ROLE OF EPICARDIAL ADIPOSE TISSUE SECRETED INTERLEUKIN-34 IN FIBROBLAST TO\r\nMYOFIBROBLAST TRANSDIFFERENTIATION AND ATRIAL FIBROSIS

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Divya Jyothi Madipally (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: The adiposity of the heart has been proven to be significantly associated with cardiac dysfunction. Chronic low-grade inflammation of the adipose tissue and cardiac fibrosis are common complications in type 2 diabetes mellitus (T2DM). Characterized by excessive deposition of extracellular matrix (ECM) proteins like collagen types I and III, and transdifferentiation of cardiac fibroblasts to myofibroblasts, cardiac fibrosis is majorly involved in the etiology of cardiac remodeling in T2DM. These fibrogenic actions are suggested to be mediated by the inappropriate release of adipocytokines, triggering a local inflammatory state in the heart. The aim of this study was to measure the cytokines secreted by the EAT and evaluate their correlation with atrial fibrosis in patients with T2DM. Sixty-four patients undergoing cardiac surgery were enrolled in this study. Masson's trichrome staining was performed on frozen sections of right atrial appendage (RAA) to quantify myocardial fibrosis. EAT medium was used for measuring 49 cytokines using a combination of multiplex ELISAs. Primary cardiac fibroblasts were incubated with or without Interleukin-34 (IL-34), Transforming Growth Factor-[beta] (TGF-[beta]), and with or without TGF-[beta] receptor (TGF-[beta]R) and CSF1- receptor (CSF1-R) inhibitors. Immunofluorescent staining for [alpha]-Smooth Muscle Actin ([alpha]-SMA) was performed to evaluate fibroblast to myofibroblast transdifferentiation, and western blotting analysis of collagen types-I and III was performed to evaluate fibrogenesis. Histology revealed increased myocardial fibrosis in the RAA of patients with T2DM. Myocardial fibrosis also correlated with the plasma glycated hemoglobin A1c (HbA1c) levels. Of the cytokines secreted by EAT explants 11 correlated with myocardial fibrosis, and 3 correlated with the presence of T2DM. Among these cytokines, IL-34 and soluble IL-6 receptor [beta] were correlating with the RAA fibrosis. Furthermore, IL-34 promoted fibrogenesis in cardiac fibroblasts. Interestingly, neither the inhibition of TGF-[beta]R involved in most fibrotic models nor CSF1-R, the principal receptor for IL-34, attenuated IL-34 induced fibroblast differentiation. In conclusion, elevated levels of IL-34 in the EAT of patients with T2DM correlated with atrial fibrosis and promoted fibroblast to myofibroblast transdifferentiation independent of TGF[beta]-R and CSF1-R.

Additional Information

Publication

Dissertation

Language: English

Date: 2023

Subjects

Cardiac fibrosis;Epicardial adipose tissue;Cardiac fibroblasts;Type 2 Diabetes Mellitus;Interleukin-34

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