Peng Dewei, He Xiaoli, Ren Bowen, Wang Qian, Peng Lulu, Jiang Yue, Huo Shengqi, Men Lintong, Shi Wei, Luo Pengcheng, Zhu Mengyin, Zhang Cuntai, Lv Jiagao, Lin Li, Li Sheng
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, P. R. China.
Mol Med. 2025 May 13;31(1):184. doi: 10.1186/s10020-025-01246-x.
High uric acid levels play a critical role in cardiovascular disease pathophysiology, being closely linked to their occurrence, progression, and prognosis. To enhance prevention and treatment of hyperuricemia-related cardiovascular diseases, understanding underlying mechanisms and identifying novel therapeutic targets are essential.
A hyperuricemic mouse model was established, and transcriptomic analysis of myocardial tissue was conducted using RNA sequencing. The role of HMGCS2 in hyperuricemia-induced cardiomyocytes was investigated through HMGCS2 knockout. The transcriptional regulation of HMGCS2 by STAT3 was explored via STAT3 knockdown, overexpression, and dual-luciferase reporter assays. To further elucidate the role of the JAK2/STAT3/hmgcs2 signaling pathway in hyperuricemia-induced cardiomyocytes, we overexpressed HMGCS2 while intervening in the JAK2/STAT3 pathway in vitro. The therapeutic potential of targeting the JAK2/STAT3/HMGCS2 pathway was evaluated in hyperuricemic mice using STAT3 and JAK inhibitors to assess effects on cardiac dysfunction.
RNA sequencing showed significant upregulation of HMGCS2 mRNA in hyperuricemic mouse cardiac tissue. Increased HMGCS2 protein levels were observed in cardiac tissue and AC16 cardiomyocytes. HMGCS2 knockdown alleviated uric acid-induced mitochondrial dysfunction, oxidative stress, and abnormal energy metabolism in AC16 cardiomyocytes. And high uric acid levels activate the IL-6/JAK2/STAT3 signaling pathway in AC16 cardiomyocytes, which regulates HMGCS2 expression. By modulating JAK2 and STAT3 expression and subsequently overexpressing HMGCS2, we identified the involvement of the JAK2/STAT3/HMGCS2 pathway in uric acid-induced mitochondrial dysfunction, oxidative stress, and energy metabolism abnormalities in AC16 cardiomyocytes. In vitro experiments demonstrated that intervention with the ruxolitinib and S3I-201 could ameliorate mitochondrial dysfunction, oxidative stress, and ATP levels in the heart tissue of hyperuricemic mice. Moreover, these treatments also reversed cardiac function abnormalities.
The JAK2/STAT3/HMGCS2 pathway may contributes to uric acid-induced cardiac dysfunction by affecting mitochondrial function, oxidative stress, and ATP metabolism, offering a potential therapeutic strategy for mitigating high uric acid-induced cardiac damage.
高尿酸水平在心血管疾病病理生理过程中起关键作用，与心血管疾病的发生、发展及预后密切相关。为加强对高尿酸血症相关心血管疾病的防治，了解其潜在机制并确定新的治疗靶点至关重要。
建立高尿酸血症小鼠模型，采用RNA测序对心肌组织进行转录组分析。通过敲除HMGCS2研究其在高尿酸血症诱导的心肌细胞中的作用。通过敲低、过表达STAT3及双荧光素酶报告基因检测探究STAT3对HMGCS2的转录调控。为进一步阐明JAK2/STAT3/HMGCS2信号通路在高尿酸血症诱导的心肌细胞中的作用，我们在体外过表达HMGCS2的同时干预JAK2/STAT3通路。使用STAT3和JAK抑制剂评估对心脏功能障碍的影响，以评价靶向JAK2/STAT3/HMGCS2通路在高尿酸血症小鼠中的治疗潜力。
RNA测序显示高尿酸血症小鼠心脏组织中HMGCS2 mRNA显著上调。在心脏组织和AC16心肌细胞中观察到HMGCS2蛋白水平升高。敲低HMGCS2可减轻尿酸诱导的AC16心肌细胞线粒体功能障碍、氧化应激及能量代谢异常。高尿酸水平激活AC16心肌细胞中的IL-6/JAK2/STAT3信号通路，该通路调节HMGCS2表达。通过调节JAK2和STAT3表达并随后过表达HMGCS2，我们确定JAK2/STAT3/HMGCS2通路参与尿酸诱导的AC16心肌细胞线粒体功能障碍、氧化应激及能量代谢异常。体外实验表明，用鲁索替尼和S3I-201干预可改善高尿酸血症小鼠心脏组织的线粒体功能障碍、氧化应激及ATP水平。此外，这些治疗还逆转了心脏功能异常。
JAK2/STAT3/HMGCS2通路可能通过影响线粒体功能、氧化应激和ATP代谢导致尿酸诱导的心脏功能障碍，为减轻高尿酸诱导的心脏损伤提供了一种潜在的治疗策略。
