Modified Lipoprotein-Derived Lipid Particles Accumulate in Human Stenotic Aortic Valves

Abstract

In aortic stenosis plasma lipoprotein-derived lipids accumulate in aortic valves. Here, we first compared the lipid compositions of stenotic aortic valves and atherosclerotic plaque cores. Both pathological tissues were found to be enriched in cholesteryl linoleate, a marker of extracellularly accumulated lipoproteins. In addition, a large proportion of the phospholipids were found to contain arachidonic acid, the common precursor of a number of proinflammatory lipid mediators. Next, we isolated and characterized extracellular lipid particles from human stenotic and non-stenotic control valves, and compared them to plasma lipoproteins from the same subjects. The extracellular valvular lipid particles were isolated from 15 stenotic and 14 non-stenotic aortic valves. Significantly more apoB-100-containing lipid particles were found in the stenotic than in the non-stenotic valves. The majority of the lipid particles isolated from the non-stenotic valves had sizes (23±6.2 nm in diameter) similar to those of plasma low density lipoprotein (LDL) (22±1.5 nm), while the lipid particles from stenotic valves were not of uniform size, their sizes ranging from 18 to more than 500 nm. The lipid particles showed signs of oxidative modifications, and when compared to isolated plasma LDL particles, the lipid particles isolated from the stenotic valves had a higher sphingomyelin/phosphatidylcholine –ratio, and also higher contents of lysophosphatidylcholine and unesterified cholesterol. The findings of the present study reveal, for the first time, that in stenotic human aortic valves, infiltrated plasma lipoproteins have undergone oxidative and lipolytic modifications, and become fused and aggregated. The generated large lipid particles may contribute to the pathogenesis of human aortic stenosis.

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

“…Acquisition of direct evidence that eLDL is indeed present extracellularly became a pressing issue, and immunohistochemical localization appeared to us the method of choice. If we may assume that enzymatic degradation and fusion of lipid particles are essentially synonymous,10 our findings are in perfect accordance with the recently published electron micrographs of isolated extracellular lipid particles from aortic valves 26. Compared with the histological structure of adaptive intimal thickening of human arteries prone to atherosclerotic lesion development,27 the composition of the human aortic valve cusp with the fibrosa suffused with insudated lipoproteins is quite different.…”

Calcific aortic stenosis

“…Lp-PLA2 is transported by apoB-containing lipoproteins and is enriched in small, dense LDL and Lp(a) 60 . Lp-PLA2 transforms Ox-PLs into lysophosphatidylcholine (LysoPC), which promotes the loss of mitochondrial membrane potential and apoptosis of VICs 57;61 . In addition, Bouchareb and colleagues recently showed that ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (also called autotaxin), a lysophospholipase D, is likely transported into the aortic valve by Lp(a) and is also secreted by VICs in response to diverse stimuli including tumor necrosis factor alpha (TNF-α) 62 .…”

Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve

“…9 Also, through nonenzymatic pathways, the oxidation of LDLs generates LPC, 10,11 a highly reactive metabolite with proosteogenic properties and present in mineralized aortic valves. 8,12 Autotaxin (ATX), encoded by the ENPP2 gene, is a lysophospholipase D enzyme that is transported in the blood plasma and secreted by different cell populations. 13 ATX uses LPC as a substrate and produces lysophosphatidic acid, which has potent proinflammatory properties.…”