出版社：American Society for Biochemistry and Molecular Biology
摘要：Lysophosphatidylcholine (LPC) may accumulate in the heart to cause fibrotic events, which is mediated through fibroblast activation and collagen accumulation. Here, we evaluated the mechanisms underlying LPC-mediated collagen induction via mitochondrial events in human cardiac fibroblasts (HCFs), coupling application of the pharmacologic cyclooxygenase-2 (COX-2) inhibitor, celecoxib, and genetic mutations in FOXO1 on the fibrosis pathway. In HCFs, LPC caused prostaglandin E 2 (PGE 2 )/PGE 2 receptor 4 (EP 4 )-dependent collagen induction via activation of transcriptional activity of forkhead box protein O1 (FoxO1) on COX-2 gene expression. These responses were mediated through LPC-induced generation of mitochondrial reactive oxygen species (mitoROS), as confirmed by ex vivo studies, which indicated that LPC increased COX-2 expression and oxidative stress. LPC-induced mitoROS mediated the activation of protein kinase C (PKC)α, which interacted with and phosphorylated dynamin-related protein 1 (Drp1) at Ser 616 , thereby increasing Drp1-mediated mitochondrial fission and mitochondrial depolarization. Furthermore, inhibition of PKCα and Drp1 reduced FoxO1-mediated phosphorylation at Ser 256 and nuclear accumulation, which suppressed COX-2/PGE 2 expression and collagen production. Moreover, pretreatment with celecoxib or COX-2 siRNA suppressed WT FoxO1; mutated Ser 256 -to-Asp 256 FoxO1-enhanced collagen induction, which was reversed by addition of PGE 2 . Our results demonstrate that LPC-induced generation of mitoROS regulates PKCα-mediated Drp1-dependent mitochondrial fission and COX-2 expression via a PKCα/Drp1/FoxO1 cascade, leading to PGE 2 /EP 4 -mediated collagen induction. These findings provide new insights about the role of LPC in the pathway of fibrotic injury in HCFs.
关键词：heart ; cell signaling ; extracellular matrix ; inflammation ; lysophospholipid ; cardiac fibrosis ; mitochondrial fission ; dynamin-related protein 1 ; forkhead box protein O1 ; protein kinase Cα
