Angiotensin II and angiotensin-1-7 redox signaling in the central nervous system

Abstract

Reactive oxygen species (ROS) are important intra-neuronal signaling intermediates in angiotensin II (AngII)-related neuro-cardiovascular diseases associated with excessive sympathoexcitation, including hypertension and heart failure. ROS-sensitive effector mechanisms, such as modulation of ion channel activity, indicate that elevated levels of ROS increase neuronal activity. Nitric oxide, which may work to counter the effects of ROS, particularly superoxide, has been identified as a signaling molecule in angiotensin-1-7 (Ang-(1-7)) stimulated neurons. This review focuses on recent studies that have revealed details on the AngII-activated sources of ROS, the downstream redox-sensitive effectors, Ang-(1-7)-stimulated increase in nitric oxide, and the neuro-cardiovascular (patho)physiological responses modulated by these reactive species. Understanding these intra-neuronal signaling mechanisms should provide insight for the development of new redox-based therapeutics for the improved treatment of angiotensin-dependent neuro-cardiovascular diseases.

Figure 1

Adenovirus-mediated overexpression of the mitochondrial-localized MnSOD (AdMnSOD) in cultured neurons inhibits the AngII-induced increase in O₂^•− levels, as measured by EPR spectroscopy. Non-infected (control) or AdMnSOD-infected catecholaminergic neurons (CATH.a neurons) were loaded with the O₂^•− sensitive, cell permeable spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) and stimulated with AngII (100 nM). AngII significantly increased the EPR amplitude in control neurons (red line) as compared to non-treated neurons (black line), indicating an increase in O₂^•− levels. This increase in O₂^•− was virtually abolished in neurons overexpressing MnSOD (blue line), suggesting mitochondria are a primary source of O₂^•− in AngII-stimulated neurons. A.U. = arbitrary units.

Figure 2

Schematic illustration of AngII and Ang-(1-7) intra-neuronal signaling involving an increase in O₂^•− and NO^•, respectively. AngII, acting through the AT1 receptor (AT1R), has been shown to increase O₂^•− from both NADPH oxidase and mitochondria (mito), while Ang-(1-7) signaling through the MasR leads to nNOS activation and an increase in NO^•. NO^• and O₂^•− react in a diffusion-limited manner to produce peroxynitrite (ONOO⁻). Previous studies indicate that the AngII-induced increase in O₂^•− modulates ion channels to increase neuronal firing rate leading to an increase in sympathetic nerve activity (SNA) and mean arterial pressure (MAP). While other studies suggest that the Ang-(1-7)-induced increase in NO^• leads to sympatho-inhibition. Future studies (indicated by ?) are needed to determine if O₂^•−, NO^•, and/or ONOO⁻ act on redox-sensitive proteins (RSP) that control ion channel activity or if these reactive species act directly on ion channel proteins to regulate ion flux and neuronal activity.