细胞生物学
信号转导
化学
前列腺素E2受体
SMAD公司
肌成纤维细胞
成纤维细胞
分子生物学
生物
纤维化
受体
生物化学
内科学
医学
体外
兴奋剂
作者
Lakshminarayan Reddy Teegala,Ravindra Gudneppanavar,Emma Elizabeth Sabu Kattuman,Matthew Snyderman,A. V. Thanusha,Kumar Venkatesh,Charles K. Thodeti,Sailaja Paruchuri
标识
DOI:10.1096/fj.202300745rr
摘要
Prostaglandin E2 (PGE2 ) has been implicated in counteracting fibroblast differentiation by TGFβ1 during pulmonary fibrosis. However, the precise mechanism is not well understood. We show here that PGE2 via EP2 R and EP4 R inhibits the expression of mechanosensory molecules Lysyl Oxidase Like 2 (LOXL2), myocardin-related transcription factor A (MRTF-A), ECM proteins, plasminogen activation inhibitor 1 (PAI-1), fibronectin (FN), α-smooth muscle actin (α-SMA), and redox sensor (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)) required for TGFβ1-mediated fibroblast differentiation. We further demonstrate that PGE2 inhibits fibrotic signaling via Yes-associated protein (YAP) but does so independently from its actions on SMAD phosphorylation and conserved cylindromatosis (CYLD; deubiquitinase) expression. Mechanistically, PGE2 phosphorylates/inactivates YAP downstream of EP2 R/Gαs and restrains its translocation to the nucleus, thus inhibiting its interaction with TEA domain family members (TEADs) and transcription of fibrotic genes. Importantly, pharmacological or siRNA-mediated inhibition of YAP significantly downregulates TGFβ1-mediated fibrotic gene expression and myofibroblast formation. Notably, YAP expression is upregulated in the lungs of D. farinae-treated wild type (WT) mice relative to saline-treated WT mice. Our results unravel a unique role for PGE2 -YAP interactions in fibroblast differentiation, and that PGE2 /YAP inhibition can be used as a novel therapeutic target in the treatment of pathological conditions associated with myofibroblasts like asthma.
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