MITOCHONDRIA‐TARGETED TREATMENT ATTENUATES VASCULAR OXIDATIVE STRESS, ENDOTHELIAL DYSFUNCTION AND HYPERTENSION

Mitochondrial reactive oxygen species (ROS) have been recently implicated in the development and progression of cardiovascular diseases. We have suggested that mitochondria targeted antioxidants can be beneficial for treatment of endothelial dysfunction, hypetension other parthological conditions. In this work we have studied specific molecular mechanisms responsible for stimulation of mitochondrial O 2 • and its downstream targets using cultured human aortic endothelial cells and angiotensin II‐induced hypertension. Depletion of cytoplasmic Nox2 isoform of NADPH oxidase inhibited stimulation of mitochondrial ROS by angiotensin II. Meanwhile, treatment with the mitochondria targeted superoxide dismutase mimetic mitoTEMPO or SOD2 overexpression inhibited production of mitochondrial O 2 • , reduced activity of redox dependent c‐Src and cytoplasmic NADPH oxidase, restored vascular NO in angiotensin II stimulated cells and reduced blood pressure in mice with angiotensin II and DOCA‐salt induced hypertension. We have suggested that mitochondrial ROS stimulates cytoplasmic oxidative stress via release of H 2 O 2 . Indeed, scavenging of mitochondrial H 2 O 2 with mitochondria targeted glutathione peroxidase mimetic mitoEbselen inhibited production of cytoplasmic O 2 • by NADPH oxidase and reduced blood pressure in angiotensin II induced hypertension. Production of angiotensin II‐induced mitochondrial ROS was inhibited by specific PKCε peptide antagonist, ATP‐sensitive potassium channel blocker 5‐hydroxydecanoate, inhibitors of complex I rotenone, inhibitors of complex II malonate or malate. These studies show that mitochondrial ROS play an important role in feed‐forward stimulation of oxidative stress by activating mitochondrial reverse electron transfer which can be treated with mitochondria‐targeted antioxidants. This work has been funded by National Institutes of Health HL094469.