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

Abstract

Heart failure (HF) affects over 64 million individuals worldwide and is strongly associated with cognitive impairment (CI), yet the underlying mechanisms remain poorly understood. Here, we identify solute carrier family 22 member 3 (SLC22A3) might be a candidate gene for HF-induced CI through Mendelian randomization and bioinformatics analysis. To investigate its functional role in vivo, we established a mouse model of HF after myocardial infarction (MI). Cognitive performance was evaluated using the Morris water maze. Expression of SLC22A3, blood-brain barrier (BBB) integrity, and neuroinflammatory signalling were examined via immunofluorescence and Western blotting. The involvement of the HA/H1R/NLRP3 signalling pathway was further evaluated using cardiac-specific SLC22A3 overexpression mice, hippocampal-specific H1R knockdown mice, NLRP3 knockout mice, and BV2 cell assays. Consistent with the findings in HF patients, cardiac SLC22A3 expression was dramatically downregulated in HF mice, accompanied by an increase in peripheral histamine (HA) levels, while HA levels in the mouse brain were also significantly raised. Using cardiac-specific SLC22A3 overexpression in HF mice, we demonstrated that restoring SLC22A3 reduced HA accumulation and improved cognitive performance. Mechanistically, HA breached the compromised BBB in HF mice, activating hippocampal microglia H1 receptor (H1R) and the NLRP3 inflammasome. In BV2 cells, HA stimulation elevated NLRP3 expression in a dose-dependent manner, an effect blocked by H1R antagonist. Knockdown of H1R or NLRP3 in the hippocampus attenuated neuroinflammation and rescued HF-induced CI. Our findings unveil a novel cardio-neuroinflammatory axis driven by SLC22A3 deficiency, highlighting HA/H1R/NLRP3 pathway as a therapeutic target for HF-induced CI.