Dataset Information

Inhibition of the Peroxisome Proliferator-Activated Receptor gamma Coactivator 1-alpha (PGC-1?)/Sirtuin 3 (SIRT3) Pathway Aggravates Oxidative Stress After Experimental Subarachnoid Hemorrhage.

ABSTRACT: BACKGROUND Emerging evidence shows that Sirtuin 3 (SIRT3) can exert an antioxidative effect in various neurodegenerative diseases, but whether and how SIRT3 modulates neuronal death after subarachnoid hemorrhage (SAH) remains to be elucidated. MATERIAL AND METHODS Experimental SAH was induced in adult mice by prechiasmatic cistern injection and primary neurons by OxyHb incubation. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and SIRT3 protein levels were examined at different time points after SAH induction. The PGC-1alpha protein gene knockdown in vivo and in vitro was achieved by transfection of lentivirus (LV) vectors expressing shPGC-1alpha or negative control (NC). Western blot, oxidative stress index, histopathology, neurological function, and cell viability analysis was performed. RESULTS Results showed that the PGC-1alpha/SIRT3 pathway was remarkably activated in vivo and in vitro after SAH. LV-shPGC-1alpha treatment significantly inhibited the activation of this pathway after SAH, accompanied by deteriorated neurologic function, aggravated oxidative stress, increased neuronal apoptosis, and enhanced cytotoxicity compared with the mice or primary neurons treated with LV-NC only. CONCLUSIONS The present results highlight the detrimental PGC-1alpha/SIRT3 pathway, involving regulation of the endogenous antioxidant activity against neuronal damage, which may provide a potential therapeutic target in SAH.

SUBMITTER: Zhang K

PROVIDER: S-EPMC7266085 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of the Peroxisome Proliferator-Activated Receptor gamma Coactivator 1-alpha (PGC-1α)/Sirtuin 3 (SIRT3) Pathway Aggravates Oxidative Stress After Experimental Subarachnoid Hemorrhage.

Zhang Ke K Cheng Hongwei H Song Lihua L Wei Wei W

Medical science monitor : international medical journal of experimental and clinical research 20200524

BACKGROUND Emerging evidence shows that Sirtuin 3 (SIRT3) can exert an antioxidative effect in various neurodegenerative diseases, but whether and how SIRT3 modulates neuronal death after subarachnoid hemorrhage (SAH) remains to be elucidated. MATERIAL AND METHODS Experimental SAH was induced in adult mice by prechiasmatic cistern injection and primary neurons by OxyHb incubation. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and SIRT3 protein levels were ...[more]

PMID: 32447338

Similar Datasets

Project description:PGC-1a is a transcriptional coactivator known to regulate a broad gene program of nutrient and mitochondrial metabolism. Many splice variants of this protein have been identified, but their functions were unknown. This experiment was designed to delineate the downstream targets of two different PGC-1alpha isoforms (PGC-1a1 and PGC-1a4) in hepatocytes, and to determine whether inflammatory signaling (via TNFR activation) modulated these targets Liver is exposed to constantly changing metabolic and inflammatory environments. It must quickly sense and adapt to metabolic need while balancing resources required to protect itself from harmful inflammatory molecules. PGC-1α is a transcriptional coactivator that mediates cellular adaptation to diverse stimuli including inflammation. PGC-1α has a protective role against inflammation in several organs, including brain, heart, kidney, muscle, and liver. However, it is not known how hepatic PGC-1α integrates extracellular signals to mitigate inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants whose expression is differentially regulated by different gene promoters. In human liver, we found that inflammatory conditions preferentially activated the alternative versus proximal PPARGC1A promoter. Gene expression analysis performed in primary mouse hepatocytes identified many shared and isoform-specific roles for PGC-1α variants during acute inflammation. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα treatment revealed that PGC-1α4 uniquely influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models showed that PGC-1α4 specifically attenuated apoptosis in response to TNFα or LPS, in contrast to PGC-1α1, which reduced expression of a wide inflammatory gene network. We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to inflammation, with PGC-1α4 being an important mitigator of apoptosis.

Dataset Information

Inhibition of the Peroxisome Proliferator-Activated Receptor gamma Coactivator 1-alpha (PGC-1?)/Sirtuin 3 (SIRT3) Pathway Aggravates Oxidative Stress After Experimental Subarachnoid Hemorrhage.

Publications

Inhibition of the Peroxisome Proliferator-Activated Receptor gamma Coactivator 1-alpha (PGC-1α)/Sirtuin 3 (SIRT3) Pathway Aggravates Oxidative Stress After Experimental Subarachnoid Hemorrhage.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets