Coronary Artery Disease Transcriptomics Reveals Two Drivers of the Endothelial Cell SR-BI Expression and LDL Transport that Underlie Atherosclerosis

Huang, L.; Huang, Y.; Zhu, J.; Peng, J.; Chen, K.; Chambliss, K.; Zhou, Q.; Vela, R.; Burns, D.; Li, B.; Peltz, M.; Fang, Y.; Xu, L.; Mineo, C.; Shaul, P.

doi:10.64898/2026.08.05.743006

bioRxiv · 10.64898/2026.08.05.743006

Coronary Artery Disease Transcriptomics Reveals Two Drivers of the Endothelial Cell SR-BI Expression and LDL Transport that Underlie Atherosclerosis

Huang, L.·Huang, Y.·Zhu, J.·Peng, J.·Chen, K.·Chambliss, K.·Zhou, Q.·Vela, R.·Burns, D.·Li, B.·Peltz, M.·Fang, Y.·Xu, L.·Mineo, C.·Shaul, P.

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Abstract

Atherosclerosis is initiated by circulating low-density lipoprotein (LDL) cholesterol transfer into the artery wall, which is mediated by scavenger receptor class B, type I (SR-BI) in endothelial cells(1). Employing single-cell RNA sequencing in human coronary artery disease (CAD) samples, here we show that endothelial SR-BI expression is increased in atheroma, and in endothelial cells with a transcript signature indicative of responding to disturbed blood flow. In vivo in mice hypercholesterolemia and disturbed blood flow independently upregulate endothelial SR-BI; the flow-related upregulation initiates endothelial cell LDL uptake and atherogenesis. Guided by transcription factor networks, it is revealed that HIF-1 binding to human Scarb1 Intron 1 governs endothelial SR-BI transcription, and in mice HIF-1 drives hypercholesterolemia-related SR-BI upregulation and artery LDL uptake. Thus, the two major instigators of atherosclerotic lesion formation, hypercholesterolemia and disturbed blood flow, both upregulate endothelial SR-BI to drive the LDL transport that underlies the disorder. Targeting the processes regulating endothelial SR-BI potentially represents a new therapeutic strategy against CAD.

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Huang, L., Huang, Y., Zhu, J., Peng, J., Chen, K., Chambliss, K., Zhou, Q., Vela, R., Burns, D., Li, B., Peltz, M., Fang, Y., Xu, L., Mineo, C., Shaul, P.. 2026-08-06. Coronary Artery Disease Transcriptomics Reveals Two Drivers of the Endothelial Cell SR-BI Expression and LDL Transport that Underlie Atherosclerosis. https://doi.org/10.64898/2026.08.05.743006

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