Abstract
Idiopathic dilated cardiomyopathy (IDCM) is a frequent cause of heart transplantation. Potentially valuable blood markers are being sought, and low‐density lipoprotein receptor‐related protein 1 (LRP1) has been linked to the underlying molecular basis of the disease. This study compared circulating levels of soluble LRP1 (sLRP1) in IDCM patients and healthy controls and elucidated whether sLRP1 is exported out of the myocardium through extracellular vesicles (EVs) to gain a better understanding of the pathogenesis of the disease. LRP1 α chain expression was analysed in samples collected from the left ventricles of explanted hearts using immunohistochemistry. sLRP1 concentrations were determined in platelet‐free plasma by enzyme‐linked immunosorbent assay. Plasma‐derived EVs were extracted by size‐exclusion chromatography (SEC) and characterized by nanoparticle tracking analysis and cryo‐transmission electron microscopy. The distributions of vesicular (CD9, CD81) and myocardial (caveolin‐3) proteins and LRP1 α chain were assessed in SEC fractions by flow cytometry. LRP1 α chain was preferably localized to blood vessels in IDCM compared to control myocardium. Circulating sLRP1 was increased in IDCM patients. CD9‐ and CD81‐positive fractions enriched with membrane vesicles with the expected size and morphology were isolated from both groups. The LRP1 α chain was not present in these SEC fractions, which were also positive for caveolin‐3. The increase in circulating sLRP1 in IDCM patients may be clinically valuable. Although EVs do not contribute to higher sLRP1 levels in IDCM, a comprehensive analysis of EV content would provide further insights into the search for novel blood markers.
Highlights
Dilated cardiomyopathy (DCM) is the most common cause of nonischaemic heart failure leading to heart transplantation [1]
The results from the present study indicate for the first time that the measurement of peripheral soluble LRP1 (sLRP1) is potentially valuable for idiopathic dilated cardiomyopathy (IDCM)
The protease inhibitor protein a-2 macroglobulin, which is highly increased in the myocardium of IDCM patients [24], was one of the first lipoprotein receptor-related protein 1 (LRP1) ligands described [32]
Summary
Dilated cardiomyopathy (DCM) is the most common cause of nonischaemic heart failure leading to heart transplantation [1]. In the majority of cases, the primary cause is unknown, giving rise to the term idiopathic dilated cardiomyopathy (IDCM). Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Vol 21, No 11, 2017 ventricular chamber enlargement or dilatation, systolic dysfunction with normal left ventricular (LV) wall thickness, progressive LV contractile dysfunction, ventricular and supraventricular arrhythmias, thromboembolism and sudden death [2,3,4,5]
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