Lipoprotein Proteomics and Aortic Valve Transcriptomics Identify Biological Pathways Linking Lipoprotein(a) Levels to Aortic Stenosis

Abstract

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels (n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.

Identification of MMP9 as a Novel Biomarker to Mitochondrial Metabolism Disorder and Oxidative Stress in Calcific Aortic Valve Stenosis

“…According to our current understanding, CAVS is a dynamic condition characterized by lipid accumulation, persistent inflammation, and active valve leaflet calcification [ 16 ]. Valvular degeneration precedes aortic stenosis and is characterized by calcification of the aortic valves, which is initially mild or moderate before worsening, with or without clinical symptoms [ 17 ].…”

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

“…Traditional focussed research methods for example have identified lipoprotein (a) as a significant risk factor for the development of calcific AS ( 204 , 205 ). Genome-wide association study (GWAS), however, have revealed a single nucleotide polymorphism with a strong independent predictive association with the development of AS; and multi-omics study has identified potential effector proteins and expressed genes linking Lp(a) to valvular calcification ( 206 , 207 ). Wang et al utilised multi-omic screening of explanted human aortic valve specimens to identify dual-specificity phosphatase 26 (DUSP26) as an upregulated gene promoting aortic valve calcification in CAVD, subsequently using in vivo mouse and in vitro human VIC studies to confirm that DUSP26 promotes CAVD via upregulation of dipeptidyl peptidase 4 (DPP4) ( 208 ).…”

Lipoprotein(a) in Cardiovascular Diseases: Insight From a Bibliometric Study

“…In recent years, the evidence revealing the association of Lp(a) with CAVS has accumulated (53)(54)(55). A transcriptomic analysis identified genes potentially influenced by Lp(a), which were involved in cardiac aging, chondrocyte development and inflammation (54).…”

“…In recent years, the evidence revealing the association of Lp(a) with CAVS has accumulated (53)(54)(55). A transcriptomic analysis identified genes potentially influenced by Lp(a), which were involved in cardiac aging, chondrocyte development and inflammation (54). Lp(a) was shown to upregulate genes involved in osteogenic differentiation and promote aortic valve calcium deposition In vitro (54,(56)(57)(58).…”

“…A transcriptomic analysis identified genes potentially influenced by Lp(a), which were involved in cardiac aging, chondrocyte development and inflammation (54). Lp(a) was shown to upregulate genes involved in osteogenic differentiation and promote aortic valve calcium deposition In vitro (54,(56)(57)(58). In a human multimodality imaging study, patients in the top Lp(a) tertile with Lp(a) >35 mg/dl showed an increased aortic valve 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) valvular calcification activity, much faster progression of valvular computed tomography calcium score, accelerated hemodynamic deterioration on echocardiography and increased risk for aortic valve replacement and death (58).…”