Ca2+-Handling Proteins and Heart Failure: Novel Molecular Targets?
Calcium (Ca2+) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca2+ is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca2+ store. These fluxes occur by the transient activity of Ca2+-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca2+-handling proteins, in particular the SR Ca2+-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca2+ available for contraction. In the steady state, the Ca2+-content of the SR is essentially a balance between Ca2+-uptake via SERCA2a pump and Ca2+-release via the cardiac SR Ca2+-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca2+ content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca2+-uptake, and (ii) reduction of SR Ca2+-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and / or Ca2+-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca2+-leak.
Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMPlevels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca2+-cycling proteins may have the potential to fill this gap.
Document Type: Review Article
Publication date: June 1, 2003
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