PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
AIP Publishing LLC
2023-12-01
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| Series: | APL Bioengineering |
| Online Access: | http://dx.doi.org/10.1063/5.0167440 |
| _version_ | 1827391531824185344 |
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| author | Jounghyun H. Lee Kevin L. Shores Jason J. Breithaupt Caleb S. Lee Daniella M. Fodera Jennifer B. Kwon Adarsh R. Ettyreddy Kristin M. Myers Benny J. Evison Alexandra K. Suchowerska Charles A. Gersbach Kam W. Leong George A. Truskey |
| author_facet | Jounghyun H. Lee Kevin L. Shores Jason J. Breithaupt Caleb S. Lee Daniella M. Fodera Jennifer B. Kwon Adarsh R. Ettyreddy Kristin M. Myers Benny J. Evison Alexandra K. Suchowerska Charles A. Gersbach Kam W. Leong George A. Truskey |
| author_sort | Jounghyun H. Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T17:12:25Z |
| format | Article |
| id | doaj.art-f6d0b5cc6b244d04bac23d3123f01c78 |
| institution | Directory Open Access Journal |
| issn | 2473-2877 |
| language | English |
| last_indexed | 2024-03-08T17:12:25Z |
| publishDate | 2023-12-01 |
| publisher | AIP Publishing LLC |
| record_format | Article |
| series | APL Bioengineering |
| spelling | doaj.art-f6d0b5cc6b244d04bac23d3123f01c782024-01-03T19:58:04ZengAIP Publishing LLCAPL Bioengineering2473-28772023-12-0174046103046103-1510.1063/5.0167440PCSK9 activation promotes early atherosclerosis in a vascular microphysiological systemJounghyun H. Lee0Kevin L. Shores1Jason J. Breithaupt2Caleb S. Lee3Daniella M. Fodera4Jennifer B. Kwon5Adarsh R. Ettyreddy6Kristin M. Myers7Benny J. Evison8Alexandra K. Suchowerska9Charles A. Gersbach10Kam W. Leong11George A. Truskey12 Department of Biomedical Engineering, Columbia University, New York, New York 10032, USA Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA Department of Biomedical Engineering, Columbia University, New York, New York 10032, USA Department of Biomedical Engineering, Columbia University, New York, New York 10032, USA University Program in Genetics and Genomics, Duke University Medical Center, Durham, North Carolina 27710, USA Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA Department of Mechanical Engineering, Columbia University, New York, New York 10032, USA Nyrada Inc., Gordon, New South Wales, Australia Nyrada Inc., Gordon, New South Wales, Australia Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA Department of Biomedical Engineering, Columbia University, New York, New York 10032, USA Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USAAtherosclerosis 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.http://dx.doi.org/10.1063/5.0167440 |
| spellingShingle | Jounghyun H. Lee Kevin L. Shores Jason J. Breithaupt Caleb S. Lee Daniella M. Fodera Jennifer B. Kwon Adarsh R. Ettyreddy Kristin M. Myers Benny J. Evison Alexandra K. Suchowerska Charles A. Gersbach Kam W. Leong George A. Truskey PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system APL Bioengineering |
| title | PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system |
| title_full | PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system |
| title_fullStr | PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system |
| title_full_unstemmed | PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system |
| title_short | PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system |
| title_sort | pcsk9 activation promotes early atherosclerosis in a vascular microphysiological system |
| url | http://dx.doi.org/10.1063/5.0167440 |
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