Signaling pathways involved in DNA synthesis and migration in response to lysophosphatidic acid and low-density lipoprotein in coronary artery smooth muscle cells

摘要

Low-density lipoprotein (LDL) and lysophosphatidic acid (LPA), one of the lipid components of lipoprotein, induced the DNA synthesis of coronary artery smooth muscle cells (CASMCs). The LDL- and LPA-induced DNA synthesis was markedly inhibited by the LPA receptor antagonist Kil6425, pertussis toxin, small interfering RNAs targeted for LPA_1 receptors, and a potent calcineurin inhibitor cydosporine A. It has been reported that LDL and LPA induced a migration response in a manner sensitive to Kil6425, pertussis toxin, and a LPA_1 receptor-specific small interfering RNA. However, cydosporine A was ineffective in inhibiting the migration response. Instead, an epidermal growth factor (EGF) receptor tyrosine kinase inhibitor markedly suppressed the migration response to LDL and LPA without having any significant effect on DNA synthesis. Thus, the LDL-induced stimulation of DNA synthesis and migration in CASMCs is mediated by its component LPA through LPA_1 receptors and G_i/o-proteins. Ca~2+/calcineurin pathways and transactivation of EGF receptors mediate LPA_1-receptor-induced DNA synthesis and migration, respectively.