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

Raphaëlle Bourgeois,Patricia L Mitchell,Jérôme Bourgault,Corey A Scipione,Yohan Bossé,Michael B Boffa,Clarisse Gotti,Philippe Pibarot,Arnaud Girard,Sylvie Bourassa,Patrick Mathieu,Arnaud Droit,Jakie Guertin,Audrey-Anne Despres,Sébastien Thériault,Nathalie Gaudreault,Nicolas Perrot,Marlys L Koschinsky,Benoit J Arsenault

doi:10.3390/metabo11070459

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.

Highlights

Calcific aortic valve stenosis (CAVS) is the most prevalent valvulopathy worldwide, affecting approximately 2% of the population over 65 years old [1,2]
CAVS shares many of the risk factors for atherosclerotic cardiovascular diseases (ACVD), such as age, male sex, hypertension, higher low-density lipoprotein (LDL) cholesterol, type 2 diabetes, tobacco use, and elevated lipoprotein(a) (Lp(a)) levels [7,8,9,10,11,12]
We identified four proteins that may be more abundant in the Lp(a) of participants without CAVS, three of them being associated with the immunoglobulin family (IgM, JCHAIN, IGKV-2D-30) and β2GPI. β2GPI activates lipoprotein lipase and triglyceriderich lipoprotein (TRL) catabolism [61]

Summary

Introduction

Calcific aortic valve stenosis (CAVS) is the most prevalent valvulopathy worldwide, affecting approximately 2% of the population over 65 years old [1,2]. Its prevalence is increasing with population aging [3]. CAVS results from an active inflammatory process, including lipoprotein infiltration and oxidation, immune cell activation and infiltration into the valve leaflets cells, and osteoblastic transition of valvular interstitial cells (VICs) leading to fibrocalcific remodelling [4,5,6]. CAVS shares many of the risk factors for atherosclerotic cardiovascular diseases (ACVD), such as age, male sex, hypertension, higher low-density lipoprotein (LDL) cholesterol, type 2 diabetes, tobacco use, and elevated lipoprotein(a) (Lp(a)) levels [7,8,9,10,11,12]. The only treatment for symptomatic end-stage process disease patients is surgical or transcatheter valve replacement [6]

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Conclusion