Cardiac acetylcholinesterase and butyrylcholinesterase have distinct localization and function

Abstract

Cholinesterase (ChE) inhibitors are under consideration to be used in the treatment of cardiovascular pathologies. A prerequisite to advancing ChE inhibitors into the clinic is their thorough characterization in the heart. The aim here was to provide a detailed analysis of cardiac ChE to understand their molecular composition, localization, and physiological functions. A battery of biochemical, microscopic, and physiological experiments was used to analyze two known ChE, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hearts of mutant mice lacking different ChE molecular forms. Overall, AChE activity was exceeded by BChE, while it was localized mainly in the atria and the ventricular epicardium of the heart base. AChE was anchored by ColQ in the basal lamina or by PRiMA at the plasma membrane and co-localized with the neuronal marker TUJ1. In absence of anchored AChE, heart rate was unresponsive to a ChE inhibitor. BChE, the major ChE in heart, was detected predominantly in ventricles, presumably as a precursor (soluble monomers/dimers). Mice lacking BChE were more sensitive to a ChE inhibitor. Nevertheless, the overall impact on heart physiology was subtle, showing mainly a role in cholinergic antagonism to the positive inotropic effect of {beta}-adrenergic stimulation. Our results help to unravel the mechanisms of ChE in cardiovascular pathologies and provide a foundation to facilitate the design of a novel, more effective pharmacotherapies, which may reduce morbidity and mortality of patients with various heart diseases. Abstract figure legend O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/596481v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@136068corg.highwire.dtl.DTLVardef@1e8118corg.highwire.dtl.DTLVardef@d83298org.highwire.dtl.DTLVardef@1e1cde7_HPS_FORMAT_FIGEXP M_FIG C_FIG Acetylcholinesterase (AChE) has the highest activity in the atria. It is present in the heart in molecular forms anchored by a proline-rich membrane anchor (PRiMA) and by collagen Q (ColQ) and hydrolyzes acetylcholine of neuronal origin (neuronal ACh). Butyrylcholinesterase (BChE) is predominant in the ventricles. It is secreted in the form of a soluble tetramer and hydrolyzes acetylcholine originating from cardiomyocytes (non-neuronal ACh). Key pointsO_LIInhibition of cholinesterases has therapeutic potential in cardiovascular pathologies C_LIO_LIBoth known cholinesterases are present in heart C_LIO_LIEach cholinesterase has distinct localization patterns in the heart and functions in cardiac physiology C_LIO_LISelective inhibition of acetylcholinesterase or butyrylcholinesterase may be used to alter specific cardiac functions C_LIO_LIButyrylcholinesterase polymorphism may have an impact on the outcome of the cholinesterase inhibitor treatment C_LI