the cAMP-dependent pro tein kinase (PKA), which acts as a strong inhibitor of SMC proliferati on. Inhibition of either MAPK kinase signaling or of COX-2 in these ce lls releases them from the influence of the growth-inhibitory PGs and results in the subsequent cell cycle traverse and proliferation. Thus, the MAPK pathway mediates either proliferation or growth inhibition i n human arterial SMCs depending on the availability of specific downst ream enzyme targets.