Lea K Seidlmayer1, Johannes Kuhn2, Annette Berbner2, Paula-Anahi Arias-Loza2, Tatjana Williams2, Mathias Kaspar3, Martin Czolbe2, Jennifer Q Kwong4, Jeffery D Molkentin4, Katrin Gertrud Heinze5, Elena N Dedkova6, Oliver Ritter7. 1. Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany Comprehensive Heart Failure Center, University of Würzburg, Straubmühlweg 2a, 97078 Würzburg, Germany seidlmayer_l@ukw.de. 2. Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany. 3. Comprehensive Heart Failure Center, University of Würzburg, Straubmühlweg 2a, 97078 Würzburg, Germany. 4. Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, MLC 7020 Cincinnati, OH 45229, USA. 5. Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. 6. Department of Pharmacology, School of Medicine, University of California Davis, 451 E. Health Sciences Drive, Genome and Biomedical Sciences Facility, Davis, CA 95616, USA. 7. Department of Internal Medicine, Cardiology, University Hospital Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany Comprehensive Heart Failure Center, University of Würzburg, Straubmühlweg 2a, 97078 Würzburg, Germany Medizinische Hochschule Brandenburg, Campus Klinikum Brandenburg/Havel, Abteilung für Kardiologie und Pneumologie, Hochstr. 29, 14770 Brandenburg an der Havel, Germany.
Abstract
AIMS: Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms. METHODS AND RESULTS: We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca(2+ )elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca(2+ )uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca(2+ )(Ca(2 +) m) but only ET-1 led to an increase in ATP concentration. ET-1-induced effects were prevented by cell treatment with the IP3 antagonist 2-aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP3 chelating protein (IP3 sponge). Furthermore, ET-1-induced mitochondrial Ca(2+) uptake was insensitive to the mitochondrial Ca(2+ )uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real-time polymerase chain reaction, we detected the presence of all three isoforms of IP3Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors. CONCLUSIONS: Stimulation of IP3Rs with ET-1 induces Ca(2+ )release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms. METHODS AND RESULTS: We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca(2+ )elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca(2+ )uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca(2+ )(Ca(2 +) m) but only ET-1 led to an increase in ATP concentration. ET-1-induced effects were prevented by cell treatment with the IP3 antagonist 2-aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP3 chelating protein (IP3 sponge). Furthermore, ET-1-induced mitochondrial Ca(2+) uptake was insensitive to the mitochondrial Ca(2+ )uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real-time polymerase chain reaction, we detected the presence of all three isoforms of IP3Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors. CONCLUSIONS: Stimulation of IP3Rs with ET-1 induces Ca(2+ )release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production. Published on behalf of the European Society of Cardiology. All rights reserved.
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