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Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis

Author

Listed:
  • Yvonne Baumer

    (University of Hawaii
    Lung and Blood Institute, National Institutes of Health)

  • Sara McCurdy

    (University of Hawaii)

  • Tina M. Weatherby

    (University of Hawaii)

  • Nehal N. Mehta

    (Lung and Blood Institute, National Institutes of Health)

  • Stefan Halbherr

    (InnoMedica Holding AG)

  • Pascal Halbherr

    (InnoMedica Holding AG)

  • Noboru Yamazaki

    (InnoMedica Holding AG)

  • William A. Boisvert

    (University of Hawaii
    Kazan Federal University)

Abstract

Endothelial cells (EC) play a key role in atherosclerosis. Although EC are in constant contact with low density lipoproteins (LDL), how EC process LDL and whether this influences atherogenesis, is unclear. Here we show that EC take up and metabolize LDL, and when overburdened with intracellular cholesterol, generate cholesterol crystals (CC). The CC are deposited on the basolateral side, and compromise endothelial function. When hyperlipidemic mice are given a high fat diet, CC appear in aortic sinus within 1 week. Treatment with cAMP-enhancing agents, forskolin/rolipram (F/R), mitigates effects of CC on endothelial function by not only improving barrier function, but also inhibiting CC formation both in vitro and in vivo. A proof of principle study using F/R incorporated into liposomes, designed to target inflamed endothelium, shows reduced atherosclerosis and CC formation in ApoE −/− mice. Our findings highlight an important mechanism by which EC contribute to atherogenesis under hyperlipidemic conditions.

Suggested Citation

  • Yvonne Baumer & Sara McCurdy & Tina M. Weatherby & Nehal N. Mehta & Stefan Halbherr & Pascal Halbherr & Noboru Yamazaki & William A. Boisvert, 2017. "Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01186-z
    DOI: 10.1038/s41467-017-01186-z
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