SIAH1 Promotes the Pyroptosis of Cardiomyocytes in Diabetic Cardiomyopathy via Regulating IκB-α/NF-κВ Signaling.

ABSTRACT

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 (1κВ-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.