Volume 30, Issue 2, 2021
DOI: 10.24205/03276716.2020.4021
Inhibition of low-molecular mass protein-7 alleviates hyperglycemia-induced myocardial apoptosis by repairing metabolism disorder and inflammation
Abstract
Diabetic cardiomyopathy (DCM) is characterized as ventricular dysfunction and poor prognosis. The pathogenesis is unclear. Here, we explored the role of low-molecular mass protein-7 (LMP7) in DCM development. DCM model was established in primary cultured rat cardiomyocytes by stimulation with elevated glucose. The cardiomyocytes were induced using different concentrations of glucose for different times to optimize the conditions, and cells were assigned into four groups: normal control group (NG), high glucose group (HG), ONX-0914 group (HG + ONX-0914 to selectively inhibit LMP7), and solvent control group followed by analysis of the mRNA and protein expression levels of LMP7, glucose transporter type 4 (GLUT4), insulin receptor substrate-1 (IRS-1), and CD36 by qRT-PCR and western blot, respectively. Inflammatory cytokines were assessed by ELISA and cell viability was examined by CCK8 assay along with analysis of myocardial apoptosis by flow cytometry. LMP7 was increased in a time-dependent manner in hyperglycemic cardiomyocytes, accompanied with decreased cell viability. Compared with NG group, GLUT4 and IRS-1 expression was significantly decreased in HG group (P?0.01) with elevated CD36 expression (P?0.01), which were all reversed in ONX-0914 group (P?0.01). Secretion of IL-6 and TNF-?, and apoptosis were significantly decreased in ONX-0914 group than those in HG group (P?0.01). LMP7 activation by hyperglycemia may regulate glucose and fatty acid transporter through the impaired insulin signaling pathway. LMP7 inhibition could alleviate hyperglycemia-induced myocardial apoptosis by repairing metabolic disorder and inflammation.
Keywords
diabetic cardiomyopathy, LMP7, apoptosis, metabolic disorder, inflammation