Ephx2, encoding soluble epoxide hydrolase, is an enzyme that hydrolyzes epoxyeicosatrienoic acids (EETs) to less active dihydroxyeicosatrienoic acids. EETs are products of arachidonic acid metabolism by cytochromes P450, involved in multiple physiological processes like coronary vasodilation and cell protection [3]. Ephx2 thus impacts these EET-related pathways, making it important in cardiovascular and other physiological functions [3]. Genetic models, such as gene knockout (KO) mouse models, have been crucial in understanding its functions.

In muscle regeneration, deletion of Ephx2 leads to the accumulation of 11,12-EET, which accelerates muscle regeneration. Mechanistically, 11,12-EET boosts the activation and proliferation of muscle stem cells by modulating fibroblast growth factor signalling [1]. In the heart, disruption of Ephx2 in cardiomyocytes, but not endothelial cells, improves functional recovery after ischemia-reperfusion, as most cardiac Ephx2 expression and activity are in cardiomyocytes [3]. In colon cancer, EPHX2 acts as a tumor suppressor by promoting fatty acid degradation [4]. Also, in Alzheimer's disease, EPHX2 may mediate the pathogenesis by affecting the entire hippocampal volume, and could be a potential therapeutic target [2].

In conclusion, Ephx2 plays diverse and significant roles in various biological processes and diseases. KO mouse models have been instrumental in revealing its functions in muscle regeneration, cardiac post-ischemic function, colon cancer progression, and Alzheimer's disease pathogenesis. Understanding Ephx2 provides insights into potential therapeutic strategies for treating related diseases.

References:

1. Chi, Zhexu, Chen, Sheng, Yang, Dehang, Ding, Kefeng, Wang, Di. 2024. Gasdermin D-mediated metabolic crosstalk promotes tissue repair. In Nature, 634, 1168-1177. doi:10.1038/s41586-024-08022-7. https://pubmed.ncbi.nlm.nih.gov/39260418/

2. Su, Wei-Ming, Gu, Xiao-Jing, Dou, Meng, Wang, Yi, Chen, Yong-Ping. 2023. Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease. In Journal of neurology, neurosurgery, and psychiatry, 94, 954-961. doi:10.1136/jnnp-2023-331142. https://pubmed.ncbi.nlm.nih.gov/37349091/

3. Edin, Matthew L, Gruzdev, Artiom, Bradbury, J Alyce, Fleming, Ingrid, Zeldin, Darryl C. 2023. Disruption of Ephx2 in cardiomyocytes but not endothelial cells improves functional recovery after ischemia-reperfusion in isolated mouse hearts. In The Journal of biological chemistry, 299, 103049. doi:10.1016/j.jbc.2023.103049. https://pubmed.ncbi.nlm.nih.gov/36822325/

4. Zhou, Yiran, Li, Xiao, Guan, Aoran, Wang, Ruotian, Li, Ruhong. 2022. EPHX2 Inhibits Colon Cancer Progression by Promoting Fatty Acid Degradation. In Frontiers in oncology, 12, 870721. doi:10.3389/fonc.2022.870721. https://pubmed.ncbi.nlm.nih.gov/35433439/