Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
J Transl Med. 2024 Oct 31;22(1):983. doi: 10.1186/s12967-024-05778-4.
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.
We aimed to trigger hyperuricemia by administering potassium oxonate in a mouse model of MI to evaluate the role of hyperuricemia in MI pathogenesis.
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.
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.
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.
高尿酸血症与心肌梗死（MI）患者的预后不良独立相关。此外，MI 可诱导局部成纤维细胞的修复反应激活，导致细胞外基质积累，从而在梗死区产生稳定的纤维化瘢痕。然而，研究人员尚未确定高尿酸血症是否会影响成纤维细胞的激活及其在梗死后心脏重构中的作用。
我们旨在通过给予黄嘌呤氧化酶钾在 MI 小鼠模型中诱发高尿酸血症，以评估高尿酸血症在 MI 发病机制中的作用。
使用痛风患者、心力衰竭患者和模型小鼠的微阵列数据集和单细胞测序数据，鉴定导致高尿酸血症对 MI 进展影响的潜在机制。建立高尿酸血症相关的 MI 小鼠模型。评估心功能，随后采集样本并进行尿酸测定。我们进行了酶联免疫吸附试验、组织学检测、免疫荧光、测序数据分析、单细胞 RNA-seq 和功能富集分析。然后，我们分离并培养心肌成纤维细胞，并进行 Western blot、定量实时聚合酶链反应和 shRNA 介导的 lumican 敲低实验。
高尿酸血症降低了 MI 后小鼠的心脏功能，增加了死亡率，并加重了不良的纤维化重塑。这些结果与成纤维细胞衍生的 lumican 水平降低密切相关。这种减少激活了 TGF-β/SMAD 信号通路，导致梗死区异常的肌成纤维细胞激活和细胞外基质沉积。此外，lumican 补充或用别嘌醇进行降尿酸治疗可缓解高尿酸血症介导的异常心脏重塑。
高尿酸血症通过降低 lumican 表达和促进成纤维细胞表型转变，加重梗死后心脏重塑。我们强调在高尿酸血症相关 MI 中降低尿酸水平的临床重要性，以预防不良的心室重构。
