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J. Biol. Chem., Vol. 279, Issue 32, 33306-33314, August 6, 2004

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Organ Hypertrophic Signaling within Caveolae Membrane Subdomains Triggered by Ouabain and Antagonized by PST 2238^*

Mara Ferrandi, Isabella Molinari, Paolo Barassi, Elena Minotti, Giuseppe Bianchi¶, and Patrizia Ferrari

From the Prassis sigma-tau Research Institute, Settimo Milanese, 20019 Milan, Italy and the ^¶Division of Nephrology, Dialysis and Hypertension, Vita e Salute University, San Raffaele Hospital, 20132 Milan, Italy

In addition to inhibition of the Na-K ATPase, ouabain activates a signal transduction function, triggering growth and proliferation of cultured cells even at nanomolar concentrations. An isomer of ouabain (EO) circulates in mammalians at subnanomolar concentrations, and increased levels are associated with cardiac hypertrophy and hypertension. We present here a study of cardiac and renal hypertrophy induced by ouabain infused into rats for prolonged periods and relate this effect to the recently described ouabain-induced activation of the Src-EGFr-ERK signaling pathway. Ouabain infusion into rats (15 µg/kg/day for 18 weeks) doubled plasma ouabain levels from 0.3 to 0.7 nM and increased blood pressure by 20 mm Hg (p < 0.001), cardiac left ventricle (+11%, p < 0.05), and kidney weight (+9%, p < 0.01). These effects in vivo are associated with a significant enrichment of 1, 1, a Na-K ATPase subunits together with Src and EGFr in isolated renal caveolae membranes and activation of ERK1/2. In caveolae, direct Na-K ATPase/Src interactions can be demonstrated by co-immunoprecipitation. The interaction is amplified by ouabain, at a high affinity binding site, detectable in caveolae but not in total rat renal membranes. The high affinity site for ouabain is associated with Src-dependent tyrosine phosphorylation of rat 1 Na-K ATPase. The antihypertensive compound, PST 2238, antagonized all ouabain-induced effects at 10 µg/kg/day in vivo or 10^-10-10^-8 M in vitro. These findings provide a molecular mechanism for the in vivo pro-hypertrophic and hypertensinogenic activity of ouabain, or by analogy those of EO in humans. They also explain the pharmacological basis for PST 2238 treatment.

Received for publication, February 27, 2004 , and in revised form, May 20, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Prassis sigma-tau Research Institute, Via Forlanini, 20019 Settimo Milanese, 20019 Milano, Italy. Tel.: 39-02-3357911; Fax: 39-02-33500408; E-mail: mara.ferrandi{at}prassis.it.

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