Endothelial Cell-Derived Cholesterol Crystals Promote Endothelial Inflammation in Early Atherogenesis

Abstract

Aims:

Endothelial inflammation is crucial in the initiation and progression of atherosclerosis, whereas cholesterol crystals (CCs) play a key role in atherogenesis. However, the effects and origination of CCs on endothelial inflammation are not well understood.

Results:

In the present study, we found that CCs appeared in the subendothelial space of the partially ligated carotid artery only 1 week after Western diet feeding, which was before immune cell infiltration. In vitro, CCs were generated by human aortic endothelial cells (HAECs) upon low-density lipoprotein treatment. These endothelial cell (EC)-derived CCs increased the expression of intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1). Mechanistic studies demonstrated that CC-induced pyroptosis was critical for endothelial inflammation. Knockdown of gasdermin D (GSDMD) inhibited CC-induced endothelial inflammation, attenuated plaque progression, and decreased macrophage content. Accordingly, the inhibition of GSDMD reduced the CC-induced increase of VCAM1 and ICAM1 in HAECs. Furthermore, CC-mediated pyroptosis was found to be caspase-1 (CASP1)-dependent. Inhibition of CASP1 also reduced endothelial inflammation and attenuated plaque progression. The expression of GSDMD was increased in human atherosclerotic plaques. These findings identify that EC-derived CCs may be an important driving force in the pathogenesis of atherosclerosis.

Innovation:

This study uncovered a new understanding that CC-induced pyroptosis contributes to endothelial inflammation in early atherogenesis.

Conclusion:

Targeting endothelial GSDMD or CASP1 contributes to the repression of vascular inflammation and atherogenesis. Antioxid. Redox Signal. 41, 201–215.