PVN adenovirus-siRNA injections silencing either NOX2 or NOX4 attenuate aldosterone/NaCl-induced hypertension in mice.

Abstract

Mineralocorticoid excess increases superoxide production by activating NADPH oxidase (NOX), and intracerebroventricular infusions of NADPH oxidase inhibitors attenuate aldosterone (Aldo)/salt-induced hypertension. It has been hypothesized that increased reactive oxygen species (ROS) in the brain may be a key mechanism in the development of hypertension. The present study investigated the brain regional specificity of NADPH oxidase and the role of NOX2 and NOX4 NADPH oxidase subunits in the hypothalamic paraventricular nucleus (PVN) in Aldo/salt-induced hypertension. PVN injections of adenoviral vectors expressing small interfering (si)RNA targeting NOX2 (AdsiRNA-NOX2) or NOX4 (AdsiRNA-NOX4) mRNAs were used to knock down NOX2 and NOX4 proteins. Three days later, delivery of Aldo (0.2 mg·kg(-1)·day(-1) sc) via osmotic pump commenced and 1% NaCl was provided in place of water. PVN injections of either AdsiRNA-NOX2 or AdsiRNA-NOX4 significantly attenuated the development of Aldo/NaCl-induced hypertension. In an additional study, Aldo/salt-induced hypertension was also significantly attenuated in NOX2 (genomic) knockout mice compared with wild-type controls. When animals from both functional studies underwent ganglionic blockade, there was a reduced fall in blood pressure in the NOX2 and NOX4 knockdown/knockout mice. Western blot analyses of the PVN of siRNA-NOX2- or siRNA-NOX4-injected mice confirmed a marked reduction in the expression of NOX2 or NOX4 protein. In cultured PVN neurons, silencing either NOX2 or NOX4 protein production by culturing PVN cells with siRNA-NOX2 or siRNA-NOX4 attenuated Aldo-induced ROS. These data indicate that both NOX2 and NOX4 in the PVN contribute to elevated sympathetic activity and the hypertensivogenic actions induced by mineralocorticoid excess.

• Authors: Baojian Xue, Terry G Beltz, Ralph F Johnson, Fang Guo, Meredith Hay, Alan Kim Johnson
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 302 Issue 3 Pg. H733-41 (Feb 01 2012) ISSN: 1522-1539 [Electronic] United States
• PMID: 22140041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Membrane Glycoproteins
• RNA, Small Interfering
• Reactive Oxygen Species
• Sodium Chloride
• Aldosterone
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, mouse

Topics

• Adenoviridae (genetics)
• Aldosterone (pharmacology)
• Animals
• Autonomic Nervous System (enzymology, physiopathology)
• Blood Pressure (physiology)
• Female
• Genetic Therapy (instrumentation, methods)
• Hypertension (chemically induced, physiopathology, therapy)
• Infusion Pumps
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidase 4
• NADPH Oxidases (genetics, metabolism)
• Paraventricular Hypothalamic Nucleus (enzymology, physiopathology)
• RNA, Small Interfering (pharmacology)
• Reactive Oxygen Species (metabolism)
• Sodium Chloride (pharmacology)