1-Methylhistidine attenuates early myocardial inflammation in type 3 cardiorenal syndrome through modulation of the p105/p50 NF-κB axis
Abstract
Type 3 cardiorenal syndrome (CRS3) is characterized by cardiac injury or dysfunction secondary to acute kidney injury (AKI), yet the contribution of AKI-associated metabolic remodeling to early myocardial inflammation remains poorly understood. Here, paired serum and myocardial untargeted metabolomics identified 1-methylhistidine (1-MH) as a metabolite elevated in both compartments, with the highest variable importance in projection score in serum. Exogenous 1-MH improved the E/A ratio and attenuated myocardial inflammation and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positivity in rats with CRS3. Similar protective effects were observed in a separate post-ischemic cohort in which 1-MH was administered immediately after renal reperfusion. In CRS serum-exposed H9c2 cells, 1-MH reduced reactive oxygen species-associated fluorescence, malondialdehyde content, and intracellular Fe 2+ levels. Transcriptomic profiling showed that 1-MH suppressed inflammatory signaling, accompanied by changes in oxidative metabolism. Integration of these transcriptomic signatures with target prediction prioritized NFKB1/p105, while ensemble docking identified recurrent candidate interaction regions within p105. Cellular thermal shift assays showed a concentration-related increase in p105 thermal stability following 1-MH treatment. 1-MH increased p105 abundance while reducing total p50 abundance and nuclear p50 accumulation. p105 overexpression increased p50 abundance and the expression of inflammatory transcripts and proteins suppressed by 1-MH. These findings demonstrate that 1-MH attenuates early myocardial inflammation in CRS3 and reduces oxidative stress-related changes in CRS serum-exposed H9c2 cells. These functional results support modulation of the p105/p50 NF-κB axis and identify p105 as a molecular link between AKI-associated metabolic remodeling and myocardial inflammatory signaling.