modulating the biliverdin reductase (bvr)/erk1/2 axis to attenuate oxidative stress in rat arterial rings

Background: 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. objectives: 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. methods: 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). results: 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. conclusions: 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.