PVN injections of adeno‐associated virus‐siRNA to silence either NOX2 or NOX4 attenuates aldosterone/NaCl‐induced hypertension in mice

Numerous studies have demonstrated that mineralocorticoid excess increases superoxide production through an activated NADPH oxidase pathway, thereby contributing to the development of cardiovascular disease. Previous studies have shown that icv infusion of apocynin, a NADPH oxidase inhibitor, attenuates aldosterone (ALDO)‐induced hypertension. The present study investigated regional specificity of different NADPH oxidase subtypes (NOX2 or NOX4) in the brain to be responsible for the elevated blood pressure during mineralocorticoid excess. Blood pressure was measured in mice with the use of telemetry implants. ALDO (0.2 mg/kg/d) was administered s.c. via osmotic pump and 2% high salt diet was provided. At the same time, PVN injections of recombinant adeno‐associated virus (AAV) carrying small interference (si) RNA for NOX2 (AAV‐siRNA‐NOX2), NOX4 (AAV‐siRNA‐NOX4) or scrambled siRNA (AAV‐siRNA‐SCM) were used to knock down NOX2 and NOX4. Either AAV‐siRNA‐NOX2 or AAV‐siRNA‐NOX4 injections significantly attenuated ALDO‐induced hypertension in comparison to AAV‐siRNA‐SCM mice. Likewise, in NOX2 knock‐out mice, ALDO/salt‐induced increases in blood pressure were much less than that in wild type mice. These data indicate that both NOX2 and NOX4 in the PVN contribute to the pressor effects during mineralocorticoid excess. (HL‐62261, HL‐59676, HL‐14388, HL‐98207, DK‐66086, and MH‐80241)