Mini-Focus: Aortic Valve Disease
Lipoprotein(a) Induces Human Aortic Valve Interstitial Cell Calcification

https://doi.org/10.1016/j.jacbts.2017.03.015Get rights and content
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Highlights

  • Lp(a) significantly increased alkaline phosphatase activity, phosphate and calcium content, and matrix vesicle formation and induced apoptosis and calcification of normal human aortic valve interstitial cells.

  • The type of minerals induced by Lp(a) resembles that seen in calcified human aortic valves as shown by Raman spectroscopy.

  • Lp(a)-induced calcification of human aortic valve interstitial cells is mediated by activation of MAPK38, GSK3β, and Wnt signaling.

  • Inhibition of GSK3β and MAPK38 significantly reduced lipoprotein(a)-induced aortic valve interstitial cell calcification.

  • Lp(a)is abundant in calcified aortic valves, and lipoprotein(a) immunoreactivity colocalized with that of oxidized phospholipids.

Summary

Lipoprotein(a), or Lp(a), significantly increased alkaline phosphatase activity, release of phosphate, calcium deposition, hydroxyapatite, cell apoptosis, matrix vesicle formation, and phosphorylation of signal transduction proteins; increased expression of chondro-osteogenic mediators; and decreased SOX9 and matrix Gla protein (p < 0.001). Inhibition of MAPK38 and GSK3β significantly reduced Lp(a)-induced calcification of human aortic valve interstitial cells (p < 0.001). There was abundant presence of Lp(a) and E06 immunoreactivity in diseased human aortic valves. The present study demonstrates a causal effect for Lp(a) in aortic valve calcification and suggests that interfering with the Lp(a)pathway could provide a novel therapeutic approach in the management of this debilitating disease.

Key Words

oxidized phospholipids
Raman spectroscopy
real-time PCR
stenosis

Abbreviations and Acronyms

ALP
alkaline phosphatase
apo(a)
apolipoprotein(a)
BMP
bone morphogenetic protein
FWHM
full width half maximum
HAVIC
human aortic valve interstitial cell
LDL
low-density lipoprotein
Lp(a)
lipoprotein(a)
LOX-1
oxidized LDL receptor 1
MAPK
mitogen-activated protein kinase
MGP
matrix Gla protein
mRNA
messenger ribonucleic acid
OxPL
oxidized phospholipid

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This work was supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Quebec, Canada. Dr. Thanassoulis is a consultant for and has received a research grant from Ionis; and is on the advisory board for Amgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.