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Abstract
Essential hypertension is a complex, multifactorial disease associated with a high cardiovascular risk and whose genetic-molecular basis is heterogeneous and largely unknown. Although multiple antihypertensive therapies are available, the large individual variability in drug response results in only a modest reduction of the cardiovascular risk and unsatisfactory control of blood pressure in the hypertensive population as a whole. Two mechanisms, among others, are associated with essential hypertension and related organ damage: mutant α-adducin variants and high concentrations of endogenous ouabain. An antihypertensive agent, rostafuroxin, selectively inhibits these mechanisms in rodents. We investigated the molecular and functional effects of mutant α-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant α-adducin variants and the ouabain–Na,K-ATPase (Na+- and K+-dependent adenosine triphosphatase) complex can interact with the Src–SH2 (Src homology 2) domain, increasing Src activity and the Src-dependent Na,K-ATPase phosphorylation and activity. Wild-type α-adducin or Na,K-ATPase in the absence of ouabain interacted less robustly with the Src-SH2 domain. Rostafuroxin disrupted the interactions between the Src-SH2 domain and mutant α-adducin or the ouabain–Na,K-ATPase complex and blunted Src activation and Na,K-ATPase phosphorylation, resulting in blood pressure normalization in the hypertensive rats. We have also shown the translatability of these data to humans in a pharmacogenomic clinical trial, as described in the companion paper.
Footnotes
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Citation: M. Ferrandi, I. Molinari, L. Torielli, G. Padoani, S. Salardi, M. P. Rastaldi, P. Ferrari, G. Bianchi, Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin. Part 1: Experimental Studies. Sci. Transl. Med. 2, 59ra86 (2010).
- Copyright © 2010, American Association for the Advancement of Science
