Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Koyani, C.
Modulation of cardiac function by low-density lipoprotein
modified via HOCl, a potent myeloperoxidase-derived oxidant
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Autor*innen der Med Uni Graz:
- Koyani Chintan Navinchandra
- Betreuer*innen:
- Malle Ernst
- Altmetrics:
- Abstract:
- Neutrophil infiltration and elevated levels of neutrophil-derived myeloperoxidase (MPO) in the myocardium are clinical markers for prediction of future cardiovascular events. Elevated plasma MPO levels were further correlated with mortality in patients with coronary artery disease, heart failure and myocardial infarction. Activated MPO generates hypochlorous acid (HOCl) from H2O2 and Cl-. HOCl is a potent oxidant that reacts with numerous biological molecules including lipoproteins. Most importantly, HOCl-modified low-density lipoproteins (HOCl-LDL) are found in human atherosclerotic lesions. Moreover, cardiomyocytes secret apoB-100 containing lipoproteins that in turn may react with MPO-generated HOCl in the myocardium. The present immunohistochemistry data reveal the presence of neutrophils, MPO and HOCl-modified epitopes in the infarcted myocardium. Interestingly, the pattern of immunostain of HOCl-modified epitopes and apoB-100 (the major apolipoprotein of LDL) in the serial sections strengthens the hypothesis of LDL modification by HOCl in vivo during cardiovascular diseases. Therefore, the major aim of the present study was to evaluate the impact of HOCl-LDL on cardiac tissue and myocyte function. HOCl-LDL altered electrophysiological characteristics of cardiomyocytes. Prolonged action potential duration, depolarized resting membrane potential and reduced maximal upstroke velocity became apparent as a result of reduced IK1 and increased INaL density. Moreover, increased Iss and INS were observed at outward positive and inward negative membrane potentials. HOCl-LDL altered calcium homeostasis, namely reduced ICa,L, calcium transient, sarcoplasmic reticulum Ca2+ content and cell shortening. Moreover, increased time to peak and reduced RT50 were observed in HOCl-LDL-treated myocytes. Altogether, the observed changes at the cellular level contributed to arrhythmic episodes and contractile dysfunction of human right atrial trabeculae in response to HOCl-LDL. Molecular biology experiments reveal that HOCl-LDL treatment oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) via LOX-1 and CD36 receptor-mediated signalling. Moreover, elevated superoxide anion production contributed to oxidation of CaMKII. KN93, a blocker of CaMKII activity, and Ranolazine, an inhibitor of INaL, protected cardiac tissue and myocytes against HOCl-LDL-induced arrhythmia and contractile dysfunction.