UNESCO Chair-Life Sciences, International Postgraduate Educational Center, 31 Acharyan St, 0040 Yerevan, Armenia
Received Date: December 17, 2015; Accepted Date: December 19, 2015; Published Date: December 26, 2015
Citation: Ayrapetyan S (2015) The Dysfunction of Camp-Dependent Na+/Ca2+ Exchange in Reverse Mode as a Primary Mechanism for Age-Dependent Cardio- Muscle Failure. J Bioequiv Availab 8:e70. doi: 10.4172/jbb.10000e70
Copyright: © 2015 Ayrapetyan S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Heart muscle failure, the risk of which is increased by aging, remains as a major cause of mortality and morbidity. The cardio-myocyte is made up of approximately 50% of myofibrils, and the remainder consists of mitochondria, nucleus, sarcoplasmic reticulum (SR) and the cytosol . Therefore, the cytoskeleton and myofibril contractility have their essential roles in metabolic regulation of myocyte volume, which could be considered as a marker for myocyte contraction. As Ca2+ has a key role in the process of muscle contractility, at present all precautionary and therapeutic methods, aimed at decreasing age-dependent heart muscle failure, are based on the concept that the elevation of SR stressinduced intracellular Ca2+([Ca2+]i) leads to the generation of a number of pathological changes of heart muscle [2,3]. However, the primary mechanism dysfunction of which brings to the increase of [Ca2+]i is not clear yet. Though myocyte dehydration is one of the essential hallmarks for aging, our knowledge on its role in heart muscle failure, particularly in increase of [Ca2+]iis rather limited. As water is a dominant component of cells and serves as a common medium for metabolic reactions, its physicochemical properties has determining role in regulation of cell metabolism. The regulatory role of intracellular water on cell metabolism is realized by controlling intracellular macromolecules, including DNA activities through the “folding –unfolding” mechanisms , by surfacedependent changes of a number of functionally active proteins, having enzymes , receptors  and ionic channel properties . The facts that water structure is extra sensitive to physical and chemical factors  and cell membrane is highly permeable for water , make the water molecules as primary messengers between cell bathing medium and intracellular metabolism . As intracellular osmotic pressure exceeds the extracellular one, water influx is osmotically driven into cell, which is balanced by metabolism-dependent water efflux. It has been shown that depending on their directions water fluxes through the membrane have activation or inactivation effect on ionic currents: water influx has activation effect on Na+ (INa) and Ca2+ (ICa) currents and inactivation effect on K+ (Ik) current, while water efflux has the opposite effect on these currents [7,11-14]. From these data it is predicted that metabolism-dependent water efflux has a great physiological meaning as it inhibits the electrochemical driving of Na+ and Ca2+ influxes into myocyte.
There are minimum three enzyme systems that are actively involved in metabolic controlling of cell hydration and heart muscle contractility: transporting ATP-ases, having anti-gradient ions transporting functions through the membrane; kinases, regulating contractility of myofibrils; and enzyme systems involved in intracellular oxidation processes, producing water molecules in cytoplasm. It is known that among the aforementioned enzyme systems controlling cell hydration, Na+/K+-ATPase has a central role, which is due to the following properties of Na+/K+-ATPase: a) being working molecules for Na+/K+-pump, Na+/K+-ATPase generates Na+ gradient on membrane, serves as an energy source for a number of secondary ionic transporters in membrane, including Na+/ Ca2+ and Na+/H+ exchange ; b) being the highest ATP energy utilizing mechanism, it determines the rate of oxidative phosphorylation processes resulting the ATP synthesis and the release of H2O in cytoplasm;  c) having electrogenic character, it pumps water from the cells [17-19] and d) besides the transporting function, Na+/K+-ATPase has also multisided intracellular signaling functions, including controlling of [Ca2+]i and phosphorylation and dephosphorylation processes [20,21]. It is known that Na+/K+- pump functions with higher rate in pacemaker cells because of high permeability for Na+ . Therefore, all above mentioned mechanisms are active and Na+/K+-pump serves as a central membrane mechanism through which the metabolic controlling of pacemaker activity of cells, including pacemaker of heart muscle is realized [23-25]. Previously it has been shown that Na+/K+-pump regulates membrane excitability not only by membrane hyperpolarization but also by potential-independent mechanisms such as water efflux-induced inactivation of INa+and ICa and surface-dependent decrease of a number of ionic channels in membrane [7,11].
It is known that the dysfunction of Na+/K+-pump, is a common consequence of any pathology, including age-induced heart muscle failure. However, the dysfunction of which properties of Na+/K+-pump is a primary mechanism for generation of age-induced cardio-muscle dehydration and failure of muscle contractility is not clear yet.
At present it is well established that Na+/K+-ATPase in membrane of cardio-myocyte has three catalytic isoforms, having different affinities to cardio glycosades: low(α1), middle (α2) and high (α3) . Among them α3 isoform has only signaling function [20,21]. Earlier we have shown that ≤ 10-9M ouabain (agonist for α3 receptors) stimulates Na+/ Ca2+ exchange in reverse mode (R Na+/Ca2+) by increasing intracellular contents of cAMP, which leads to membrane hyperpolarization and inhibition of pacemaker activity . Based on the literature data, that cAMP-activated Ca2+ -ATPase in SR membrane pushes Ca ions from cytoplasm into SR , the aforementioned data on nM ouabaininduced activation of R Na+/Ca2+ exchange can be explained by the decrease of [Ca2+ ]i.
Our recent study has shown that in spite of the affinities of α1 and α2 isoforms to ouabain, the affinity of α3 isoform to ouabain has pronounced age-dependent depressing character, which is due to the dysfunction of R Na+/Ca2+exchange .
The most essential discovery was that in spite of the fact that R Na+/Ca2+ exchange functions in stoichiometry of 3Na:1Ca [26,30] its activation by ≤10-9M ouabain leads to muscle hydration which has strong metabolism-dependent and age-induced weakening character [29,31,32].
Thus, based on the above mentioned data it is suggested that the dysfunction of the pathway through which cAMP-dependent R Na+/ Ca2+ exchange stimulates the release of intracellular water molecules (water efflux from the myocyte) can be considered as a primary mechanism for age-dependent increase of membrane permeability for Na+ and Ca2+ leading to heart muscle failure. Therefore, the elucidation of the mechanism(s) through which cAMP-dependent R Na+/Ca2+ exchange stimulate(s) the rate of glycolysis (H2O-release) could serve as a novel therapeutic target for age-dependent heart muscle failure.