TY - JOUR
T1 - Lipid mass spectrometry imaging and proteomic analysis of severe aortic stenosis
AU - Lim, Jihyeon
AU - Aguilan, Jennifer T.
AU - Sellers, Rani S.
AU - Nagajyothi, Fnu
AU - Weiss, Louis M.
AU - Angeletti, Ruth Hogue
AU - Bortnick, Anna E.
N1 - Funding Information:
We acknowledge Edward Nieves’ assistance with mass spectrometry, Amanda Beck, Jeffrey Harding and Barbara Canella’s assistance in sectioning and photomicrography (all from the Montefiore Health System and Albert Einstein College of Medicine). We thank Genevieve T. Aguilan for composing Fig. 1.
Funding Information:
Funded by the Department of Medicine, Division of Cardiology at Montefiore Health System and Albert Einstein College of Medicine, with additional support from American Heart Association Mentored Clinical and Population Award 17MCPRP33630098, the Empire Clinical Research Investigator Program, and National Institutes of Health 1K23HL146982-01A1 (AEB), National Institutes of Health UL1TR001073, National Institutes of Health 1S10RR025128 and Shared Instrumentation Grant 1S10RR029398-01 (RHA). Acknowledgements
Publisher Copyright:
© 2020, Springer Nature B.V.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Severe aortic stenosis (AS) is prevalent in adults ≥ 65 years, a significant cause of morbidity and mortality, with no medical therapy. Lipid and proteomic alterations of human AS tissue were determined using mass spectrometry imaging (MSI) and liquid chromatography electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS) to understand histopathology, potential biomarkers of disease, and progression from non-calcified to calcified phenotype. A reproducible MSI method was developed using healthy murine aortic valves (n = 3) and subsequently applied to human AS (n = 2). Relative lipid levels were spatially mapped and associated with different microdomains. Proteomics for non-calcified and calcified microdomains were performed to ascertain differences in expression. Increased pro-osteogenic and inflammatory lysophosphatidylcholine (LPC) 16:0 and 18:0 were co-localized with calcified microdomains. Proteomics analysis identified differential patterns in calcified microdomains with high LPC and low cholesterol as compared to non-calcified microdomains with low LPC and high cholesterol. Calcified microdomains had higher levels of: apolipoproteins (Apo) B-100 (p < 0.001) and Apo A-IV (p < 0.001), complement C3 and C4-B (p < 0.001), C5 (p = 0.007), C8 beta chain (p = 0.013) and C9 (p = 0.010), antithrombotic proteins alpha-2-macroglobulin (p < 0.0001) and antithrombin III (p = 0.002), and higher anti-calcific fetuin-A (p = 0.02), while the osteoblast differentiating factor transgelin (p < 0.0001), extracellular matrix proteins versican, prolargin, and lumican (p < 0.001) and regulator protein complement factor H (p < 0.001) were higher in non-calcified microdomains. A combined lipidomic and proteomic approach provided insight into factors potentially contributing to progression from non-calcified to calcific disease in severe AS. Additional studies of these candidates and protein networks could yield new targets for slowing progression of AS.
AB - Severe aortic stenosis (AS) is prevalent in adults ≥ 65 years, a significant cause of morbidity and mortality, with no medical therapy. Lipid and proteomic alterations of human AS tissue were determined using mass spectrometry imaging (MSI) and liquid chromatography electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS) to understand histopathology, potential biomarkers of disease, and progression from non-calcified to calcified phenotype. A reproducible MSI method was developed using healthy murine aortic valves (n = 3) and subsequently applied to human AS (n = 2). Relative lipid levels were spatially mapped and associated with different microdomains. Proteomics for non-calcified and calcified microdomains were performed to ascertain differences in expression. Increased pro-osteogenic and inflammatory lysophosphatidylcholine (LPC) 16:0 and 18:0 were co-localized with calcified microdomains. Proteomics analysis identified differential patterns in calcified microdomains with high LPC and low cholesterol as compared to non-calcified microdomains with low LPC and high cholesterol. Calcified microdomains had higher levels of: apolipoproteins (Apo) B-100 (p < 0.001) and Apo A-IV (p < 0.001), complement C3 and C4-B (p < 0.001), C5 (p = 0.007), C8 beta chain (p = 0.013) and C9 (p = 0.010), antithrombotic proteins alpha-2-macroglobulin (p < 0.0001) and antithrombin III (p = 0.002), and higher anti-calcific fetuin-A (p = 0.02), while the osteoblast differentiating factor transgelin (p < 0.0001), extracellular matrix proteins versican, prolargin, and lumican (p < 0.001) and regulator protein complement factor H (p < 0.001) were higher in non-calcified microdomains. A combined lipidomic and proteomic approach provided insight into factors potentially contributing to progression from non-calcified to calcific disease in severe AS. Additional studies of these candidates and protein networks could yield new targets for slowing progression of AS.
KW - Calcific aortic valve stenosis
KW - Cholesterol
KW - Mass spectrometry imaging
KW - Proteomics
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U2 - 10.1007/s10735-020-09905-5
DO - 10.1007/s10735-020-09905-5
M3 - Article
C2 - 32794037
AN - SCOPUS:85089356652
SN - 1567-2379
VL - 51
SP - 559
EP - 571
JO - Journal of Molecular Histology
JF - Journal of Molecular Histology
IS - 5
ER -
