OPLAH, also known as 5-oxoprolinase, is an enzyme in the γ-glutamyl cycle. It functions by scavenging 5-oxoproline, and its activity is related to oxidative stress regulation, which is crucial for maintaining normal cellular function and is involved in multiple biological processes and disease-related pathways [1,3,4].

OPLAH ablation in full-body knock-out (KO) mice led to higher 5-oxoproline levels, increased oxidative stress, cardiac and renal fibrosis, elevated left ventricular filling pressures, and impaired left ventricular relaxation, while maintaining a normal left ventricular ejection fraction. These KO mice also had a higher mortality rate following cardiac ischaemia/reperfusion injury compared to wild-type mice. Additionally, they showed increased organ weights. In human HFpEF patients, 5-oxoproline levels were significantly elevated in plasma compared to healthy controls [1]. In Chinese hamsters with type 2 diabetes mellitus, downregulation of OPLAH in skeletal muscle was associated with increased oxidative stress, insulin resistance, and impaired glucose uptake. Silencing OPLAH in human skeletal muscle cells led to similar effects, including increased reactive oxygen species, decreased GSH content, inhibited PI3K/Akt/GLUT4 signaling pathway, and reduced glucose uptake [2].

In conclusion, OPLAH plays a vital role in regulating oxidative stress. Studies using KO mouse models have revealed its significance in heart failure with a preserved ejection fraction and type 2 diabetes mellitus. These models have been instrumental in understanding how OPLAH deficiency can lead to pathological changes related to oxidative stress-associated diseases, providing insights into potential therapeutic targets for these conditions [1,2].

References:

1. van der Pol, Atze, Gil, Andres, Tromp, Jasper, Bischoff, Rainer, van der Meer, Peter. . OPLAH ablation leads to accumulation of 5-oxoproline, oxidative stress, fibrosis, and elevated fillings pressures: a murine model for heart failure with a preserved ejection fraction. In Cardiovascular research, 114, 1871-1882. doi:10.1093/cvr/cvy187. https://pubmed.ncbi.nlm.nih.gov/30032247/

2. Shi, Zeya, Huo, Yitong, Hou, Jianan, Chen, Zhenwen, Chen, Zhaoyang. 2022. Proteomic analysis of skeletal muscle in Chinese hamsters with type 2 diabetes mellitus reveals that OPLAH downregulation affects insulin resistance and impaired glucose uptake. In Free radical biology & medicine, 193, 23-33. doi:10.1016/j.freeradbiomed.2022.09.029. https://pubmed.ncbi.nlm.nih.gov/36195162/

3. van der Pol, Atze, Gil, Andres, Silljé, Herman H W, Bischoff, Rainer, van der Meer, Peter. . Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH. In Science translational medicine, 9, . doi:10.1126/scitranslmed.aam8574. https://pubmed.ncbi.nlm.nih.gov/29118264/

4. Bachhawat, Anand K, Yadav, Shambhu, Jainarayanan, Ashwin K, Dubey, Pratiksha. . Heart failure and the glutathione cycle: an integrated view. In The Biochemical journal, 477, 3123-3130. doi:10.1042/BCJ20200429. https://pubmed.ncbi.nlm.nih.gov/32886767/