Immunoresponsive Gene 1-Itaconate Exacerbates Hypertension by Inhibiting the Cystathionine Gamma-Lyase/Hydrogen Sulfide Pathway.

The role of immunoresponsive gene 1 (IRG1)-itaconate (ITA) in hypertension remains poorly understood. This study aimed to investigate this role and the underlying mechanisms. IRG1 expression and ITA levels were assessed by Western blotting, targeted metabolomics, and ELISA. We employed global Irg1 (mouse gene coding IRG1)-knockout mice, smooth muscle cell (SMC)-specific Irg1 overexpression mice, and mice receiving intraperitoneal ITA injection. Hypertension was induced by angiotensin II (Ang II) infusion. Blood pressure was measured by tail-cuff method and radiotelemetry, while vascular structure and function were evaluated by histology, vascular ring assays, and Western blotting. The target proteins of ITA were identified through thermal proteomic profiling, cellular thermal shift assay, surface plasmon resonance, and molecular docking. IRG1 expression and ITA levels were significantly upregulated in mouse aortas and vascular smooth muscle cells (VSMCs) under hypertensive conditions. Irg1 knockout markedly attenuated Ang II-induced hypertension and vascular remodeling, whereas SMC-specific Irg1 overexpression or exogenous ITA exacerbated these pathological phenotypes. Mechanistically, ITA directly bound to cystathionine gamma-lyase (CTH) at cysteine 229, inhibiting its enzymatic activity and hydrogen sulfide (H2S) production. These findings demonstrate that IRG1-ITA promotes hypertension and vascular remodeling by directly targeting CTH and suppressing H2S production, suggesting a novel therapeutic target.