New uses of oubain and oubain-like molecules in apoptosis...

Details New uses of oubain and oubain-like molecules in apoptosis... New uses of oubain and oubain-like molecules in apoptosis...

A - Human Necessities

61

K

A61K 31/70 (2006.01) A61K 31/704 (2006.01) A61K 31/7042 (2006.01) A61K 31/7048 (2006.01)

Patent

CA 2273699

Longterm elevation of the intracellular Na /K+ ratio inhibits macromolecule synthesis and proliferation in the majority of cell types studied so far, including vascular smooth muscle cells (VSMC). We report here that inhibition of the Na+,K+ pump in VSMC by ouabain or 1 hr preincubation in K+-depleted medium attenuated apoptosis triggered by serum withdrawal, staurosporine or okadaic acid. In the absence of ouabain, both DNA degradation and caspase-3 activation in VSMC undergoing apoptosis were insensitive to modification of the extracellular Na+/K+ ratio as well as to hyperosmotic cell shrinkage. In contrast, protection of VSMC from apoptosis by ouabain was abolished under equimolar substitution of Na+o with K+o, showing that the antiapoptotic action of Na+,K+ pump inhibition was caused by inversion of the intracellular Na+/K+ ratio. Unlike VSMC, the same level of increment of the [Na+]i/[K+]i ratio caused by 2-hr preincubation of Jurkat cells with ouabain did not affect chromatin cleavage and caspase-3 activity triggered by treatment with Fas ligand, staurosporine or hyperosmotic shrinkage. Thus, our results show for the first time that similarly to cell proliferation, maintenance of a physiologically low intracellular Na+/K+ ratio is required for progression of VSMC apoptosis.

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