Mild hyperlipidemia in mice aggravates platelet responsiveness in thrombus formation and exploration of platelet proteome and lipidome

Johanna P. van Geffen, Frauke Swieringa, Kim van Kuijk, Bibian M. E. Tullemans, Fiorella A. Solari, Bing Peng, Kenneth J. Clemetson, Richard W. Farndale, Ludwig J. Dubois, Albert Sickmann, Rene P. Zahedi, Robert Ahrends, Erik A. L. Biessen, Judith C. Sluimer, Johan W. M. Heemskerk, Marijke J. E. Kuijpers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)

Abstract

Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in Apoe(-/-) and Ldlr(-/-) mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (Apoe(-/-) mice). Bone marrow from wild-type or Ldlr(-/-) mice was transplanted into irradiated Ldlr(-/-) recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in Apoe(-/-) and Ldlr(-/-) mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype.

Original languageEnglish
Article number21407
Number of pages17
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 8 Dec 2020

Keywords

  • LOW-DENSITY-LIPOPROTEIN
  • PROCOAGULANT ACTIVITY
  • GLYCOPROTEIN-VI
  • HYPERCHOLESTEROLEMIA
  • ATHEROSCLEROSIS
  • KINASE
  • CHOLESTEROL
  • COAGULATION
  • ACTIVATION
  • INHIBITION

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