Abstract
BACKGROUND Circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates plasma cholesterol content by degrading LDL receptor, are correlated with the risk of acute myocardial infarction (AMI). Recent studies suggested that PCSK9 improves cardiac function beyond its effects on LDL cholesterol levels after cardiac ischemic injury, but its precise mechanism remains unclear.
METHODS We examined the interrelationship and functional significance of PCSK9 and cardiac myeloid cells in ischemic hearts from AMI-induced Pcsk9-/- and Lyz2crePcsk9fl/flmice, as well as in serum samples from coronary artery disease (CAD) patients treated with PCSK9 antibodies (Ab). Single-cell RNA sequencing (scRNA-seq) was conducted to identify heterogenous cardiac macrophage clusters and to investigate the impact of adaptive remodeling due to PCSK9 deficiency during AMI. Additionally, the regulatory effect of the myeloid-PCSK9/VEGF-C pathway was assessed in vitro as a potential therapeutic strategy.
RESULTS Our study demonstrated that PCSK9 deficiency induces diverse changes in myeloid cells and macrophages, potentially offering cardiac protection following AMI, irrespective of LDL cholesterol homeostasis. The scRNA-seq identified a subset of PCSK9-dependent cardiac macrophages (PDCMs) enriched in activator protein-1 (AP-1)–related pathways, functioning as reparative macrophages. These PDCMs were shown to enhance vascular endothelial growth factor C (VEGF-C) secretion and activate Akt signaling in cardiac endothelial cells, leading to improved cardiac remodeling. Notably, CAD patients treated with PCSK9 inhibitors exhibited increased numbers of myeloid cells with PDCM-like features, including elevated VEGF-C levels, consistent with our findings in mice.
COUNCLUSIONS Targeting PCSK9 in myeloid cells could offer cardioprotective effects by increasing AP-1 activity and VEGF-C expression of PDCMs, presenting a novel approach to preventing cardiac dysfunction in AMI. This strategy could expand the clinical use of existing PCSK9 inhibitors beyond just lowering LDL cholesterol.
What is New?
Myeloid-PCSK9 deficiency attenuated cardiac dysfunction post-acute myocardial infarction (AMI) without affecting plasma lipid levels. These findings position PCSK9 as a novel immune regulator of macrophages, revealing functions independent of its role in LDL cholesterol regulation.
We demonstrated PCSK9-dependent cardiac macrophages (PDCMs) that play a reparative role under ischemic conditions influenced by PCSK9, using single-cell RNA sequencing (scRNA-seq) of CD45+ leukocytes following AMI.
Strong enrichment of AP-1 family proteins in PDCMs led to reparative VEGF-C signaling in endothelial cells and improved cardiac remodeling, independent of PCSK9’s conventional role in cholesterol homeostasis.
In coronary artery disease (CAD) patients, PCSK9 inhibition augmented myeloid cell populations towards a reparative phenotype and elevated VEGF-C levels, aligning with our findings in mice.
What Are the Clinical Implications?
Myeloid-derived PCSK9 is pathobiologically significant, directly influencing immune functions and contributing to cardiac remodeling after AMI, suggesting that targeting myeloid-specific PCSK9 could be a valuable therapeutic approach.
Given that the reparative effects of PCSK9 inhibitors on macrophages are preserved in CAD patients, this strategy could broaden the clinical applications of existing PCSK9 inhibitors beyond LDL cholesterol regulation.
Competing Interest Statement
G.T.O. and S.S. are employed by Imvastech Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding Statement
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1A3B2079811 and RS-2023-00217798). The human study was financially supported by Imvastech Inc. (IRB of Severance Hospital; 4-2023-0509).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
All animal experiments were approved by the Institution Animal Care and Use Committees (IACUC) of Ewha Womans University, Seoul, Korea (IACUC No. 19-004, and 21-051). The Institutional Review Board of Severance Hospital (Seoul, Korea; IRB: 4-2023-0509) approved the protocol for collecting human blood samples.
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Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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Data Availability
scRNA-seq data for this project have been deposited at NCBI?s Gene Expression Omnibus (GEO) and GSE number is pending.
