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Bone marrow-derived naïve B lymphocytes improve heart function after myocardial infarction: a novel cardioprotective mechanism for empagliflozin

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Abstract

The role of adaptive immunity in myocardial recovery post myocardial infarction (MI), particularly the immune response by B lymphocytes, remains elusive. Bone marrow immune microenvironment in response to MI is remotely regulated by the hypothalamic pituitary adrenal (HPA) axis. We utilized the cardioprotective actions of SGLT2 inhibitor to identify and characterize bone marrow B cell subsets that respond to myocardial injury. Initially, we preformed ligation of left anterior descendant (LAD) coronary artery in male C57BL/6J mice to monitor the dynamic changes of immune cells across tissues. Mechanistic insights from mouse models demonstrated arrest of bone marrow B cell maturation and function 24 h post MI. A secondary MI model (twice MIs) in mice was established for the first time to evaluate the dosage-dependent cardioprotection of empagliflozin (EMPA). Single-cell RNA-Seq further demonstrated that EMPA restored bone marrow naïve B cell (B220+CD19+CD43−IgM+IgD+) counts and function. Additionally, we recruited 14 acute MI patients with single LAD disease, and profiled B cells post percutaneous coronary intervention (PCI) (compared to 18 matched no-MI controls). We revealed a positive correlation of increased B cell counts with enhanced ejection fraction in MI patients with PCI while lymphopenia was associated with patients with heart failure. Mechanistically, MI triggers the release of glucocorticoids from neuroendocrine system, inducing NHE1-mediated autophagic death of bone marrow B cells while repressing B cell progenitor proliferation and differentiation. Infusion of B cells derived from bone marrow significantly improved cardiac function and diminished infarct size post MI. These findings provide new mechanistic insights into regulation of adaptive immune response post MI, and support targeting bone marrow B cell development for improved ventricular remodeling and reduced heart failure after MI.

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Data availability

The RNA-seq (GSE193425) and scRNA-seq (GSE193316) datasets are available via GEO. All other data are available in the main text or the Supplementary Materials. Requests for reagents should be directed to the corresponding author.

Abbreviations

MI:

Myocardial infarction

I/R:

Ischemia/reperfusion

SGLT2:

Sodium-glucose cotransporter 2

scRNA-Seq:

Single-cell RNA sequencing

BM:

Bone marrow

EF:

Ejection fraction

GR:

Glucocorticoids

NHE1:

Na+/H+-exchanger 1

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Funding

The National Key Research and Development Program of China (2017YFC1700402); The National Outstanding Youth Science Fund Project of National Natural Science Foundation of China (81822048); Fundamental Research Funds for the Central Universities (22120210162); The Frontier Science Research Center for Stem Cells, Ministry of Education.

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  1. Yue Xu and Kai Jiang have contributed equally to this work.

Authors and Affiliations

  1. Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministry of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Yue Xu, Kai Jiang, Feng Chen, Jie Qian, Dandan Wang, Kun Chen, Haiyun Wang & Yaozu Xiang

  2. Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China

    Yizhang Wu, Chunjiang Zhou & Bing Yang

  3. Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Yong Yu

  4. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06511, USA

    John Hwa

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  1. Yue Xu
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Contributions

All authors contributed to the study conception and design. YaX designed the study. YuX, KJ, FC, YW, CZ and DW performed the animal experiments and the in vitro experiments. YaX, YuX, KJ, KC, JQ, YY, JH, HW and BY analyzed the data. YaX wrote the manuscripts. YuX and KJ are co-first authors based on their equally contribution.

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Correspondence to Yaozu Xiang.

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Xu, Y., Jiang, K., Chen, F. et al. Bone marrow-derived naïve B lymphocytes improve heart function after myocardial infarction: a novel cardioprotective mechanism for empagliflozin. Basic Res Cardiol 117, 47 (2022). https://doi.org/10.1007/s00395-022-00956-1

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