Central redox signaling mechanisms in neurogenic hypertension.

摘要

Cardiovascular-regulatory networks in the central nervous system (CNS) play a critical role in the maintenance of arterial pressure. Dysregulated signaling in these circuits is a key factor in essential hypertension. Although angiotensin-II (Ang-II) has emerged as a primary culprit in driving neuro-cardiovascular dysfunction, little is known regarding the molecules and pathways involved. Recent evidence has clearly implicated the excessive production of reactive oxygen species (ROS) in central cardioregulatory nuclei as a key step in the pathogenesis of Ang-II-dependent neurogenic hypertension. In addition, NADPH oxidases (Nox enzymes) have been identified as the primary enzymatic source of Ang-II-derived ROS in the CNS, and the different Nox enzymes exhibit unique expression patterns within cardiovascular nuclei. However, the relative functional contributions of these Nox enzymes to the pathogenesis of neurogenic hypertension are poorly understood. Likewise, little is known regarding the signaling mechanisms downstream of Nox enzyme-derived ROS that are capable of initiating long-term neuronal changes in central cardiovascular circuits. Utilizing recent advances in molecular genetics, coupled with state-of-the-art integrative cardiovascular physiology, we tested the hypothesis that Ang-II-dependent neurogenic hypertension is caused by the excessive production of Nox enzyme-derived ROS in forebrain CVOs that initiates long-lasting alterations in cardiovascular neuronal activity through the activation of calcium/calmodulin kinase II (CaMKII), redox-sensitive transcription factors, and interactions with prostaglandin signaling pathways. Using targeted adenoviral delivery of short hairpin interfering RNA to the CNS, we selectively inhibited expression of NADPH oxidase homologues within specific brain regions to examine their differential roles in central Ang-II blood pressure regulation. In addition, using an arsenal of molecular and genetic techniques, we investigated the roles of CaMKII and prostaglandins---redox-sensitive signaling molecules that play a known role in the actions of Ang-II in the periphery---in the pathogenesis of Ang-II-dependent hypertension. Lastly, we explored the utility of bioluminescence imaging for spatio-temporal mapping of transcription factor activity in cardio-regulatory nuclei in the CNS of living mice. These studies have begun to dissect out both the upstream and downstream effectors of ROS in forebrain CVOs, and have greatly advanced our understanding of the mechanisms linking the CNS with cardiovascular disease.