Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Abstract

BackgroundWe have demonstrated previously that enzymatically degraded low‐density lipoprotein (eLDL) is an essential causative component for the initiation of atherosclerosis. Here, we investigated the different stages of human aortic valve sclerosis for the presence of eLDL and effectors of the innate immune system, as well as the interaction of eLDL with isolated valvular interstitial cells/myofibroblasts to discover possible pathways leading to aortic valve sclerosis.Methods and ResultsHuman aortic valvular tissue was obtained from 68 patients undergoing valve replacement surgery. Patients were classified into 3 groups (mild, moderate, or severe aortic valve sclerosis), and clinical data for statistical analysis were gathered from all patients. Immunohistochemical staining demonstrated extensive extracellular deposits of eLDL throughout all grades of aortic valve sclerosis. Complementary analysis of lipid composition revealed higher concentrations of the decisive components of eLDL (ie, unesterified cholesterol and linoleic acid) compared with internal control tissues. Further, the complement component C3d and terminal complement complexes colocalized with eLDL compatible with the proposal that subendothelially deposited eLDL is enzymatically transformed into a complement activator at early stages of valvular cusp lesion development. Gene expression profiles of proteases and complement components corroborated by immunohistochemistry demonstrated an upregulation of the protease cathepsin D (a possible candidate for LDL degradation to eLDL) and the complement inhibitor CD55. Surprisingly, substantial C‐reactive protein expression was not observed before grade 2 aortic valve sclerosis as investigated with microarray analysis, reverse transcription–polymerase chain reaction analysis, and immunohistochemistry. Finally, we demonstrated cellular uptake of eLDL by valvular interstitial cells/myofibroblasts.ConclusionsThe present study is a startup of a hypothesis on the pathogenesis of aortic valve sclerosis declaring extracellular lipoprotein modification, subsequent complement activation, and cellular uptake by valvular interstitial cells/myofibroblasts as integral players.

Lipoprotein(a)-Associated Molecules Are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis

“…The first group of patients comprised 14 patients with mild to moderate CAVS who had available ethylenediaminetetraacetic acid plasma samples stored frozen at –70°C. The second group comprised 68 patients undergoing AVR for symptomatic CAVS with prospective collection of aortic valve leaflets and were recently described (26) . Formalin-fixed nonrheumatic aortic valves with varying degrees of macroscopic disease were analyzed for the presence of apolipoprotein(a) (apo[a]), ATX, oxidation-specific epitopes, and macrophages.…”

Enzymatically modified LDL atherosclerosis and beyond paving the way to acceptance

“…A pathogenetic impact of eLDL (and also ox-LDL) is not restricted to atherosclerosis. Recently, we demonstrated that subendothelially deposited eLDL is enzymatically transformed into a complement activator at early stages of aortic valve sclerosis development and also taken up by myofibroblasts (99). Very recently, we demonstrated a strong presence of apolipoprotein (a), oxidized phospholipids (OxPL), malondialdehyde-lysine, autotaxin, and macrophages, particularly in advanced lesions rich in cholesterol crystals and calcification.…”

C reactive protein and enzymatically modified LDL cooperatively promote dendritic cell-mediated T cell activation

“…CRP bound to eLDL and strongly activated complement pathway [42]. CRP [43] and eLDL [10] were found colocalized with the terminal complement complex in atherosclerotic plaques. Furthermore, the present study demonstrated that CRP and eLDL cooperatively promoted maturation and activation of DCs which drove the activation and proliferation of T cells.…”

“…Enzymatically modified low density lipoprotein (eLDL) is one of the most important players in the pathogenesis of atherosclerosis by increasing endothelium injuries, enhancing the recruitment of inflammatory cells, promoting the production and release of inflammatory mediators including radical oxygen species (ROS) and cytokines, and stimulating the proliferation of vascular smooth muscle cells [4][5][6][7][8][9][10]. Besides, eLDL promotes monocyte adhesion to endothelial cells through increasing ROS production, NF-κB activation, and endothelial inflammation [10][11][12].…”

“…Besides, eLDL promotes monocyte adhesion to endothelial cells through increasing ROS production, NF-κB activation, and endothelial inflammation [10][11][12].…”