Disruption of PCSK9 Suppresses Inflammation and Attenuates Abdominal Aortic Aneurysm Formation

Zekun Peng; Shuang-Jie Lv; Hong Chen; Haojie Rao; Ziyi Guo; Qing Wan; Jianfeng Yang; Yuze Zhang; De-Pei Liu; Hou-Zao Chen; Miao Wang

doi:10.1161/ATVBAHA.123.320391

Disruption of PCSK9 Suppresses Inflammation and Attenuates Abdominal Aortic Aneurysm Formation

Arterioscler Thromb Vasc Biol. 2024 Nov 26. doi: 10.1161/ATVBAHA.123.320391. Online ahead of print.

Authors

Zekun Peng^#¹, Shuang-Jie Lv^#², Hong Chen^#¹, Haojie Rao¹, Ziyi Guo¹, Qing Wan¹, Jianfeng Yang¹, Yuze Zhang¹, De-Pei Liu², Hou-Zao Chen², Miao Wang^{1

3

4}

Affiliations

¹ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. (Z.P., H.C., H.R., Z.G., Q.W., J.Y., Y.Z., M.W.).
² State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. (S.-j.L., D.-P.L., H.-z.C.).
³ Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. (M.W.).
⁴ National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Central China Subcenter of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University (M.W.).

^# Contributed equally.

PMID: 39588646
DOI: 10.1161/ATVBAHA.123.320391

Abstract

Background: Abdominal aortic aneurysm (AAA) is a chronic vascular inflammatory disease without effective medications. PCSK9 (proprotein convertase subtilisin/kexin 9), a serine protease from the proprotein convertase family, has recently been associated with AAA in human genome-wide association studies. However, its role in AAA is unknown.

Methods: Transcriptional and histological expression of PCSK9 was examined in AAA tissues and healthy controls. The impact of PCSK9 deletion and inhibition on AAA formation was assessed in mice with hyperlipidemia and Ang II (angiotensin II) overproduction. AAA lesion morphology was assessed by tissue staining. MMP (matrix metalloproteinase) activity was evaluated by gelatin zymography, and leukocyte-vessel wall interaction was monitored by intravital microscopy. RNA sequencing was used to characterize the downstream signaling of PCSK9.

Results: PCSK9 expression was upregulated and colocalized with macrophages in human and mouse AAAs. Pcsk9 deletion attenuated AAA formation, improved survival, and decreased systemic inflammation, without altering circulating cholesterol levels. Pcsk9 deficiency reduced aortic infiltration of macrophages and elastin degradation, without affecting vascular smooth muscle cell apoptosis and proliferation. Mechanistically, PCSK9 was essential in leukocyte-endothelium adhesion and expression of proinflammatory cytokines and MMP9 by macrophages. RNA sequencing of stimulated macrophages revealed that Pcsk9 deficiency upregulated histone deacetylase SIRT1 (sirtuin-1) and suppressed NF-κB (nuclear factor-κB) inflammatory signaling. SIRT1 inhibition attenuated the proinflammatory actions of PCSK9. Furthermore, administration of PCSK9 small interfering RNA or antibody constrained AAA formation/progression and inhibited vascular inflammation.

Conclusions: PCSK9 critically mediates macrophage inflammation and elastin degradation, promoting AAA formation. PCSK9 inhibitors bear a promise to curtail AAA, beyond being used as cholesterol-lowering drugs.

Keywords: aortic aneurysm, abdominal; cytokines; inflammation; macrophages; sirtuin-1.