Angiotensin II signaling in the brain: compartmentalization of redox signaling?

Abstract

Angiotensin II (Ang II) is a profoundly important signaling component of the renin-angiotensin system. Its principal functions are related to cardiovascular homeostasis, and its many targets include vascular myocytes, endothelium, cardiac myocytes, fibroblasts, diverse cells in the kidney and adrenal gland, and cells in the central and peripheral nervous systems. Ang II contributes to the physiological regulation in healthy states1 but can also induce or contribute to pathophysiological events seen in certain diseases.2,3⇓ The cellular effects of Ang II are mediated by its interaction with membrane receptors, of which two subtypes have been identified.4 AT1 receptors are found in vascular tissue, heart, and brain, whereas AT2 receptors are found in adrenal and uterine cells. Many of the downstream events triggered by Ang II binding to the AT1 receptor have been found to involve signal transduction steps that require reactive oxygen species (ROS).5–9⇓⇓⇓⇓ The generation of ROS in mammalian systems begins with univalent transfer of an unpaired electron to O2, yielding superoxide. As an anion, superoxide does not easily cross cell membranes, so its signaling domain is generally restricted to the subcellular compartment where it is synthesized. Superoxide is well suited to act as a signaling molecule because it is relatively reactive, but not excessively so. Dismutation of two superoxide anions yields hydrogen peroxide, an uncharged molecule that passes easily through cell membranes and can therefore transmit redox signals between subcellular compartments. Like superoxide, H2O2 behaves nicely as a signaling molecule because it is not overly reactive and can therefore diffuse toward its intended targets without excessively oxidizing other molecules along the way. Reduction of H2O2 with an electron yields hydroxyl radical, which is virtually useless as a signaling molecule because …