PROTAC-mediated PCSK9 degradation attenuates atherosclerosis and improves plaque composition via suppression of NF-κB/TNF-α pathway - PubMed
4 hours ago
- #PCSK9 Degradation
- #Atherosclerosis Treatment
- #Anti-inflammatory Therapy
- A PROTAC molecule named Cadd4 was developed to selectively degrade the PCSK9 protein, a known target for hyperlipidemia and atherosclerosis.
- In vitro studies showed Cadd4 induced dose-dependent PCSK9 degradation in various cell types and reduced LPS-induced inflammatory responses.
- In vivo tests on ApoE-/- mice on a high-fat diet revealed Cadd4 administration reduced atherosclerotic plaque area and inflammation, and improved plaque collagen content.
- Cadd4 outperformed alirocumab in suppressing matrix metalloproteinase expression and enhancing collagen, likely by inhibiting the NF-κB/TNF-α pathway.
- The anti-atherosclerotic effects of Cadd4 were lipid-independent, as it did not alter plasma lipid profiles, highlighting its anti-inflammatory role.
- Findings suggest Cadd4 has therapeutic potential for atherosclerotic cardiovascular disease by degrading PCSK9 and improving plaque composition.