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Secretory products from epicardial adipose tissue induce adverse myocardial remodeling after myocardial infarction by promoting reactive oxygen species accumulation.

ABSTRACT: Adverse myocardial remodeling, manifesting pathologically as myocardial hypertrophy and fibrosis, often follows myocardial infarction (MI) and results in cardiac dysfunction. In this study, an obvious epicardial adipose tissue (EAT) was observed in the rat model of MI and the EAT weights were positively correlated with cardiomyocyte size and myocardial fibrosis areas in the MI 2- and 4-week groups. Then, rat cardiomyocyte cell line H9C2 and primary rat cardiac fibroblasts were cultured in conditioned media generated from EAT of rats in the MI 4-week group (EAT-CM). Functionally, EAT-CM enlarged the cell surface area of H9C2 cells and reinforced cardiac fibroblast activation into myofibroblasts by elevating intracellular reactive oxygen species (ROS) levels. Mechanistically, miR-134-5p was upregulated by EAT-CM in both H9C2 cells and primary rat cardiac fibroblasts. miR-134-5p knockdown promoted histone H3K14 acetylation of manganese superoxide dismutase and catalase by upregulating lysine acetyltransferase 7 expression, thereby decreasing ROS level. An in vivo study showed that miR-134-5p knockdown limited adverse myocardial remodeling in the rat model of MI, manifesting as alleviation of cardiomyocyte hypertrophy and fibrosis. In general, our study clarified a new pathological mechanism involving an EAT/miRNA axis that explains the adverse myocardial remodeling occurring after MI.

SUBMITTER: Hao S

PROVIDER: S-EPMC8438091 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsHuman epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression.Methods and resultsWe enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS (P < 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend P < 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A*03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A3*01 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences.ConclusionsOur study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies.

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Secretory products from epicardial adipose tissue induce adverse myocardial remodeling after myocardial infarction by promoting reactive oxygen species accumulation.

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