Zhang Dandan, Li Yilan, Wang Weijie, Lang Xueyan, Zhang Yanxiu, Zhao Qianqian, Yan Jingru, Zhang Yao
Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China.
Front Pharmacol. 2022 Sep 26;13:928762. doi: 10.3389/fphar.2022.928762. eCollection 2022.
Diabetic cardiomyopathy (DCM) is a prevalent complication in patients with diabetes, resulting in high morbidity and mortality. However, the molecular mechanisms of diabetic cardiomyopathy have yet to be fully elucidated. In this study, we investigated a novel target, NOX1, an isoform of superoxide-producing NADPH oxidase with key functional involvement in the pathophysiology of DCM. The DCM rat model was established by a high-fat diet combined with streptozotocin injections. DCM rats elicited myocardial fibrosis exacerbation, which was accompanied by a marked elevation of NOX1 expression in cardiac tissue. In particular, a specific NOX1 inhibitor, ML171, effectively decreased myocardial fibrosis and protected against cardiac dysfunction in DCM rats. Rat neonatal cardiac fibroblasts were incubated with high glucose (HG, 33 mM) as an model of DCM. We also observed that the expression of NOX1 was upregulated in HG-cultured cardiac fibroblasts. Silencing of NOX1 was found to attenuate myocardial fibrosis and oxidative stress in HG-induced cardiac fibroblasts. Furthermore, the upregulation of NOX1 by hyperglycemia induced activation of the TLR2/NF-κB pathway both and , whereas these effects were significantly attenuated with NOX1 gene silencing and further enhanced with NOX1 gene overexpression. In summary, we demonstrated that NOX1 induced activation of the TLR2/NF-κB pathway and increased reactive oxygen species production accumulation, which ultimately increased myocardial fibrosis and deteriorated cardiac function in diabetic cardiomyopathy. Our study revealed that NOX1 was a potential therapeutic target for DCM.
糖尿病性心肌病（DCM）是糖尿病患者中常见的并发症，导致高发病率和死亡率。然而，糖尿病性心肌病的分子机制尚未完全阐明。在本研究中，我们研究了一个新的靶点——NOX1，它是一种产生超氧化物的NADPH氧化酶的亚型，在DCM的病理生理学中具有关键的功能作用。通过高脂饮食联合链脲佐菌素注射建立DCM大鼠模型。DCM大鼠出现心肌纤维化加重，同时心脏组织中NOX1表达显著升高。特别是，一种特异性的NOX1抑制剂ML171有效减轻了DCM大鼠的心肌纤维化并预防了心脏功能障碍。将大鼠新生心脏成纤维细胞与高糖（HG，33 mM）一起孵育，作为DCM模型。我们还观察到HG培养的心脏成纤维细胞中NOX1的表达上调。发现沉默NOX1可减轻HG诱导的心脏成纤维细胞中的心肌纤维化和氧化应激。此外，高血糖诱导的NOX1上调在体内和体外均激活了TLR2/NF-κB途径，而这些作用在NOX1基因沉默时显著减弱，在NOX1基因过表达时进一步增强。总之，我们证明NOX1诱导TLR2/NF-κB途径激活并增加活性氧产生积累，最终增加糖尿病性心肌病中的心肌纤维化并使心脏功能恶化。我们的研究表明NOX1是DCM的一个潜在治疗靶点。
