PCSK9 inhibition in myeloid cells enhances cardioprotection beyond its LDL cholesterol-lowering effects
Notice bibliographique
Résumé
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 Lyz2 cre Pcsk9 fl/fl mice, 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. Clinical Perspective 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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».