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Low concentrations of ouabain activate vascular smooth muscle cell proliferation
Julius C Allen1, Joel Abramowitz, Aslihan Koksoy
1Baylor College of Medicine, Houston, Texas 77030, USA. juliusa@bcm.tmc.edu
Abstract:
In vascular smooth muscle cells the sodium pump complex can act as an intracellular signal transducing complex activated by low ouabain concentrations, which inhibit sufficient pumps to activate a transduction cascade via transactivation of EGFR, but insufficient pumps to alter intracellular ions. Higher concentrations interfere with proliferation. This biphasic ouabain response occurs in human, canine, and rat VSMC at concentrations that reflect the differing ouabain affinities of the alpha1 isoforms of the three species. This supports the proposal that this effect occurs via ouabain binding to the alpha1 subunit of the Na pump. These data suggest a new transducing function of ouabain-Na pump interaction, distinct from the cellular ionic effects resulting from pump inhibition. This transducing function occurs at ouabain concentrations that do not perturb cytoplasmic ion content and requires specific localization of pumps to caveolae.
Insights
Low ouabain concentrations activate signaling in vascular smooth muscle cells by interacting with the sodium pump (Na+ pump), distinct from ion changes. This biphasic response involves specific pump localization.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Molecular Pharmacology
Background:
- The sodium pump (Na+/K+-ATPase) is crucial for maintaining cellular ion gradients.
- Vascular smooth muscle cells (VSMCs) play a key role in blood pressure regulation.
- Ouabain, a cardiac glycoside, is known to inhibit the sodium pump.
Purpose of the Study:
- To investigate the signaling role of the sodium pump in VSMCs.
- To characterize the biphasic response of VSMCs to ouabain.
- To explore the mechanism of ouabain-induced signal transduction independent of ion flux.
Main Methods:
- Studied human, canine, and rat VSMCs.
- Utilized varying concentrations of ouabain.
- Investigated epidermal growth factor receptor (EGFR) transactivation.
- Examined intracellular ion concentrations.
- Assessed pump localization to caveolae.
Main Results:
- Low ouabain concentrations activated a signal transduction cascade via EGFR transactivation without altering intracellular ions.
- Higher ouabain concentrations inhibited proliferation.
- The biphasic response correlated with species-specific ouabain affinities for the alpha1 isoform of the Na+ pump.
- Signaling occurred at ouabain concentrations that did not perturb cytoplasmic ion content.
- Specific localization of sodium pumps to caveolae was required for this transducing function.
Conclusions:
- Ouabain-Na+ pump interaction mediates a novel transducing function in VSMCs, separate from ionic effects.
- This signaling pathway is concentration-dependent and species-specific, involving the alpha1 subunit.
- Caveolae-localized sodium pumps are essential for this ouabain-induced signal transduction at non-ionic concentrations.