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

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

  • Basic Res Cardiol. 2022 Sep 28;117(1):47. doi: 10.1007/s00395-022-00956-1.
Yue Xu # 1,  Kai Jiang # 1,  Feng Chen 1,  Jie Qian 1,  Dandan Wang 1,  Yizhang Wu 2,  Chunjiang Zhou 2,  Yong Yu 3,  Kun Chen 1,  John Hwa 4,  Bing Yang 2,  Haiyun Wang 1,  Yaozu Xiang 5
Affiliations

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.
  • 2 Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 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.
  • 4 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06511, USA.
  • 5 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. [email protected].
  • # Contributed equally.
PMID: 36171393 DOI: 10.1007/s00395-022-00956-1
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.

Keywords

Adaptive immune; Bone marrow-derived naïve B lymphocytes; Cardioprotection; Glucocorticoids; Myocardial infarction.

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