The function of B cells in myocardial infarction-accelerated atherosclerosis

Introduction

Survivors of acute myocardial infarction (MI) are at a particularly high risk for accelerated atherosclerosis and recurrent atherothrombosis. Nevertheless, mechanistic preclinical studies in atherosclerosis research worldwide are typically conducted in unchallenged (without MI) atherosclerosis-prone mice and thus do not address the specific pathophysiology of post-MI atherosclerotic cardiovascular disease.

Study Overview

We conducted a single-cell RNA sequencing coupled to B cell receptor (BCR) sequencing analysis of sorted CD45+ splenocytes from atherosclerosis-prone mice that were fed an atherogenic diet for eight weeks in total. These mice were subjected four weeks after the initiation of the atherogenic diet feeding either to sham microsurgery or to permanent ligation of the left anterior descending coronary artery to induce MI.

Findings

We found that splenic mature B lymphocytes from atherosclerotic mice that suffered an MI display:

• Altered glucocorticoid-induced responses
• A more diversified BCR repertoire, which contains twelve unique clonotypes (named B-MIracle clones) that are not present in atherosclerotic mice without MI.

Research Aims

Here, I aim to:

1. Investigate the effect of glucocorticoid-induced signaling in B cells in post-MI atherosclerosis in vivo by employing mouse models that allow the inducible genetic manipulation of different components of the glucocorticoid-induced signaling axis.
2. Utilize the full heavy and light chain nucleotide sequences from our single-cell BCR-seq data to clone and produce the respective antibodies of the B-MIracle clones and examine their effect in accelerated atherosclerosis after MI in vivo.
3. Address the relevance of these findings in atherosclerosis progression in patients with a recent MI by analyzing sorted peripheral B cell subsets and serum samples.

Conclusion

These studies may lead to the identification of precise therapeutic targets for secondary prevention of cardiovascular disease.