# Platelets impair the resolution of inflammation in atherosclerotic plaques in insulin-resistant mice after lipid lowering

## TL;DR

Platelets hinder the healing of atherosclerotic plaques in insulin-resistant mice, reducing the benefits of lipid-lowering treatments.

## Contribution

This study reveals that platelets impair inflammation resolution in atherosclerosis during lipid-lowering treatment in insulin-resistant models.

## Key findings

- Platelet depletion in mice reduced inflammatory gene expression in plaque macrophages.
- Platelet-depleted mice showed smaller necrotic cores and more collagen in plaques.
- Clinical data showed lower platelet counts correlated with reduced proinflammatory signaling in patients after lipid lowering.

## Abstract

Insulin resistance impairs benefits of lipid-lowering treatment, as evidenced by higher cardiovascular disease risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid lowering. In mice with obesity and insulin resistance, we induced advanced plaques and then implemented lipid lowering to promote atherosclerotic plaque inflammation resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, single-cell RNA-seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased proinflammatory signaling pathways in circulating nonclassical monocytes after lipid lowering. These findings highlight that platelets hinder inflammation resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation resolution.

Platelets impair inflammation resolution in atherosclerotic plaques and interfere with benefits of lipid-lowering in insulin-resistant mice with clinical data consistent with these findings.