Sharma Kuldeepak, Sterle Mateja Skufca, Mozina Hugon
Department of Medicine, Institute of Pharmacology and Toxicology, University of Ljubljana, Ljubljana, Slovenia.
Prehospital Unit, Community Health Centre, Ljubljana, Slovenia.
Iran J Pharm Res. 2024 Dec 4;23(1):e156828. doi: 10.5812/ijpr-156828. eCollection 2024 Jan-Dec.
Biliverdin reductase (BVR) plays a central role in bile pigment metabolism by reducing biliverdin (BV) to bilirubin (BR), a potent antioxidant that scavenges reactive oxygen species (ROS) under normal and pathological conditions. Elevated oxidative stress activates extracellular signal-regulated protein kinases 1/2 (ERK1/2) signaling, which strongly interacts with BVR's C and D motifs, forming the BVR/ERK1/2 axis. In pathological states, increased ERK1/2 activity inhibits BVR's ability to convert BV to BR, exacerbating oxidative damage and contributing to cardiovascular disease. Therefore, the interaction between BVR and ERK1/2 is critical in modulating oxidative stress.
This study aimed to evaluate the effects of BR and the ERK1/2 inhibitor PD-98059, both individually and in combination, on ROS levels, ERK1/2 activity, and vascular responses under normoxic and hypoxia-reoxygenation (H-R) injury conditions.
Aortic rings from rats were subjected to equal distending pressure after oxidative stress induction using 22'-Azobis (2-amidinopropane) dihydrochloride (ABAP) in an organ bath. Different doses of BR were administered in combination with the ERK1/2 inhibitor PD-98059 to assess their impact on ROS depletion, vascular relaxation, and maximal effect (Emax).
The combination of BR and PD-98059 significantly enhanced aortic relaxation and Emax under both normoxic and H/R conditions compared to either treatment alone. Inhibiting ERK1/2 with PD-98059 appeared to upregulate BVR activity, increasing BR synthesis and reducing oxidative damage in aortic rings.
Biliverdin reductase plays a vital role in defending against oxidative stress and endothelial dysfunction through its dual-specificity kinase activity and interaction with ERK1/2. ERK1/2 inhibition further enhances BR's ROS-scavenging ability and vascular protective effects. Targeting the interaction between BVR and ERK1/2 holds potential as an effective therapeutic strategy for conditions characterized by excessive ROS levels, such as cardiovascular diseases.
胆绿素还原酶（BVR）在胆汁色素代谢中起核心作用，它将胆绿素（BV）还原为胆红素（BR），胆红素是一种强效抗氧化剂，在正常和病理条件下可清除活性氧（ROS）。氧化应激升高会激活细胞外信号调节蛋白激酶1/2（ERK1/2）信号通路，该通路与BVR的C和D基序强烈相互作用，形成BVR/ERK1/2轴。在病理状态下，ERK1/2活性增加会抑制BVR将BV转化为BR的能力，加剧氧化损伤并导致心血管疾病。因此，BVR与ERK1/2之间的相互作用在调节氧化应激中至关重要。
本研究旨在评估胆红素（BR）和ERK1/2抑制剂PD-98059单独及联合使用对常氧和缺氧复氧（H-R）损伤条件下ROS水平、ERK1/2活性和血管反应的影响。
在器官浴中使用2,2'-偶氮二异丁脒二盐酸盐（ABAP）诱导氧化应激后，对大鼠主动脉环施加相等的扩张压力。将不同剂量的BR与ERK1/2抑制剂PD-98059联合使用，以评估它们对ROS清除、血管舒张和最大效应（Emax）的影响。
与单独使用任何一种处理相比，BR和PD-98059联合使用在常氧和H/R条件下均显著增强了主动脉舒张和Emax。用PD-98059抑制ERK1/2似乎上调了BVR活性，增加了BR合成并减少了主动脉环中的氧化损伤。
胆绿素还原酶通过其双特异性激酶活性以及与ERK1/2的相互作用，在抵御氧化应激和内皮功能障碍中起着至关重要的作用。抑制ERK1/2可进一步增强BR的ROS清除能力和血管保护作用。针对BVR与ERK1/2之间的相互作用作为一种有效的治疗策略，对于以ROS水平过高为特征的疾病（如心血管疾病）具有潜力。
