Background: Myocardial fibrosis and inflammation induce adverse cardiac remodeling post-myocardial infarction (MI). () is beneficial for diverse cardiovascular diseases. However, the therapeutic effect and molecular mechanism underlying cardiac remodeling are largely unclear.
Methods: A MI mouse model was constructed through permanent left anterior descending (LAD) coronary artery ligation. Transforming growth factor-β1 (TGF-β1) or lipopolysaccharide (LPS) was used for stimulating cardiac fibroblasts (CFs) or RAW264.7 macrophages to construct the collagen synthesis and inflammation model . The cardiac structure and function were detected through hematoxylin-eosin staining, Masson staining, and echocardiography, while myocardial fibrosis and inflammation markers were determined by Western-blot, immunohistochemistry, RT-PCR, and ELISA. Additionally, the Silent information regulator 1 (SIRT1)/nuclear factor-κB (NF-κB) mediated NOD like receptor 3 (NLRP3) inflammasome and TGF-β receptor I (TGFBR1) signaling pathways were also evaluated. A SIRT1 selective inhibitor (EX-527) was used for confirming the pharmacological mechanism of .
Results: , alleviated ventricular remodeling, enhanced heart function, and ameliorated collagen I, collagen III, IL-1β, and IL-18 levels dose-dependently. Moreover, significantly suppressed NLRP3-caspase1 inflammasome and TGFBR1/Smads signaling in MI mice. , significantly suppressed collagen and inflammation markers, NLRP3 inflammasome and TGFBR1/Smads signaling in TGF-β1-induced CFs or LPS-stimulated RAW264.7 cells. Mechanistically, suppressed NF-κB activity while promoting SIRT1 expression. SIRT1 suppression by EX-527 partially abolished the protective effects of in TGF-β1-induced CFs.
Conclusion: protects from adverse cardiac remodeling by attenuating myocardial fibrosis and inflammation post-MI through the regulation of SIRT1 and its downstream signaling pathways.
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| http://dx.doi.org/10.1016/j.jgr.2025.01.001 | DOI Listing |
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