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Published on: November 7, 2017
Impact of elevated uric acid on ventricular remodeling in infarcted rats with experimental hyperuricemia
Chien-Chang Chen1, Yu-Jung Hsu, Tsung-Ming Lee
1Institute of Biomedical Engineering, National Cheng-Kung University, and Divison of Cardiovascular Surgery, Chia-yi Christian Hospital, Chia-yi City, Taiwan.
Insights
Hyperuricemia exacerbates ventricular remodeling after myocardial infarction by increasing superoxide and endothelin-1. Allopurinol, ABT-627, and tempol treatments attenuated this remodeling, suggesting these pathways are key targets.
Area of Science:
- Cardiovascular Research
- Renal Physiology
- Oxidative Stress Biology
Background:
- Hyperuricemia is linked to cardiovascular disease but often viewed as a marker, not a direct cause.
- Prior studies in normouricemic animals do not fully address hyperuricemia's role in post-myocardial infarction ventricular remodeling.
- This study investigates the adverse effects of elevated uric acid on ventricular remodeling in a rat model of myocardial infarction.
Purpose of the Study:
- To determine if hyperuricemia adversely affects ventricular remodeling after myocardial infarction in rats.
- To elucidate the underlying mechanisms involving oxidative stress and endothelin-1.
- To evaluate the efficacy of different therapeutic interventions.
Main Methods:
- Male Wistar rats underwent myocardial infarction (ligation) and were treated with vehicle, oxonic acid (to induce hyperuricemia), or oxonic acid plus allopurinol, benzbromarone, ABT-627, or tempol.
- Measurements included myocardial superoxide, isoprostane, xanthine oxidase activity, endothelin-1 expression, and cardiac function.
- Ventricular remodeling was assessed by hypertrophy and fibrosis.
Main Results:
- Hyperuricemic infarcted rats showed significantly increased superoxide production (1.7×) and endothelin-1 expression (protein 1.2×, mRNA 1.4×) compared to normouricemic controls.
- These changes correlated with worsened left ventricular dysfunction, hypertrophy, and fibrosis.
- Allopurinol treatment prevented these adverse effects; benzbromarone did not, despite similar urate lowering.
- ABT-627 and tempol also attenuated remodeling, indicating roles for endothelin-1 and redox pathways.
Conclusions:
- Hyperuricemia promotes unfavorable ventricular remodeling post-myocardial infarction, likely via superoxide and endothelin-1 pathways.
- Uric acid lowering alone may not improve remodeling if superoxide and endothelin-1 pathways are not inhibited.
- Allopurinol, ABT-627, and tempol demonstrate potential in attenuating adverse ventricular remodeling.
Abstract:
Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.
