ApoC-III is a novel inducer of calcification in human aortic valves

Abstract

Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein–lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker.

The Lipocalin Apolipoprotein D Functional Portrait: A Systematic Review

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Lipoprotein(a) Induces Vesicular Cardiovascular Calcification Revealed With Single-Extracellular Vesicle Analysis

“…How Lp(a) induces the release of calcifying EVs is unclear, but several related mechanisms have been suggested for Lp(a)mediated calcification in VICs (24), including inflammatory related pathways involving oxidized lipids and pro-inflammatory proteins like apolipoprotein C3 found on Lp(a) particles (11,13). Inflammation can alter EVs, and EVs contribute to and reflect inflammatory processes in cardiovascular calcification (8,9).…”

“…Cardiovascular cells release calcifying EVs that get trapped in collagen extracellular matrix, aggregate, and form scaffolds that mineralize and grow forming vascular and valvular microcalcification (6,10) that eventually coalesce into large macrocalcification. Triggers for this process are unclear but could involve inflammation and alterations in lipid metabolism that drive cardiovascular calcification (8,(11)(12)(13).…”

Apolipoproteins and lipoprotein(a) as factors modulating fibrin clot properties in patients with severe aortic stenosis

“…Increased level of circulating oxidized LDL (OxLDL) is associated with enhanced fibrocalcific tissue remodelling of AS valves [6]. Moreover, apoC-III has been found to induce aortic valves calcification [7].…”