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PGC-1? dictates endothelial function through regulation of eNOS expression.

ABSTRACT: Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1? (PGC-1?) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1? in vascular function using mice with endothelial specific loss of function (PGC-1? EC KO) and endothelial specific gain of function (PGC-1? EC TG). Here we report that endothelial PGC-1? is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1? sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1? EC TG mice were protected. Mechanistically, PGC-1? promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1? expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor ? (ERR?) is required to coordinate the PGC-1? -induced eNOS expression. In conclusion, endothelial PGC-1? expression protects from vascular dysfunction by promoting NO• bioactivity through ERR? induced expression of eNOS.

SUBMITTER: Craige SM

PROVIDER: S-EPMC5133545 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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PGC-1α dictates endothelial function through regulation of eNOS expression.

Craige Siobhan M SM Kröller-Schön Swenja S Li Chunying C Kant Shashi S Cai Shenghe S Chen Kai K Contractor Mayur M MM Pei Yongmei Y Schulz Eberhard E Keaney John F JF

Scientific reports 20161202

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1α (PGC-1α) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1α in vascular function using mice with endothelial specific loss of function (PGC-1α EC KO) and endothelial specific gain of function (PGC-1α EC TG). Here we report that endothelial PGC-1α is ...[more]

PMID: 27910955

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Project description:Purpose: Mitochondrial dysfunction in adipose tissue has emerged as key to the development of obesity and diabetes. Salvianolic acid B (SalB) is a water-soluble ingredient derived from Salvia miltiorrhiza that has been shown to possess potential anti-obese and anti-diabetic activities. However, the cellular mechanism of SalB on mitochondrial function with respect to these metabolic disorders has not been elucidated. Therefore, we aim to investigate the effects of SalB on mitochondrial function in 3T3-L1 adipocytes and analyze the underlying molecular mechanism. Methods: The effects of SalB on adipocyte differentiation, glucose uptake, and glycerol release were evaluated in 3T3-L1 adipocytes. Differentiated adipocytes were treated with SalB (50 μM) with or without PPARγ antagonist (GW9662, 20 μM) for 48 h, and mitochondrial oxygen consumption rate (OCR) as well as extracellular acidification rate (ECAR) were assessed using an XF Extracellular Flux Analyzer. The mitochondrial distribution of adipocytes was assessed using Mito Tracker Green (MTG) and observed under a fluorescent microscope. In addition, the mRNA expression levels of peroxisome proliferators-activated receptor γ/α (PPARγ/α), CCAAT/enhancer binding proteinα (C/EBPα), Nuclear respiratory factor 1/2 (NRF1/2), Uncoupling protein 2 (UCP2), and phosphofructokinase 2/fructose-2, 6-bisphosphatase 2 (PFKFB2) were detected by RT-PCR. Finally, changes in the protein levels of peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α) were determined by western blotting and immunofluorescence analysis. Results: Treatment with SalB increased glucose uptake and mitochondrial respiration, reduced glycerol release and promoted adipocyte differentiation by increasing mRNA expression of adipogenic transcription factors including PPARγ, C/EBPα, and PPARα. Furthermore, SalB enhanced adipocytes mitochondrial content, mitochondrial respiration and glycolysis capacity, which had been attenuated by GW9662 treatment through the increased expression of PGC-1α. Conclusion: Our results provide novel insights into the role of PGC-1α and mitochondria as probable mediators of SalB activity in the regulation of adipocyte differentiation in 3T3-L1 adipocytes.

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PGC-1? dictates endothelial function through regulation of eNOS expression.

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PGC-1α dictates endothelial function through regulation of eNOS expression.

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