Abstract 4365563: Treg-derived Sparc confers cardioprotection against acute myocardial infarction in mice via promoting collagen synthesis and deposition
Abstract
Introduction: We previously reported that cardiac Tregs exhibited a unique phenotype after acute myocardial infarction (AMI) and promoted tissue repair through the secretion of secreted acidic cysteine-rich glycoprotein (Sparc). However, the underlying mechanisms remained unclear. We hypothesize that Treg-derived Sparc following AMI exerts protective effects by promoting collagen synthesis in cardiac fibroblasts and collagen deposition in the heart. Absence of Treg-derived Sparc can lead to impaired scar formation and increased cardiac rupture. Methods: Mice with Treg-specific Sparc knockout (Foxp3 Cre Sparc flox/flox ) and DEREG mice transferred with Sparc-deficient Tregs were subjected to AMI. Echocardiography, immunohistochemistry, transmission electron microscopy and RNA sequencing were used to investigate the impact of Treg-derived Sparc deficiency on cardiac repair after AMI. Additionally, co-culture experiment of cardiac fibroblasts and Sparc-overexpressing Tregs were conducted, Western blot was used to explore the activation levels of pathways, both Western blot and Reverse Transcription-Polymerase Chain Reaction were used to explore the expression levels of α-SMA, type I collagen, and type III collagen. Results: The expression of Sparc in cardiac Tregs peaked at 7 days post MI. The absence of Treg-derived Sparc led to increased mortality and cardiac rupture rates both in Foxp3 Cre Sparc flox/flox mice and DEREG mice transferred with Sparc-deficient Tregs. Additionally, impaired scar formation was observed in Foxp3 Cre Sparc flox/flox mice, characterized by reduced collagen maturity and disorganized and loose collagen fiber organization in the infarcted area. RNA sequencing revealed that the deficiency of Treg-derived Sparc significantly downregulated the extracellular matrix synthesis-related pathways in the cardiac infarcted zone. In vitro co-culture experiments showed that cardiac fibroblasts co-cultured with Sparc-overexpressing Tregs exhibited significant activation of the SAPK/JNK/c-JUN pathway and increased secretion of type I collagen. Conclusion: Treg-derived Sparc can promote collagen synthesis in cardiac fibroblasts by inducing the activation of SAPK/JNK/c-JUN pathway, and can promote the maturation of scar tissue in the infarcted area, playing an important role in facilitating tissue repair and preventing heart rupture after AMI.
Article Details
Authors (4)
Junyi He
Yuhan Shen
State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences–Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology
Ni Xia
Department of Cardiology, Hubei Key Laboratory of Biological Targeted Therapy, Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (M.Z., Y.Y.Q., T.Z., M.L.L., T.T.T., N.X., S.F.N., B.J.L., Z.F.Z., J.J., M.Y.G., J.Y.L., X.C.).
Xiang Cheng