Abstract 126: Lysophosphatidic Acid Induces Early Growth Response Protein 1 Expression via the Protein Kinase Cδ-Regulated ERK and JNK Activation in Vascular Smooth Muscle Cells
Lysophosphatidic acid (LPA) modulates vascular cell function in vitro and in vivo via regulating the expression of specific genes. Previously we reported that a transcriptional mechanism controls LPA-induced expression of early growth response protein 1 (Egr-1) in vascular smooth muscle cells (SMCs). Egr-1 is a master transcription factor mediating the expression of various genes that have been implied to modulate a broad spectrum of vascular pathologies. In this study, we determined the essential intracellular signaling pathway leading to LPA-induced Egr-1 expression. Our data demonstrate that activation of ERK-1/2 and JNK, but not p38 MAPK, is required for LPA-induced Egr-1 expression in SMCs. We show the first evidence that MEK/ERK-mediated JNK activation leads to LPA-induced gene expression. Examining the upstream kinases that mediate ERK and JNK activation leading to Egr-1 expression, we found that LPA-induced activation of MAPKs and expression of Egr-1, are dependent on PKC activation. We observed that LPA rapidly activates PKC δ and θ. Overexpression of dominant negative PKCδ, but not dominant negative PKCθ, diminished activation of ERK and JNK and blocked LPA-induced expression of Egr-1 mRNA and protein. We have also evaluated LPA receptor involvement. Our data reveal an intracellular regulatory mechanism: LPA induction of Egr-1 expression is via the LPA cognate receptor, LPA1-dependent and PKCδ-mediated ERK and JNK activation. This study provides the first evidence that PKCδ mediates ERK and JNK activation in the LPA signaling pathway and that this pathway is required for LPA-induced gene regulation as evidenced by Egr-1 expression.
- © 2012 by American Heart Association, Inc.