LMCD1 aggravates cardiac fibrosis after myocardial infarction via activating STAT5A.

Cardiac fibrosis, a maladaptive remodeling process following myocardial infarction (MI), is a key driver of heart failure, the precise molecular regulators governing cardiac fibroblast activation remain incompletely understood. LIM and cysteine-rich domains 1 (LMCD1) has been shown to promote renal and lung fibrosis, but its role in cardiac fibrosis is unknown. We hypothesized that LMCD1 promoted cardiac fibrosis post-MI. Re-analysis of publicly available single-cell RNA sequencing datasets revealed a significant upregulation of LMCD1 in cardiac fibroblasts after MI. LMCD1 was upregulated in mouse hearts subjected to left anterior descending (LAD) artery ligation and in primary cardiac fibroblasts stimulated with TGF-β1. Silencing of LMCD1 improved cardiac function (increased ejection fraction and fractional shortening) and reduced fibrotic area, concomitant with decreased fibrosis-related proteins (fibronectin, COL1A1, and α-SMA). In TGF-β1-induced primary cardiac fibroblasts, LMCD1 knockdown inhibited cell proliferation and fibrosis-related proteins expression, while its overexpression showed the opposite trend. Mechanistically, pathway enrichment analysis linked LMCD1 to the IL2-STAT5 signaling. LMCD1 silencing reduced the phosphorylation and total protein levels of STAT5A in infarcted mouse heart tissues. Co-immunoprecipitation assays confirmed a direct interaction between LMCD1 and STAT5A. Furthermore, STAT5A overexpression reversed the inhibitory effect of LMCD1 knockdown on TGF-β1-induced fibrosis in primary cardiac fibroblasts. In conclusion, our study identifies LMCD1 as a novel driver of post-MI fibrosis, which functions by activating STAT5A in cardiac fibroblasts, offering a potential new target for anti-fibrotic therapy.