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Ouabain-dependent signaling in caveolae as a novel therapeutic target for hypertension

M Ferrandi1, I Molinari, G Bianchi

  • 1Prassis sigma tau Research Institute, Milan, Italy. mara.ferrandi@prassis.it

Cellular and Molecular Biology (Noisy-Le-Grand, France)
|May 31, 2007
PubMed

Insights

Endogenous Ouabain (EO) and Adducin contribute to hypertension. Rostafuroxin, a novel drug, effectively lowers blood pressure and cardiac hypertrophy by blocking the Ouabain-triggered signaling pathway.

Area of Science:

  • Cardiovascular Research
  • Pharmacology
  • Molecular Biology

Background:

  • Endogenous Ouabain (EO) and Adducin polymorphism are implicated in hypertension pathogenesis.
  • The Na-K ATPase-Src-EGFr-ERK pathway in caveolae is activated by Ouabain, contributing to hypertension and cardiac remodeling.

Purpose of the Study:

  • To investigate Rostafuroxin's mechanism of action as an antihypertensive and antihypertrophic agent.
  • To evaluate Rostafuroxin's ability to antagonize Endogenous Ouabain/Ouabain and Adducin effects.

Main Methods:

  • In vivo and cell-free studies were conducted.
  • Vascular tone and cardiac hypertrophy models were used.
  • Analysis of Src-dependent signaling pathways was performed.

Main Results:

  • Rostafuroxin selectively antagonizes the hypertensive and cardiac hypertrophy effects of EO/Ouabain and Adducin.
  • Rostafuroxin inhibits Ouabain-induced Src-dependent signaling.
  • Rostafuroxin reduces Ouabain-mediated increases in myogenic vascular tone.

Conclusions:

  • Rostafuroxin represents a new class of antihypertensive drugs targeting EO/Ouabain and Adducin pathways.
  • Its novel mechanism involves antagonizing specific molecular signaling involved in hypertension.
  • Rostafuroxin demonstrates efficacy and good tolerability in preclinical and clinical studies.

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