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 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.
Highlights
The prevalence of cardiovascular disease (CVD) is rising worldwide, making it the leading cause of deaths in developed countries
Neutrophils, MPO, apoB-100, and hypochlorous acid (HOCl)-Modified Epitopes Accumulate in the Infarcted
Using a specific monoclonal antibody [28], we observed abundant staining of HOCl-modified epitopes associated with cardiomyocytes in the infarcted border regions, indicating that the MPO-H2 O2 -Cl− system is active in the infarcted myocardium (Figure 1A)
Summary
The prevalence of cardiovascular disease (CVD) is rising worldwide, making it the leading cause of deaths in developed countries. Inflammation, and immune cells play pivotal roles in the development and progression of CVD [1,2]. One of the most common first-line immune cell responses to cardiac inflammation and ischemia is neutrophil infiltration into the myocardium [3]. Neutrophils contain myeloperoxidase (MPO) and the enzyme, stored in azurophilic granules, is released into the extracellular space upon cell activation [4]. Clinical trials have correlated high circulatory MPO levels with the mortality in patients with coronary artery diseases, acute ischemic stroke, and heart failure (HF) [5]. High circulatory MPO levels are associated with an increased risk of atherosclerosis, ischemic heart disease, and myocardial infarction (MI) [6,7]
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