Targeting PCSK9 in Vascular Smooth Muscle Cells: An Effective Strategy to Suppress Ferroptosis and Attenuate...

Area of Science:

• Cardiovascular Biology
• Cellular Pathology
• Pharmacology

Background:

• Abdominal aortic aneurysm (AAA) lacks effective pharmacotherapy.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in cardiovascular disease.
• Ferroptosis, a form of regulated cell death, plays a role in AAA pathogenesis.

Purpose of the Study:

• To investigate if PCSK9 drives ferroptosis in vascular smooth muscle cells (VSMCs).
• To determine if pharmacological degradation of PCSK9 can mitigate AAA progression.
• To elucidate the mechanism by which PCSK9 influences ferroptosis in VSMCs.

Main Methods:

• Examined PCSK9 expression in human AAA and murine models.
• Utilized SMC-specific PCSK9 overexpression and knockdown in vivo and in vitro.
• Assessed ferroptosis markers (iron, lipid peroxidation, GPX4), ferritinophagy (FTH1, NCOA4, LC3, LAMP1), and cell viability.
• Administered the PCSK9-degrading peptide Cadd4 in AAA models.

Main Results:

• PCSK9 is enriched in AAA lesions and promotes aortic dilation, medial degradation, and MMP expression.
• PCSK9 overexpression induces ferroptosis and ferritinophagy in VSMCs by decreasing FTH1 and NCOA4.
• PCSK9 knockdown attenuates ferroptosis, while autophagy inhibition rescues ferroptotic indices.
• Cadd4 treatment reduces aortic dilation, preserves vascular structure, and normalizes ferroptosis and ferritinophagy markers in AAA models.

Conclusions:

• PCSK9 drives ferritinophagy-dependent ferroptosis in VSMCs, contributing to AAA pathogenesis.
• Pharmacological degradation of PCSK9 using Cadd4 is a potential therapeutic strategy for AAA.
• Targeting PCSK9-mediated ferroptosis offers a novel approach for AAA treatment.