Cardiac acetylcholinesterase and butyrylcholinesterase have distinct localization and function

Cholinesterase (ChE) inhibitors are under consideration for use 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 collagen Q (ColQ) in the basal lamina or by PRiMA at the plasma membrane and co-localized with the neuronal marker TUJ1. In the absence of anchored AChE, the heart rate was unresponsive to a ChE inhibitor. BChE, the major ChE in the 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 novel, more effective pharmacotherapies, which may reduce morbidity and mortality of patients with various heart diseases.