PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system

Area of Science:

• Cardiovascular Biology
• Vascular Inflammation
• Atherosclerosis Research

Background:

• Atherosclerosis, a precursor to cardiovascular disease (CVD), is exacerbated by proprotein convertase subtilisin/kexin 9 (PCSK9) through low-density lipoprotein receptor (LDLR) degradation and vascular inflammation.
• PCSK9's role extends beyond lipid metabolism to actively promoting inflammatory processes within blood vessels.

Purpose of the Study:

• To investigate the impact of PCSK9 activation and repression on atherosclerosis initiation using a vascular microphysiological system.
• To evaluate the efficacy of a novel small molecule PCSK9 inhibitor in mitigating PCSK9-driven vascular inflammation.

Main Methods:

• Generated PCSK9 over-expressed (P+) or repressed (P-) human induced pluripotent stem cells (iPSCs).
• Differentiated iPSCs into vascular smooth muscle cells (viSMCs) and endothelial cells (viECs) to construct tissue-engineered blood vessels (TEBVs).
• Assessed monocyte adhesion and inflammatory marker secretion (VCAM-1, TNF-α, IL-6) in TEBVs under modified LDL (eLDL) and TNF-α stimulation, testing the PCSK9 inhibitor NYX-1492.

Main Results:

• P+ TEBVs exhibited increased monocyte adhesion compared to wild type (WT) or P- TEBVs when challenged with eLDL and TNF-α.
• P+ viECs showed significant dysfunction, including elevated secretion of VCAM-1, TNF-α, and IL-6.
• NYX-1492 treatment reduced monocyte adhesion in P+ TEBVs and decreased VCAM-1 and TNF-α secretion, indicating reduced inflammation.

Conclusions:

• PCSK9 inhibition demonstrates potential in reducing vascular inflammation, complementing its lipid-lowering effects.
• Targeting PCSK9 may offer enhanced anti-atherosclerotic benefits, particularly for individuals with chronic inflammation.
• The developed TEBV model serves as a valuable platform for studying atherosclerosis and screening therapeutic compounds.