SLC22A3 deficiency leads to cognitive impairment through the cardio-neuroinflammatory axis mediated HA/H1R/NLRP3 pathway in heart failure mice - PubMed

4 hours ago

Heart failure (HF) affects over 64 million individuals globally and is linked to cognitive impairment (CI), but the mechanisms are unclear.
Solute carrier family 22 member 3 (SLC22A3) is identified as a candidate gene for HF-induced CI through Mendelian randomization and bioinformatics analysis.
A mouse model of HF after myocardial infarction (MI) was used to study SLC22A3's role, with cognitive performance assessed via the Morris water maze.
HF mice showed downregulated cardiac SLC22A3 expression, increased peripheral histamine (HA) levels, and raised HA levels in the brain.
Restoring SLC22A3 in HF mice reduced HA accumulation and improved cognitive performance.
HA breached the compromised blood-brain barrier (BBB) in HF mice, activating hippocampal microglia H1 receptor (H1R) and the NLRP3 inflammasome.
In BV2 cells, HA stimulation increased NLRP3 expression dose-dependently, blocked by H1R antagonist.
Knockdown of H1R or NLRP3 in the hippocampus reduced neuroinflammation and rescued HF-induced CI.
The study reveals a cardio-neuroinflammatory axis driven by SLC22A3 deficiency, with the HA/H1R/NLRP3 pathway as a therapeutic target for HF-induced CI.

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