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.
Highlights
Calcific aortic valve disease (CAVD) is a chronic disorder with increasing prevalence in the Western world but lacks pharmacological therapies
Valvular interstitial cells (VICs) maintain a quiescent fibroblast phenotype in healthy heart valves [1], which when challenged by pathologic stimuli, undergo myofibroblastic or osteoblastic differentiation, promoting tissue fibrosis and calcification leading to CAVD and aortic stenosis (AS) [1]
The knowledge of specific effects of apolipoproteins on aortic valve (AV) disease pathogenesis is largely limited to studies on apolipoprotein B–containing lipoproteins that serve as carriers for oxidized phospholipids [4], angiotensin-converting enzyme [5], as well as lipoprotein(a) [lp(a)] that carries proinflammatory lipids and promotes CAVD [2]
Summary
Calcific aortic valve disease (CAVD) is a chronic disorder with increasing prevalence in the Western world but lacks pharmacological therapies. We first validated a previously established peptide library [25, 27] on human HDL size fractions [27] (Supporting Information 1), examined apolipoproteins in AVs from the five CAVD donors, and verified the relative distributions demonstrated by our global proteomics analysis (Fig. 1B).
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