Epoxyeicosatrienoic Acids and Fibrosis: Recent Insights for the Novel Therapeutic Strategies

Figures

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  Figure 1. EET regioisomers synthesized from arachidonic acid by CYPs and their conversion to DHETs by sEH.

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  Figure 2. Anti-renal fibrosis mechanisms of EETs. The fibrotic preventative effects of EETs are mediated by the reduction of apoptosis, inflammation, and endoplasmic reticulum stress. EETs activate PPAR-γ, downregulate NF-κB, reduce UUO-induced tubular cell death, and inhibit TGF-β1/Smad3 signaling pathways. EETs lessen collagen deposition and renal cell apoptosis via the regulation of protein expression, including TGF-β1/Smads, MMPs, MAPKs, and apoptosis-related proteins. Thus, EETs could be a promising strategy for the clinical treatment of renal fibrosis.

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  Figure 3. Anti-cardiac fibrosis mechanisms of EETs. EETs could diminish fibrosis associated with cardiac hypertrophy and remodeling, as well as apoptosis and inflammation. EETs block the fibrotic response in Ang II-infusion hearts by inhibiting CaN/NFATC3 signaling. The increase of EETs is shown to reduce cardiac fibroblast activation, proliferation, migration, and secretion capacity by inhibiting the Gα12/13/RhoA/ROCK pathway via NO/cGMP activation. Additionally, enhanced EET formation minimizes cardiomyocyte hypertrophy and remodeling, while limiting collagen accumulation through the inhibition of the oxidative-stress-mediated NF-κB pathway via PPAR-γ activation.

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  Figure 4. Anti-pulmonary fibrosis mechanisms of EETs. EETs inhibit the proliferation and collagen synthesis of mouse fibroblasts, partially reversing TGF-β1-induced α-SMA expression and EMT. These effects are found to be partially mediated via downregulation of the Smad3 and p38MAPK signaling pathways. Exogenous EET treatment attenuates TNF-α-induced apoptosis and pulmonary vascular remodeling, protecting against oxidative stress and apoptosis following lung ischemia/reperfusion by activating the PI3K/Akt signaling pathways.

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  Figure 5. Anti-hepatic fibrosis mechanisms of EETs. The protective effect against hepatic fibrosis is mostly due to inhibition of HSC activation and NF-κB signaling by EETs, sEH inhibition reduced collagen deposition, and the mRNA level of the ECM components. EETs alter the activity of MMPs and inhibit ER stress, which could affect ECM synthesis and the progression of hepatic fibrosis.