Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes
Chintan N. Koyani,
Susanne Scheruebel,
Ge Jin,
Ewald Kolesnik,
Klaus Zorn-Pauly,
Heinrich Mächler,
Gerald Hoefler,
Dirk von Lewinski,
Frank R. Heinzel,
Brigitte Pelzmann,
Ernst Malle
Affiliations
Chintan N. Koyani
Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria
Susanne Scheruebel
Division of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria
Ge Jin
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria
Ewald Kolesnik
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria
Klaus Zorn-Pauly
Division of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria
Heinrich Mächler
Department of Surgery, Division of Cardiac Surgery, Medical University of Graz, 8036 Graz, Austria
Gerald Hoefler
Diagnostic and Research Center for Molecular BioMedicine, Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
Dirk von Lewinski
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria
Frank R. Heinzel
Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany
Brigitte Pelzmann
Division of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria
Ernst Malle
Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria
Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease.
