Cardiomyocytes-specific deletion of monoamine oxidase B reduces irreversible myocardial ischemia/reperfusion injury

Jacqueline Heger; Christine Hirschhäuser; Julia Bornbaum; Akylbek Sydykov; Astrid Dempfle; André Schneider; Thomas Braun; Klaus-Dieter Schlüter; Rainer Schulz

doi:10.1016/j.freeradbiomed.2021.01.020

Cardiomyocytes-specific deletion of monoamine oxidase B reduces irreversible myocardial ischemia/reperfusion injury

Free Radic Biol Med. 2021 Mar:165:14-23. doi: 10.1016/j.freeradbiomed.2021.01.020. Epub 2021 Jan 18.

Authors

Jacqueline Heger¹, Christine Hirschhäuser², Julia Bornbaum², Akylbek Sydykov³, Astrid Dempfle⁴, André Schneider⁵, Thomas Braun⁵, Klaus-Dieter Schlüter², Rainer Schulz²

Affiliations

¹ Justus-Liebig-University Giessen, Physiologisches Institut, Giessen, Germany. Electronic address: Jacqueline.Heger@physiologie.med.uni-giessen.de.
² Justus-Liebig-University Giessen, Physiologisches Institut, Giessen, Germany.
³ Justus-Liebig-University Giessen, Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany.
⁴ Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-University Kiel, Institute for Medical Informatics and Statistics, Kiel, Germany.
⁵ Max-Planck-Institute for Heart and Lung Research (MPI), Bad Nauheim, Germany.

PMID: 33476795
DOI: 10.1016/j.freeradbiomed.2021.01.020

Abstract

Monoamine oxidase B (MAO-B), a protein localized at the outer mitochondrial membrane, catalyzes the oxidative deamination of biogenic amines thereby producing reactive oxygen species (ROS). Increased ROS formation contributes to myocardial ischemia/reperfusion (I/R); however, the importance of different ROS producing enzymes for increased I/R-induced ROS formation and the subsequent I/R injury is still a matter of debate. Here we describe the first cardiomyocytes-specific MAO-B knockout mouse and test the hypothesis that lack of cardiomyocyte MAO-B protects the heart from I/R injury. A cardiac-specific and tamoxifen-inducible MAO-B knockout mouse (MAO-B KO) was generated using the Cre/lox system; Cre-negative MAO-B^fl/fl littermates served as controls (WT). Lack of MAO-B was verified by Western blot and immunohistochemistry. Cardiac function of MAO-B KO and WT was analyzed by echocardiography, quantification of mitochondrial ROS production, and measurement of myocardial infarct size (in % of ventricle) in hearts exposed to global I/R using the Langendorff technique. MAO-B protein expression was significantly down-regulated in MAO-B KO mice after two weeks of tamoxifen feeding followed by ten weeks of feeding with normal chow. ROS formation stimulated by the MAO-B-specific substrate β-phenylethylamin (PEA; 250 μM) was significantly lower in mitochondria isolated from MAO-B KO compared to WT hearts (WT 4.5 ± 0.8 a. u.; MAO-B KO 1.2 ± 0.3 a. u.). Echocardiography revealed no significant differences in LV dimensions as well as ejection fraction (EF) between WT and MAO-B KO mice (EF: WT 67.3 ± 8.8%; MAO-B KO 67.7 ± 6.5%). After I/R, infarct size was significantly lower in MAO-B KO hearts (WT 69.3 ± 15.1%; MAO-B KO 46.8 ± 12.0%). CONCLUSION: Lack of cardiomyocytes-specific MAO-B reduces infarct size suggesting that MAO-B activity contributes to acute reperfusion injury.

Keywords: Ischemia/reperfusion; Langendorff-perfused hearts; Mitochondria; Monoamine oxidase B (MAO-B).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Mice
Mice, Inbred C57BL
Mice, Knockout
Monoamine Oxidase / genetics
Myocardial Reperfusion Injury* / genetics
Myocytes, Cardiac
Reactive Oxygen Species

Substances

Reactive Oxygen Species
Monoamine Oxidase