# Modulating the Biliverdin Reductase (BVR)/ERK1/2 Axis to Attenuate Oxidative Stress in Rat Arterial Rings

## TL;DR

This study shows that combining bilirubin and an ERK1/2 inhibitor reduces oxidative stress and improves vascular function in rat aortic rings.

## Contribution

The study demonstrates that ERK1/2 inhibition enhances the antioxidant and vascular protective effects of bilirubin.

## Key findings

- The combination of bilirubin and PD-98059 significantly improved aortic relaxation and Emax under normoxic and H/R conditions.
- ERK1/2 inhibition upregulated BVR activity, increasing bilirubin synthesis and reducing oxidative damage.
- Targeting the BVR/ERK1/2 axis may offer a therapeutic strategy for oxidative stress-related cardiovascular diseases.

## Abstract

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.