Biology subjects

Fischmeister, R.

Publications and source records attributed to Fischmeister, R..

3 recordsLinked to original sources

bioRxiv2024

Cardiac acetylcholinesterase and butyrylcholinesterase have distinct localization and function

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

physiology↗

bioRxiv2023

Cardiac gene therapy with PDE2A limits remodeling and arrhythmias in mouse models of heart failure induced by catecholamines

BACKGROUNDConstitutive cardiac PDE2 activation was shown to protect against contractile dysfunction and arrhythmia in heart failure (HF). However, it remains unknown whether an acute elevation of PDE2 is efficient to prevent maladaptive remodeling and arrhythmia. In this study we tested whether increasing acutely PDE2A activity in preclinical models of HF using cardiac PDE2 gene transfer could be of therapeutic value. METHODS AND RESULTSC57BL/6 male mice were injected with serotype 9 adeno-associated viruses (AAV9) encoding for PDE2A, or luciferase (LUC). Cardiac function assessed by echocardiography unveiled neither structural change nor dysfunction consecutive to PDE2A overexpression while AAV9 inoculation led to a {approx}10-fold rise of PDE2A protein levels. Two weeks after AAV9 injections, mice were implanted with osmotic minipumps delivering NaCl or isoproterenol (Iso) (60 mg/kg/day) or Iso and phenylephrine (Iso+Phe, 30 mg/kg/day each) for 2 weeks. In LUC mice, chronic infusion with Iso increased left ventricular (LV) weight over body weight ratio, promoted fibrosis and decreased ejection fraction, but animals overexpressing PDE2A were protected towards these deleterious effects. Similarly, concomitant treatment with Iso+Phe promoted LV contractile dysfunction, fibrosis and apoptosis in LUC mice, while PDE2A overexpression limited these adverse outcomes. Furthermore, inotropic responses to Iso of ventricular cardiomyocytes isolated from Iso+Phe-LUC mice loaded with 1 {micro}mol/L Fura-2AM and stimulated at 1 Hz to record calcium transients and sarcomere shortening were dampened. Chronic treatment with catecholamines favoured spontaneous calcium waves upon {beta}-AR stimulation at the cellular level and promoted susceptibility to ventricular arrhythmias in vivo evoked by catheter-mediated ventricular pacing after Iso and atropine injection. However, these adverse effects were blunted by the cardiac gene therapy with PDE2A. CONCLUSIONGene therapy with PDE2A limits cardiac adverse left ventricle remodeling and dysfunction induced by catecholamines as well as ventricular arrhythmias, providing evidence that acutely increasing PDE2A activity could prevent progression towards HF.

physiology↗

bioRxiv2021

EPAC1 Inhibition Protects the Heart from Doxorubicin-Induced Toxicity

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administered in vivo, Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 KO mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.

pathology↗