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

doi:10.3390/antiox11010025

Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes

Antioxidants (Basel). 2021 Dec 23;11(1):25. doi: 10.3390/antiox11010025.

Authors

Chintan N Koyani^{1

2}, Susanne Scheruebel³, Ge Jin^{2

4}, Ewald Kolesnik², Klaus Zorn-Pauly³, Heinrich Mächler⁵, Gerald Hoefler⁶, Dirk von Lewinski², Frank R Heinzel^{7

8}, Brigitte Pelzmann³, Ernst Malle¹

Affiliations

¹ Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.
² Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria.
³ Division of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.
⁴ The 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
⁵ Department of Surgery, Division of Cardiac Surgery, Medical University of Graz, 8036 Graz, Austria.
⁶ Diagnostic and Research Center for Molecular BioMedicine, Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria.
⁷ Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany.
⁸ Deutsches Zentrum für Herz-Kreislauf-Forschung (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany.

Abstract

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 I_Ca,L and I_K1, and increased I_NaL, 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 I_NaL 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.

Keywords: MPO-H2O2-Cl- system; action potential; calcium transient; cardiomyocytes; cardiovascular disease; hypochlorite/hypochlorous acid; ion channel; low-density lipoprotein; redox imbalance; scavenger receptor.

Abstract

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