Repetitive ROS Injury Leads to Inactivation of NRF2‐Induced Antioxidant Defense and Mitochondrial Dysfunction in Ischemic Heart Failure

Abstract

Ischemic heart failure (IHF) is associated with an imbalance of reactive oxygen species (ROS) and antioxidants. In IHF, the failing heart is repeatedly exposed to increased ROS secondary to multiple factors including mitochondrial dysfunction. Repetitive injury, such as occurs in IHF with increased ROS, can have effects much different from a single treatment. Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2), is the master regulator of antioxidant genes. Nrf2 binds to Kelch like‐ECH‐associated protein (KEAP) 1 under normal conditions. When stressed by ROS, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it activates the antioxidant response element (ARE) pathway. We found that Nrf2 was paradoxically decreased in left ventricles from rats with IHF, as are antioxidant genes. In isolated adult rat cardiac myocytes subjected to repetitive H2O2 treatment, this repetitive ROS exposure decreased Nrf2 expression, nuclear binding activity, and reduced cytoplasmic Nrf2 translocation to the nucleus. Moreover, mitochondria isolated from the stressed cardiac myocyte showed decreased expression of mitochondrial dynamics related proteins, including OPA1, Parkin, and VCP, consistent with our findings with in vivo heart failure. The Nrf2 knockout heterozygous mice had impaired cardiac function. Overall, our data show that repetitive ROS treatment leads to paradoxical inactivation of the Nrf2‐induced antioxidant defense and mitochondrial dysfunction in heart failure.