Therapeutic targeting of mitochondrial superoxide in hypertension

INTRODUCTION Superoxide (O 2 • ) has been implicated in the pathogenesis of many human diseases including hypertension, however commonly employed antioxidants have proven ineffective in clinical trials. It is possible that these agents are not adequately delivered to the subcellular sites of O 2 • production. HYPOTHESIS Because the mitochondria are important source of O 2 • , we postulated that mitochondrial targeting of O 2 • scavenging would have therapeutic benefit. RESULTS In this study, we found that the hormone angiotensin II increased endothelial mitochondrial O 2 • . Treatment with the mitochondria‐targeted SOD mimetic mitoTEMPO decreased mitochondrial O 2 • , inhibited the total cellular O 2 • , reduced cellular NADPH oxidase activity and restored endothelial NO, while a similar dose of non‐targeted TEMPOL was not effective. These effects were mimicked by overexpressing the mitochondrial MnSOD (SOD2), while SOD2 depletion with siRNA increased both basal and angiotensin II‐stimulated cellular O 2 • . Treatment of mice in vivo with mitoTEMPO after the onset of angiotensin II‐ and DOCA‐salt induced hypertension decreased blood pressure by 30 mm Hg, decreased vascular O 2 • , increased NO • production and improved endothelium‐dependent relaxation. Transgenic mice overexpressing mitochondrial SOD2 demonstrated attenuated angiotensin II‐induced hypertension and vascular oxidative stress similar to mice treated with mitoTEMPO. CONCLUSION These studies show that mitochondrial O 2 • is important for the development of hypertension and that mitochondria‐targeted SOD mimetic could have therapeutic benefits in this and possibly other diseases. Supported by AHA and NIH grant No 09GRNT2220128, HL058000 and HL075209.