NME6 Gene Knockdown Improves Cardiac Function and Reduces Immune Infiltration in Heart Failure Mice

Heart failure (HF) is a growing global health challenge marked by severe mitochondrial dysfunction and immune dysregulation, yet the precise molecular links remain elusive. Current treatments often manage symptoms but don't fully address these underlying pathological mechanisms. Identifying key mitochondrial genes that modulate immune responses could offer novel therapeutic targets, moving beyond symptomatic relief to address the core drivers of HF progression. This study investigates such genes and their association with immune cell infiltration.

Researchers identified differentially expressed genes in HF and performed functional enrichment analyses. They used summary data-based Mendelian randomization (SMR) to assess diagnostic potential. Immune cell infiltration analysis correlated gene expression with immune profiles. Single-cell RNA sequencing (scRNA-seq) data (GSE145154) determined cell-specific expression. A transverse aortic constriction (TAC)-induced HF mouse model was established to assess cardiac function via echocardiography, and histopathological analyses evaluated myocardial injury, fibrosis, and apoptosis. Immune cell populations were also examined in vivo, specifically after NME6 knockdown.

Functional enrichment analysis linked HF-related genes to mitochondrial organization and pathways like mTOR signaling. SMR analysis identified NDUFS2 and NME6 as diagnostically relevant. Immune infiltration analysis showed correlations between these genes and immune cell populations. scRNA-seq revealed NME6 was predominantly expressed in T cells and neutrophils. Clinical data indicated that BNP, CRP, neutrophils, monocytes, and inflammatory factor levels tended to increase with HF severity.

In the TAC-induced HF mouse model, NME6 knockdown lessened the left ventricular end-diastolic diameter, indicating improved cardiac function.

This suggests a critical role for NME6 in modulating HF pathology.