Inflammation-mediated dysfunction of cardiomyocytes is the main cause of diabetic cardiomyopathy (DCM). The present study aimed to investigate the roles of siah E3 ubiquitin protein ligase 1 (SIAH1) in DCM. The online dataset GSE4172 was used to analyze the differentially expressed genes in myocardial inflammation of DCM patients. RT-qPCR was conducted to detect mRNA levels. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to detect cytokine release. Western blot was used to detect protein expression. Lactate dehydrogenase (LDH) assay was used to determine cytotoxicity. In vitro ubiquitination assay was applied to determine the ubiquitination of nuclear factor kappa B inhibitor alpha (1&kapaВ-α). Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was used to detect the death of cardiomyocytes. Flow cytometry was applied for determining cardiomyocyte pyroptosis. The results showed that SIAH1 was overexpressed in human inflammatory cardiomyopathy. High expression of SIAH1 was associated with inflammatory response. SIAH1 was also overexpressed lipopolysaccharide (LPS)-induced inflammatory cardiomyopathy model in vitro. However, SIAH1 knockdown suppressed the inflammatory-related pyroptosis of cardiomyocytes. SIAH1 promoted the ubiquitination of 1κВ-α and activated nuclear factor kappa В (NF-κВ) signaling, which promoted the pyroptosis of cardiomyocytes. In conclusion, SIAH1 exacerbated the progression of human inflammatory cardiomyopathy via inducing the ubiquitination of 1κВ-α and activation of NF-κВ signaling. Therefore, SIAHI/IκB-α/NF-κB signaling may be a potential target for human inflammatory cardiomyopathy.

中文翻译：

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SIAH1 通过调节 IκB-α/NF-κВ 信号传导促进糖尿病心肌病心肌细胞焦亡

炎症介导的心肌细胞功能障碍是糖尿病心肌病（DCM）的主要原因。本研究旨在探讨siah E3泛素蛋白连接酶1（SIAH1）在DCM中的作用。利用在线数据集GSE4172分析DCM患者心肌炎症的差异表达基因。进行RT-qPCR来检测mRNA水平。进行酶联免疫吸附测定（ELISA）来检测细胞因子的释放。 Western blot用于检测蛋白表达。乳酸脱氢酶（LDH）测定用于测定细胞毒性。采用体外泛素化实验测定核因子κB抑制剂α(1&kapaВ-α)的泛素化情况。末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记 (TUNEL) 测定用于检测心肌细胞的死亡。应用流式细胞术测定心肌细胞焦亡。结果表明，SIAH1在人类炎症性心肌病中过度表达。 SIAH1的高表达与炎症反应相关。 SIAH1也是过表达脂多糖（LPS）诱导的体外炎症性心肌病模型。然而，SIAH1 敲除抑制了与炎症相关的心肌细胞焦亡。 SIAH1促进1κВ-α泛素化并激活核因子κВ（NF-κВ）信号，从而促进心肌细胞焦亡。总之，SIAH1 通过诱导 1κВ-α 泛素化和 NF-κВ 信号激活，加剧了人类炎症性心肌病的进展。因此，SIAHI/IκB-α/NF-κB信号传导可能是人类炎症性心肌病的潜在靶点。