| Popis: |
Oxidative stress and mitochondrial dysfunction have major roles in the pathophysiology of cardiovascular disease. Mitochondria are the predominant source of energy production in the heart. Mitochondrial dysfunction decreases ATP production, while increasing reactive oxygen species (ROS) production. Early mitochondrial dysfunction leads to a vicious cycle, where excess ROS damages the mitochondria, leading to increased ROS production and impaired ATP production, decreasing the heart’s energetic capacity. Therefore, targeted mitochondrial antioxidants are a promising therapeutic target for cardiovascular disease and identification of novel endogenous mitochondrial antioxidants could lead to the discovery of new therapeutic targets. ABCB10 is a mitochondrial transporter with an unknown substrate. Our laboratory showed that hearts from mice with a heterozygous deletion of ABCB10 had decreased cardiac function and increased oxidative stress after ischemia reperfusion. Administration of an antioxidant ameliorated these effects, indicating that ABCB10 may have antioxidant effects. Therefore, we hypothesize that ABCB10 protects cardiac myocytes against oxidative injury through antioxidant effects in the cytosol and/or mitochondria. To test this hypothesis, we overexpressed ABCB10 in isolated adult rat ventricular myocytes (ARVMs) and exposed these cells to an oxidative challenge. ABCB10 overexpression protected cardiac myocytes against an oxidative insult, increasing cell viability and decreasing cytosolic ROS levels. ABCB10 overexpression also increased levels of HO-1, a cardioprotective and antioxidant-generating enzyme. We generated cardiac-specific ABCB10 knockout mice to explore the role of cardiac ABCB10 in vivo. We found that cardiac-specific deletion of ABCB10 in mice caused early death and mitochondrial dysfunction, evidenced by increased mitochondrial ROS production and decreased mitochondrial oxygen consumption. Additionally, microarray gene analysis revealed that hearts from ABCB10 knockout mice downregulated mitochondrial transcription and translation processes, indicating impaired mitochondrial proteostasis. These findings demonstrate that ABCB10 exerts an antioxidant effect, due, at least in part, to upregulation of the HO-1 antioxidant system. The ABCB10 mitochondrial transporter is involved in regulating mitochondrial oxidant levels and proteostasis and may be a novel therapeutic target in states associated with oxidative stress. |
