Implications of the OLFR2 Receptor in Lipid Peroxidation-Induced Endothelial Dysfunction in Diabetic Mouse Aorta

Introduction/Objectives: Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and reduced insulin production. Among the mechanisms contributing to these complications, lipid peroxidation and oxidative stress play critical roles by exacerbating inflammation and vascular dysfunction. One method commonly used to study lipid peroxidation is the use of tert-Butyl Hydroperoxide (t-BHP). Recent studies have identified that products derived from lipid peroxidation can activate olfactory receptor type 2 (Olfr2). Activation of Olfr2 leads to oxidative stress production and the subsequent activation of the NLR family pyrin domain containing 3 (NLRP3) and other inflammasome factors. Despite these findings, the precise relationship between Olfr2 activation by lipid peroxidation and endothelial dysfunction remains poorly understood. Therefore, we hypothesize that lipid peroxidation activates Olfr2 receptors, leading to endothelial dysfunction. Methods: The thoracic aortas from 14-16 weeks old male wild-type, lean and db/db mice were isolated and mounted in a wire myograph. Concentration-response curves to phenylephrine (PE; 1 nM to 30 µM) and acetylcholine (ACh; 1 nM to 30 µM) were obtained. Following a 30-minute incubation period with t-BHP (100 nM) and 30-minute incubation period with citral (10 µM) and t-BHP (100 nM), concentration response curves to the same agonists were then repeated. The expression of Olfr2, NLRP3, and AIM2 was evaluated by RT-qPCR. Data are expressed as mean ± S.E.M. (n=4-6). The negative logarithm of the effective concentration 50 (pEC 50 ) and the maximum efficacy (E max ) were calculated by non-linear regression curve. Statistical significance was accepted at *p<0.05. Results: In the thoracic aortas, incubation with t-BHP: 1) reduced the ACh-induced relaxant responses in wild-type (E max =39.7 ± 5.5%*; pEC 50 =6.1 ± 0.2%) and db/db mice (E max =3.3 ± 2.3%*; pEC 50 =6.1 ± 0.4%), and 2) increased the contractile responses in wild-type (E max =7.5 ± 0.3 mN*; pEC 50 =7.2 ± 0.1 mN) and lean (E max =7.8 ± 0.4* mN; pEC 50 =7.5 ± 0.1 mN). On the other hand, incubation with citral plus t-BHP: 1) enhanced the relaxant responses in wild-type (E max =78.3 ± 2.9%*; pEC 50 =6.2 ± 0.4%) and db/db mice (E max =10.9 ± 3.3%*; pEC 50 =6.2 ± 0.4%), and 2) decreased the contractile responses in wild-type (E max =5.3 ± 0.3* mN; pEC 50 =6.7 ± 0.1 mN), lean (E max =5.4 ± 0.3* mN; pEC 50 =7.3 ± 0.2 mN), and db/db mice (E max =4.7 ± 1*; pEC 50 =7.6 ± 1.0 mN). The expression of Olfr2, NLRP3, and AIM2 increased with t-BHP incubation, while citral and t-BHP incubation reduced it in thoracic aortas from wild-type. Conclusions: This study focuses on the impact of an olfactory receptor on vascular function. Regarding our hypothesis, we propose that these effects on vascular reactivity could be mediated by the Olfr2 receptor. NIH DK132948 (Institute on Cardiovascular Disease Research) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.