A Comparative Analysis of the Lipoprotein(a) and Low-Density Lipoprotein Proteomic Profiles Combining Mass Spectrometry and Mendelian Randomization

Bourgeois, Raphaëlle; Girard, Arnaud; Perrot, Nicolas; Guertin, Jakie; Mitchell, Patricia L.; Couture, Christian; Gotti, Clarisse; Bourassa, Sylvie; Poggio, Paolo; Mass, Elvira; Capoulade, Romain; Scipione, Corey A.; Després, Audrey-Anne; Couture, Patrick; Droit, Arnaud; Boffa, Michael B.; Thériault, Sébastien; Koschinsky, Marlys L.; Mathieu, Patrick; Arsenault, Benoît J.

doi:10.1016/j.cjco.2020.11.019

Cited by 12 publications

(12 citation statements)

References 49 publications

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“…Lp(a) subfractions were isolated from these 43 participants, as previously described [ 35 , 83 , 84 ]. Briefly, fresh serum was ultracentrifugated with a gradient of iodixanol solution (Optiprep).…”

Section: Methodsmentioning

confidence: 99%

“…The proteome of Lp(a) was evaluated as previously described [ 35 ]. Briefly, proteins from Lp(a) samples were precipitated overnight with acetone at −20 °C, then resuspended, reduced, alkylated, and, finally, digested with trypsin.…”

Section: Methodsmentioning

confidence: 99%

“…Analyses of Lp(a) and LDL proteomes have also identified a potential role of Lp(a) in wound healing and complement activation [ 34 ]. In a comparative analysis of the Lp(a) and LDL proteomes isolated from the same individuals, we also recently reported profound differences between these two fractions, with Lp(a) carrying many more proteins that LDLs [ 35 ]. It is, however, unknown if the proteome of Lp(a) differs across disease states such as CAVS.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…15 Proteomic analysis has been conducted for Lp(a) particles and shows profound differences from LDL particles. 16 In the first analysis 9 proteins were associated with LDL and 31 with Lp(a). 15 proteins were confirmed to be associated with Lp(a).…”

Section: Structure and Geneticsmentioning

confidence: 99%

“…These proteins were involved in negative regulation of peptidase activity, regulation or transport of insulin growth factors, extracellular structure organization, protein processing and binding. 16 Proteins such as transthyretin, vitronectin, paraoxonase-1 and protease inhibitors might be preferentially transported by Lp(a). It is interesting that the genetic study suggesting an interaction of Lp(a) with apoH was not reproduced in this study.…”

Section: Structure and Geneticsmentioning

confidence: 99%

Elevated Lipoprotein(a): Background, Current Insights and Future Potential Therapies

Handhle¹,

Viljoen²,

Wierzbicki³

2021

VHRM

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Lipoprotein(a) forms a subfraction of the lipid profile and is characterized by the addition of apolipprotein(a) (apo(a)) to apoB100 derived particles. Its levels are mostly genetically determined inversely related to the number of protein domain (kringle) repeats in apo(a). In epidemiological studies, it shows consistent association with cardiovascular disease (CVD) and most recently with extent of aortic stenosis. Issues with standardizing the measurement of Lp(a) are being resolved and consensus statements favor its measurement in patients at high risk of, or with family histories of CVD events. Major lipid-lowering therapies such as statin, fibrates, and ezetimibe have little effect on Lp(a) levels. Therapies such as niacin or cholesterol ester transfer protein (CETP) inhibitors lower Lp(a) as well as reducing other lipid-related risk factors but have failed to clearly reduce CVD events. Proprotein convertase subtilisin kexin-9 (PCSK9) inhibitors reduce cholesterol and Lp(a) as well as reducing CVD events. New antisense therapies specifically targeting apo(a) and hence Lp(a) have greater and more specific effects and will help clarify the extent to which intervention in Lp(a) levels will reduce CVD events.

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Proteomic studies on apoB‐containing lipoprotein in cardiovascular research: A comprehensive review

Gianazza

Zoanni

Mallia

et al. 2021

Mass Spectrometry Reviews

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The complexity of cardiovascular diseases (CVDs), which remains the leading cause of death worldwide, makes the current clinical pathway for cardiovascular risk assessment unsatisfactory, as there remains a substantial unexplained residual risk. Simultaneous assessment of a large number of plasma proteins may be a promising tool to further refine risk assessment, and lipoprotein-associated proteins have the potential to fill this gap. Technical advances now allow for highthroughput proteomic analysis in a reproducible and cost-effective manner.Proteomics has great potential to identify and quantify hundreds of candidate marker proteins in a sample and allows the translation from isolated lipoproteins to whole plasma, thus providing an individual multiplexed proteomic fingerprint. This narrative review describes the pathophysiological roles of atherogenic apoBcontaining lipoproteins and the recent advances in their mass spectrometry-based proteomic characterization and quantitation for better refinement of CVD risk assessment.

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A Comparative Analysis of the Lipoprotein(a) and Low-Density Lipoprotein Proteomic Profiles Combining Mass Spectrometry and Mendelian Randomization

Cited by 12 publications

References 49 publications

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

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

Elevated Lipoprotein(a): Background, Current Insights and Future Potential Therapies

Proteomic studies on apoB‐containing lipoprotein in cardiovascular research: A comprehensive review

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