2. Academic Validation
  3. Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis

Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis

  • Nat Commun. 2017 Oct 24;8(1):1129. doi: 10.1038/s41467-017-01186-z.
Yvonne Baumer 1 2,  Sara McCurdy 1,  Tina M Weatherby 3,  Nehal N Mehta 2,  Stefan Halbherr 4,  Pascal Halbherr 4,  Noboru Yamazaki 4,  William A Boisvert 5 6
Affiliations

Affiliations

  • 1 Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, BSB311, Honolulu, HI, 96813, USA.
  • 2 Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bldg 10-CRC, 9000 Rockville Pike, Bethesda, MD, 20814, USA.
  • 3 Pacific Biosciences Research Center, Biological Electron Microscope Facility, University of Hawaii, 2538 The Mall, Snyder Hall, Honolulu, HI, 96822, USA.
  • 4 InnoMedica Holding AG, Baarerstrasse 34, Zug, 6300, Switzerland.
  • 5 Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, BSB311, Honolulu, HI, 96813, USA. wab@hawaii.edu.
  • 6 Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., Kazan, 420008, Russia. wab@hawaii.edu.
PMID: 29066718 DOI: 10.1038/s41467-017-01186-z
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.

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