# Proprotein Convertase Subtilisin/Kexin Type 9 Induces Platelet‐Derived Transforming Growth Factor‐β to Promote Myocardial Fibrosis After Myocardial Infarction

## TL;DR

This study shows that PCSK9 promotes heart scarring after heart attacks by activating platelets and increasing TGF-β, which worsens recovery.

## Contribution

The study reveals a novel mechanism by which PCSK9 contributes to myocardial fibrosis through platelet-derived TGF-β.

## Key findings

- Inhibiting PCSK9 reduces myocardial fibrosis in mice after myocardial infarction.
- PCSK9 induces platelet activation and TGF-β secretion, leading to fibroblast transformation into myofibroblasts.
- Transcriptome analysis shows PCSK9 suppresses immune and adhesion pathways in the heart.

## Abstract

The recovery of cardiac function after acute myocardial infarction is crucial for the prognosis of patients with myocardial infarction. Proprotein convertase subtilisin/Kexin Type 9 (PCSK9) inhibitors are widely used in patients with acute myocardial infarction due to their potent low‐density lipoprotein‐lowering effects. Recent studies have shown that elevated levels of circulating PCSK9 are associated with increased platelet reactivity and thrombosis; however, the effect and mechanism of PCSK9 on cardiac repair after myocardial infarction through the induction of platelet activation remain unclear. Therefore, the objective of this study was to investigate and clarify the specific effect of PCSK9 on cardiac repair processes following myocardial infarction. The detailed molecular and cellular mechanisms through which PCSK9 regulates cardiac repair after myocardial infarction by inducing platelet activation were observed.

Hearts from wild‐type (WT) C57BL/6J mice and PCSK9 knockout (PCSK9−/−) mice were subjected to left coronary artery (LAD) ligation to establish a myocardial infarction model. Six weeks postoperation, echocardiographic analysis and Masson staining revealed that inhibiting the increase in PCSK9 expression after myocardial infarction significantly reduced myocardial fibrosis. Transcriptome sequencing of mouse myocardial tissue suggested that PCSK9 suppresses immune regulation and adhesion pathways and that the platelet marker integrin subunit alpha 2b (Itga2b) is a potential key molecule. Subsequent in vivo and in vitro experiments demonstrated that PCSK9 promotes platelet activation and induces the fibrogenic phenotypic transformation of fibroblasts by transforming growth factor‐β (TGF‐β). In further studies, coculture experiments of fibroblasts and platelets revealed that PCSK9 promotes the conversion of fibroblasts to myofibroblasts by inducing platelet‐derived TGF‐β secretion.

PCSK9 promotes platelet activation, induces the secretion of platelet‐derived TGF‐β, and thereby accelerates myocardial fibrosis after myocardial infarction.