LYSOPHOSPHATIDIC ACID AND INTRACELLULAR SIGNALING IN VASCULAR SMOOTH-MUSCLE CELLS

Growth of vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of atherosclerosis and hypertension. Lysophosphati dic acid (LPA), a natural phospholipid is thought to be an important V SMC mitogen and has recently been suggested to play an important role in the development of vascular disease. In the present study, we descr ibe the effects of LPA on intracellular signalling pathways in VSMC. L PA (5 mu g/ml) induced an increase of cytosolic free calcium concentra tion ([Ca2+](i)) in the presence and absence of extracellular Ca2+ and markedly stimulated the Na+/H+ exchanger. LPA dose-dependently caused a stimulation of the 42-kDa mitogen-activated protein kinase (MAP kin ase) isoform with a maximum at 5 min. Also, LPA induced a 5-fold incre ase in [H-3]thymidine incorporation into cell DNA above the basal valu e, as well as a 42% increase in cell number. Pretreatment of VSMC with pertussis toxin (PTX) (100 ng/ml) for 24 h markedly blunted the LPA-d ependent intracellular signalling transduction including the increase in [Ca2+](i), activation of the Na+/H+ exchanger, activation of MAP ki nase and the increase in cell DNA synthesis. These findings demonstrat e that the effects of LPA on intracellular signalling transduction pat hway as well as on VSMC growth are mediated by PTX-sensitive guanosine triphosphate (GTP) binding protein (G(i) protein). (C) 1997 Elsevier Science Ireland Ltd.