Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis

Yvonne Baumer, Sara McCurdy, Tina M. Weatherby, Nehal N. Mehta, Stefan Halbherr, Pascal Halbherr, Noboru Yamazaki and William A. Boisvert ()
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Yvonne Baumer: University of Hawaii
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

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01186-z

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