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Catalase ameliorates diabetes-induced cardiac injury through reduced p65/RelA- mediated transcription of BECN1.

ABSTRACT: Catalase is an antioxidative enzyme that converts hydrogen peroxide (H₂ O₂ ) produced by superoxide dismutase from highly reactive superoxide (O₂^- ) to water and oxygen molecules. Although recent findings demonstrate that catalase, autophagy and the nuclear factor ?B (NF-?B) signalling pathway are centrally involved in diabetic cardiomyopathy (DCM), the interplay between the three has not been fully characterized. Thus, the mechanism responsible for catalase-mediated protection against heart injury in diabetic mice was investigated in this study, as well as the role of NF-?B-p65 in the regulation of autophagic flux was investigated in this study. Western blot analysis revealed that catalase inhibited NF-?B activity and decreased LC3-II (microtubule-associated protein 1 light chain 3) and beclin-1 (Atg6) expression. Furthermore, up-regulation of autophagy was detrimental for cardiac function in diabetic mice. Catalase overexpression reduced the level of NF-?B subunit in the nucleus, where it initiates autophagy through activation of the key autophagy gene BECN1. To evaluate the role of the NF-?B pathway in diabetes-induced autophagy, Bay11-7082, an NF-?B inhibitor, was injected into diabetic mice, which suppressed NF-?B and attenuated diabetes-induced autophagy and myocardial apoptosis. In agreement with the in vivo results, Bay11-7082 also inhibited high-glucose-induced activation of NF-?B and the up-regulation of LC3-II and beclin-1 expression in H9c2 cells. In addition, high-glucose-induced activation of autophagic flux and apoptosis were largely attenuated by p65 siRNA, suggesting that catalase ameliorates diabetes-induced autophagy, at least in part by increasing the activity of the NF-?B pathway and p65-mediated transcription of BECN1.

SUBMITTER: Wang X

PROVIDER: S-EPMC5706580 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Catalase ameliorates diabetes-induced cardiac injury through reduced p65/RelA- mediated transcription of BECN1.

Wang Xu X Tao Youli Y Huang Yewei Y Zhan Kungao K Xue Mei M Wang Ying Y Ruan Dandan D Liang Yangzhi Y Huang Xiaozhong X Lin Jianjun J Chen Zhiwei Z Lv Lingchun L Li Santie S Chen Gen G Wang Yang Y Chen Ruijie R Cong Weitao W Jin Litai L

Journal of cellular and molecular medicine 20170623 12

Catalase is an antioxidative enzyme that converts hydrogen peroxide (H2 O2 ) produced by superoxide dismutase from highly reactive superoxide (O2- ) to water and oxygen molecules. Although recent findings demonstrate that catalase, autophagy and the nuclear factor κB (NF-κB) signalling pathway are centrally involved in diabetic cardiomyopathy (DCM), the interplay between the three has not been fully characterized. Thus, the mechanism responsible for ca ...[more]

PMID: 28643395

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Project description:Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-?B signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-?B transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-?B complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at postmortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous de novo missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bidirectional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-?B responses compared with healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-?B complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-?B pathway for human skeletal homeostasis and represent a new genetic cause of HBM.

Dataset Information

Catalase ameliorates diabetes-induced cardiac injury through reduced p65/RelA- mediated transcription of BECN1.

Publications

Catalase ameliorates diabetes-induced cardiac injury through reduced p65/RelA- mediated transcription of BECN1.

Similar Datasets

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