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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Koyani, CN; Scheruebel, S; Jin, G; Kolesnik, E; Zorn-Pauly, K; Mächler, H; Hoefler, G; von, Lewinski, D; Heinzel, FR; Pelzmann, B; Malle, E.
Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes.
Antioxidants (Basel). 2021; 11(1): Doi: 10.3390/antiox11010025 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Führende Autor*innen der Med Uni Graz
Koyani Chintan Navinchandra
Malle Ernst
Pelzmann Brigitte
Scherübel-Posch Susanne
Co-Autor*innen der Med Uni Graz
Heinzel Frank
Höfler Gerald
Jin Ge
Kolesnik Ewald
Mächler Heinrich
von Lewinski Dirk
Zorn-Pauly Klaus

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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.

Find related publications in this database (Keywords)
action potential
calcium transient
cardiovascular disease
hypochlorous acid
ion channel
low-density lipoprotein
MPO-H2O2-Cl- system
redox imbalance
scavenger receptor
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