Anacardic acid mitigates post‑MI cardiac fibrosis via suppressing p38/JNK-GATA3 pathway and H3K9ac‑dependent epigenetic regulation.
Myocardial fibrosis (MF), a hallmark of cardiovascular diseases (CVDs) such as myocardial infarction (MI), drives progressive cardiac dysfunction and adverse remodeling. Histone acetylation is a critical epigenetic regulator in cardiovascular pathology. Anacardic acid (AA), a histone acetyltransferase inhibitor (HATi) with pleiotropic bioactivities, has been studied in various disease contexts; however, its antifibrotic efficacy and mechanisms in MF remain unclear.
In vivo, a mouse model of post-infarction MF was established by permanent left anterior descending (LAD) ligation. Using pirfenidone (PFD, an antifibrotic by inhibiting TGF-β) as a positive control, AA's effects were assessed by cardiac function, histopathology, and quantification of fibrotic burden. In vitro, primary cardiac fibroblasts (CFs) stimulated with TGF-β1 were used to delineate mechanisms, focusing on proliferation, migration, myofibroblast differentiation, and transcription of fibrosis-related genes.
In vivo, AA and PFD comparably attenuated cardiac fibrosis and collagen deposition, downregulated fibrosis-related gene expression, and improved heart failure biomarkers in MI mice. Transcriptomic profiling indicated that MAPK pathway and GATA3 expression were reduced in AA-treated MI mouse hearts but increased in CFs in human MI single-cell RNA-sequencing datasets. In vitro, AA inhibited TGF-β1-induced CF proliferation, migration, and myofibroblast differentiation by suppressing p38/JNK phosphorylation, limiting GATA3 nuclear translocation, and reducing H3K9ac levels, thereby decreasing transcription of α-SMA, Col1a1, and Col3a1.
AA protects against post-infarction MF by suppressing the p38/JNK-GATA3 pathway and downregulating H3K9ac-dependent epigenetic activation, supporting AA as a potential antifibrotic strategy and therapeutic candidate for cardiac fibrosis.
In vivo, a mouse model of post-infarction MF was established by permanent left anterior descending (LAD) ligation. Using pirfenidone (PFD, an antifibrotic by inhibiting TGF-β) as a positive control, AA's effects were assessed by cardiac function, histopathology, and quantification of fibrotic burden. In vitro, primary cardiac fibroblasts (CFs) stimulated with TGF-β1 were used to delineate mechanisms, focusing on proliferation, migration, myofibroblast differentiation, and transcription of fibrosis-related genes.
In vivo, AA and PFD comparably attenuated cardiac fibrosis and collagen deposition, downregulated fibrosis-related gene expression, and improved heart failure biomarkers in MI mice. Transcriptomic profiling indicated that MAPK pathway and GATA3 expression were reduced in AA-treated MI mouse hearts but increased in CFs in human MI single-cell RNA-sequencing datasets. In vitro, AA inhibited TGF-β1-induced CF proliferation, migration, and myofibroblast differentiation by suppressing p38/JNK phosphorylation, limiting GATA3 nuclear translocation, and reducing H3K9ac levels, thereby decreasing transcription of α-SMA, Col1a1, and Col3a1.
AA protects against post-infarction MF by suppressing the p38/JNK-GATA3 pathway and downregulating H3K9ac-dependent epigenetic activation, supporting AA as a potential antifibrotic strategy and therapeutic candidate for cardiac fibrosis.
Authors
Huang Huang, Wang Wang, Yan Yan, Wang Wang, Lin Lin, Li Li, Liu Liu, Wang Wang, Li Li, Mao Mao, Liu Liu, Chen Chen, Kong Kong, Shen Shen, Jiang Jiang, Li Li, Li Li, Zhang Zhang, Zhang Zhang, Wang Wang, Sun Sun, Guo Guo, Jiang Jiang
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