ApoC-III is a novel inducer of human valvular calcification

ABSTRACT: Pharmacological interventions to treat valvular calcification are not currently part of clinical guidelines. Low-density lipoprotein lowering therapies to treat calcific aortic valve disease (CAVD) failed in clinical trials. However, apolipoproteins are known promotors of atherosclerosis and may play a role in CAVD pathogenesis beyond their lipid-binding capabilities. Lipoprotein particles carry oxidized lipids that promote valvular disease, but whether apolipoproteins themselves possess pathogenic properties in CAVD is less clear. We assessed 12 apolipoproteins in non-fibrotic/non-calcific (NF/NC), fibrotic (F) and calcific (C) aortic valve tissues by proteomics and immunohistochemistry and evaluated effects of enriched apolipoproteins on calcification. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I and apoM) were enriched in the C vs. NF/NC tissues. Apo(a), apoB, apoC-III, apoE and apoJ colocalized with the disease-prone fibrosa and calcific regions on histological sections. Circulating apoC-III on lipoprotein(a) was identified as a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also contributes to CAVD is unknown. ApoC-III was increased in F and C tissues and observed within the calcification-prone fibrosa layer as well as around calcification and induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated calcification pathway. This study provides the 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, modifiable driver of CAVD beyond its potential role as a biomarker.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Aortic Valve

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Sasha Singh  

LAB HEAD: Elena Aikawa

PROVIDER: PXD021858 | Pride | 2020-12-14

REPOSITORIES: Pride