Blood Pressure Control Goes Nuclear

Abstract

See related article, pages 902–910 The control of blood pressure is regulated with extreme precision, and requires integration of information from the central nervous system, the kidneys, the vasculature, and the heart. Salt and water balances, sympathetic activity, arterial stiffness, and the tone of resistance vessels determine the chronic regulation of intravascular pressure. It is a standard experiment for physicians-in-training to manipulate these activities using classical physiological techniques and observe the homeostatic mechanisms that return blood pressure to its normal levels. Given the many controls that exist to maintain blood pressure within a narrow and appropriate range, it is all the more remarkable that clinical hypertension is as common as it is, affecting more than 50 million Americans and 75% of the population older than 65 years of age. The paracrine and endocrine mechanisms that regulate blood pressure are now reasonably well understood, and indeed provide the pharmacological basis for most antihypertensive therapies. In contrast, the intracellular events that tune blood pressure are less well characterized. In particular, nuclear events that control blood pressure are not well known. This is a major gap in our understanding of the problem insofar as long-term changes in gene regulation are a likely proximate cause of the systematic events that result in chronic hypertension. A report in this issue of Circulation Research by Irani and colleagues,1 which clearly defines a role for the multifunctional nuclear protein apurinic/apyrimidinic endonuclease (APE1, also known as redox factor-1) in chronic regulation of vascular tone in vivo, represents an important step toward understanding how nuclear proteins may integrate diverse signals to tune the genetic program that regulates blood pressure. APE1 is a multifunctional protein (Figure, A). It contains tandem cysteine residues within its amino terminus that exert a reducing activity that is responsible for regulating redox-sensitive …