Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin. Part 1: Experimental Studies

作者：Ferrandi Mara; Molinari Isabella; Torielli Lucia; Padoani Gloria; Salardi Sergio; Rastaldi Maria Pia; Ferrari Patrizia; Bianchi Giuseppe^*

来源：Science Translational Medicine, 2010, 2(59): 59ra86.

DOI：10.1126/scitranslmed.3001815

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 alpha-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 alpha-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant alpha-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 alpha-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 alpha-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.

• 出版日期2010-11-24