Allopurinol treatment increased 4-week post-myocardial infarction survival from 48.6% to 74.3% and ameliorated adverse cardiac remodeling in a mouse model of hyperuricemia.
Does hyperuricemia induced by potassium oxonate exacerbate adverse cardiac remodeling and mortality after myocardial infarction in a mouse model?
Hyperuricemia exacerbates post-MI adverse cardiac remodeling and mortality by suppressing fibroblast-derived lumican, highlighting the potential therapeutic value of uric acid-lowering therapies like allopurinol to prevent adverse ventricular remodeling.
Absolute Event Rate: 74.3% vs 48.6%
p-value: p=<0.05
BACKGROUND: Hyperuricemia is independently associated with a poor prognosis in patients with myocardial infarction (MI). Furthermore, MI induces activation of the repair response in local fibroblasts, resulting in extracellular matrix accumulation that generates a stable fibrotic scar in the infarcted area. However, researchers have not determined whether hyperuricemia affects fibroblast activation and its involvement in postinfarction cardiac remodeling. OBJECTIVES: We aimed to trigger hyperuricemia by administering potassium oxonate in a mouse model of MI to evaluate the role of hyperuricemia in MI pathogenesis. METHODS: Microarray datasets and single-cell sequencing data from gout patients, heart failure patients, and model mice were used to identify the underlying mechanisms responsible for the effect of hyperuricemia on MI progression. A hyperuricemia-related MI mouse model was established. Cardiac function was assessed, followed by sample collection and a uric acid assay. We conducted an enzyme-linked immunosorbent assay, histological detection, immunofluorescence, sequencing data processing, single-cell RNA-seq, and functional enrichment analysis. We then isolated and cultured cardiac fibroblasts and performed Western blotting, quantitative real-time polymerase chain reaction, and shRNA-mediated lumican knockdown assays. RESULTS: Hyperuricemia decreased cardiac function, increased mortality, and aggravated adverse fibrosis remodeling in mice after MI. These outcomes were closely related to reduced levels of fibroblast-derived lumican. This reduction activated the TGF-β/SMAD signaling pathway to induce aberrant myofibroblast activation and extracellular matrix deposition in the infarcted area. Furthermore, lumican supplementation or uric acid-lowering therapy with allopurinol alleviated hyperuricemia-mediated abnormal cardiac remodeling. CONCLUSION: Hyperuricemia aggravates postinfarction cardiac remodeling by reducing lumican expression and promoting fibroblast phenotype transition. We highlight the clinical importance of lowering uric acid levels in hyperuricemia-related MI to prevent adverse ventricular remodeling.
Zhuang et al. (Thu,) conducted a other in Myocardial infarction with hyperuricemia. Allopurinol vs. Vehicle was evaluated on Post-MI survival at 4 weeks (p=<0.05). Allopurinol treatment increased 4-week post-myocardial infarction survival from 48.6% to 74.3% and ameliorated adverse cardiac remodeling in a mouse model of hyperuricemia.