Macrophage-specific Trim21 knockdown reversed the exacerbated cardiac fibrosis and systolic dysfunction caused by myeloid-specific Aldh2 rs671 mutation after myocardial infarction.
Does macrophage-specific Trim21 knockdown improve cardiac fibrosis and systolic function in Aldh2 rs671 mutant models after myocardial infarction?
TRIM21 acts as an E3 ubiquitin ligase for the ALDH2 rs671 mutant, and its targeted knockdown in macrophages rescues defective efferocytosis and mitigates adverse cardiac remodeling after myocardial infarction.
Effect estimate: ~39% reduction in cardiac systolic function caused by myeloid-specific Aldh2 rs671 mutation; Trim21 knockdown reversed cardiac fibrosis and systolic dysfunction
Heart failure (HF) persists as the primary cause of death among patients recovering from acute myocardial infarction (AMI). Protein ubiquitination has been implicated as a key modulator of HF pathogenesis, yet the role of ubiquitination in the Aldh2 rs671 mutant-the most common single-nucleotide variant in human populations-remains poorly understood. We discovered TRIM21 as a previously unrecognized E3 ubiquitin ligase for the ALDH2 rs671 mutant and elucidated its mechanistic involvement in HF progression. Using Aldh2 bone marrow chimeric mice to model AMI, we observed that wild-type mice transplanted with Aldh2 rs671 donor bone marrow developed severe myocardial fibrosis and markedly reduced cardiac systolic function two weeks post-infarction compared to controls. This phenotype arose from defective macrophage efferocytosis caused by myeloid-specific Aldh2 rs671 mutation. Through high-resolution mass spectrometry proteomics, we identified TRIM21 as the E3 ligase targeting ALDH2. TRIM21 catalyzed K48-linked ubiquitination at ALDH2 lysine 73. Macrophage-specific Trim21 knockdown via AAV-shTrim21 reversed both the exacerbated cardiac fibrosis and systolic dysfunction by restoring macrophage efferocytosis. These findings delineate the upstream E3 ubiquitin ligase and the ubiquitination site of ALDH2, revealing a potential therapeutic target for HF.
Han et al. (Tue,) conducted a other in acute myocardial infarction and heart failure. Macrophage-specific Trim21 knockdown via AAV-shTrim21 vs. AAV-scramble control was evaluated on Cardiac systolic function and cardiac fibrosis two weeks post-myocardial infarction (~39% reduction in cardiac systolic function caused by myeloid-specific Aldh2 rs671 mutation; Trim21 knockdown reversed cardiac fibrosis and systolic dysfunction). Macrophage-specific Trim21 knockdown reversed the exacerbated cardiac fibrosis and systolic dysfunction caused by myeloid-specific Aldh2 rs671 mutation after myocardial infarction.