Cadd4 peptide degrades PCSK9, suppresses ferroptosis, and attenuates abdominal aortic aneurysm progression

Effective pharmacotherapy for abdominal aortic aneurysm (AAA) remains elusive, with current treatments primarily surgical. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is well-known for its role in cholesterol metabolism, but its involvement in vascular pathology, specifically in vascular smooth muscle cells (VSMCs), is less understood. This study investigates whether PCSK9 drives a specific form of programmed cell death, ferroptosis, in VSMCs, contributing to AAA progression, and explores a novel peptide-based strategy to mitigate this.

Researchers investigated PCSK9's role in AAA using human AAA samples, murine models induced by porcine pancreatic elastase (PPE) or Angiotensin II (Ang II), and primary VSMCs. They generated SMC-specific PCSK9 overexpression (PCSK9SMC OE) mice. In vitro, they overexpressed or knocked down PCSK9 in primary VSMCs and induced ferroptosis with Ang II. The cell-permeable peptide Cadd4 was used to promote PCSK9 degradation in both VSMC cultures and in vivo models. Key endpoints included aortic diameter, elastin fragmentation, collagen deposition, MMP2/9 expression, iron accumulation, lipid peroxidation, GPX4 levels, and ferritinophagy markers (FTH1, NCOA4, LC3-II/I ratio, FTH1-LAMP1 colocalization).

PCSK9 was significantly enriched in VSMCs of human AAA and murine models. SMC-specific PCSK9 overexpression (PCSK9SMC OE) markedly increased aortic diameter, aggravated elastin fragmentation, enhanced collagen deposition, and elevated MMP2/9 expression in mice. Within aortic lesions, PCSK9SMC OE mice showed enhanced iron accumulation and lipid peroxidation, alongside reduced glutathione GPX4, consistent with ferroptosis. In primary VSMCs, PCSK9 overexpression suppressed GPX4 and glutathione, increased malondialdehyde and Fe2+ levels, and impaired viability, while PCSK9 knockdown attenuated Ang II-induced ferroptosis. Mechanistically, PCSK9 triggered ferritinophagy, evidenced by decreased ferritin heavy chain-1 (FTH1) and nuclear receptor coactivator-4 (NCOA4), an increased LC3-II/I ratio, and enhanced FTH1-LAMP1 colocalization. Autophagy inhibition with bafilomycin A1 blocked Fe2+ accumulation and rescued ferroptotic indices. The cell-permeable peptide Cadd4 promoted PCSK9 degradation, restored FTH1 and NCOA4 levels, and suppressed ferroptosis in VSMCs. > In both PPE and Ang II murine models, Cadd4 significantly reduced aortic dilation, preserved medial structure, and normalized ferroptosis and ferritinophagy markers.