Title: Cardiotonic Steroids: Novel Mechanisms of Na+ i-Mediated and - Independent Signaling Involved in the Regulation of Gene Expression, Proliferation and Cell Death
Volume: 1
Issue: 3
Author(s): Sergei N. Orlov, Olga A. Akimova and Pavel Hamet
Affiliation:
Keywords:
cardiotonic steroids, na+, k+-atpase, gene expression, proliferation, cell death
Abstract: Vascular remodeling and hypertrophy/hyperplasia of the heart and kidney are known to be major servomechanisms of long-term maintenance of elevated blood pressure and the development of cardiovascular and renal complications seen in hypertension. Several lines of evidence suggest that these abnormalities are genetically determined and evoke an imbalance between cell proliferation and death. During the last 2 decades, it was shown that the level of cardiotonic steroids (CTS), i.e. potent and selective Na+,K+-ATPase inhibitors, is increased in several forms of volumeexpanded hypertension. We focus our review on recent data implicating CTS in the regulation of cell proliferation and death. At low concentrations, CTS augment proliferation of vascular smooth muscle cells (VSMC) as well as renal epithelial and vascular endothelial cells without significant inhibition of Na+,K+-ATPase-mediated ion fluxes. In contrast to cell proliferation, effect of CTS on cell survival is tissue-specific. In VSMC, CTS inhibit programmed cell death via a novel Na+ i-mediated, Ca2+ i-independent mechanism of expression of antiapoptotic genes including mortalin, whereas in vascular endothelial and renal epithelial cells, long-term exposure to CTS leads to cell death showing combined markers of apoptosis and necrosis. This mode of cell death is caused by interaction of CTS with Na+,K+-ATPase but is independent of inhibition of the Na+,K+-ATPase-mediated ion fluxes and inversion of the [Na+]i/[K+]i ratio. We propose that these novel signaling pathways triggered by enhanced production of endogenous CTS and/or abnormal Na+ handling contribute to cardiovascular and renal complications seen in hypertension.
