Lysophosphatidylcholine-induced mitochondrial fission contributes to collagen production in human cardiac fibroblasts[S]

• Published in: Journal of lipid research Vol. 60; no. 9; pp. 1573 - 1589
• Main Authors: Tseng, Hui-Ching, Lin, Chih-Chung, Hsiao, Li-Der, Yang, Chuen-Mao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; Blotting, Western; cardiac fibrosis; cell signaling; Collagen - metabolism; Cyclooxygenase 2 - metabolism; dynamin-related protein 1; extracellular matrix; Fibroblasts - drug effects; Fibroblasts - metabolism; forkhead box protein O1; Forkhead Box Protein O1 - metabolism; heart; inflammation; Lysophosphatidylcholines - pharmacology; lysophospholipid; Male; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Dynamics - physiology; mitochondrial fission; protein kinase Cα; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; forkhead box protein O1; inflammation; cardiac fibrosis; cell signaling; dynamin-related protein 1; protein kinase Cα; lysophospholipid; mitochondrial fission; heart; extracellular matrix
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.RA119000141

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 E2 (PGE2)/PGE2 receptor 4 (EP4)-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 Ser616, thereby increasing Drp1-mediated mitochondrial fission and mitochondrial depolarization. Furthermore, inhibition of PKCα and Drp1 reduced FoxO1-mediated phosphorylation at Ser256 and nuclear accumulation, which suppressed COX-2/PGE2 expression and collagen production. Moreover, pretreatment with celecoxib or COX-2 siRNA suppressed WT FoxO1; mutated Ser256-to-Asp256 FoxO1-enhanced collagen induction, which was reversed by addition of PGE2. 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 PGE2/EP4-mediated collagen induction. These findings provide new insights about the role of LPC in the pathway of fibrotic injury in HCFs.