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PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system.

Publication ,  Journal Article
Lee, JH; Shores, KL; Breithaupt, JJ; Lee, CS; Fodera, DM; Kwon, JB; Ettyreddy, AR; Myers, KM; Evison, BJ; Suchowerska, AK; Gersbach, CA ...
Published in: APL bioengineering
December 2023

Atherosclerosis is a primary precursor of cardiovascular disease (CVD), the leading cause of death worldwide. While proprotein convertase subtilisin/kexin 9 (PCSK9) contributes to CVD by degrading low-density lipoprotein receptors (LDLR) and altering lipid metabolism, PCSK9 also influences vascular inflammation, further promoting atherosclerosis. Here, we utilized a vascular microphysiological system to test the effect of PCSK9 activation or repression on the initiation of atherosclerosis and to screen the efficacy of a small molecule PCSK9 inhibitor. We have generated PCSK9 over-expressed (P+) or repressed (P-) human induced pluripotent stem cells (iPSCs) and further differentiated them to smooth muscle cells (viSMCs) or endothelial cells (viECs). Tissue-engineered blood vessels (TEBVs) made from P+ viSMCs and viECs resulted in increased monocyte adhesion compared to the wild type (WT) or P- equivalents when treated with enzyme-modified LDL (eLDL) and TNF-α. We also found significant viEC dysfunction, such as increased secretion of VCAM-1, TNF-α, and IL-6, in P+ viECs treated with eLDL and TNF-α. A small molecule compound, NYX-1492, that was originally designed to block PCSK9 binding with the LDLR was tested in TEBVs to determine its effect on lowering PCSK9-induced inflammation. The compound reduced monocyte adhesion in P+ TEBVs with evidence of lowering secretion of VCAM-1 and TNF-α. These results suggest that PCSK9 inhibition may decrease vascular inflammation in addition to lowering plasma LDL levels, enhancing its anti-atherosclerotic effects, particularly in patients with elevated chronic inflammation.

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Published In

APL bioengineering

DOI

EISSN

2473-2877

ISSN

2473-2877

Publication Date

December 2023

Volume

7

Issue

4

Start / End Page

046103

Related Subject Headings

  • 4003 Biomedical engineering
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lee, J. H., Shores, K. L., Breithaupt, J. J., Lee, C. S., Fodera, D. M., Kwon, J. B., … Truskey, G. A. (2023). PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system. APL Bioengineering, 7(4), 046103. https://doi.org/10.1063/5.0167440
Lee, Jounghyun H., Kevin L. Shores, Jason J. Breithaupt, Caleb S. Lee, Daniella M. Fodera, Jennifer B. Kwon, Adarsh R. Ettyreddy, et al. “PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system.APL Bioengineering 7, no. 4 (December 2023): 046103. https://doi.org/10.1063/5.0167440.
Lee JH, Shores KL, Breithaupt JJ, Lee CS, Fodera DM, Kwon JB, et al. PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system. APL bioengineering. 2023 Dec;7(4):046103.
Lee, Jounghyun H., et al. “PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system.APL Bioengineering, vol. 7, no. 4, Dec. 2023, p. 046103. Epmc, doi:10.1063/5.0167440.
Lee JH, Shores KL, Breithaupt JJ, Lee CS, Fodera DM, Kwon JB, Ettyreddy AR, Myers KM, Evison BJ, Suchowerska AK, Gersbach CA, Leong KW, Truskey GA. PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system. APL bioengineering. 2023 Dec;7(4):046103.

Published In

APL bioengineering

DOI

EISSN

2473-2877

ISSN

2473-2877

Publication Date

December 2023

Volume

7

Issue

4

Start / End Page

046103

Related Subject Headings

  • 4003 Biomedical engineering