Dataset Information

PGC-1? (Peroxisome Proliferator-Activated Receptor ? Coactivator 1-?) Overexpression in Coronary Artery Disease Recruits NO and Hydrogen Peroxide During Flow-Mediated Dilation and Protects Against Increased Intraluminal Pressure.

ABSTRACT: Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide (mtH2O2). Excessive mtH2O2 production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1? (peroxisome proliferator-activated receptor ? coactivator 1?) is implicated in the pathogenesis of CAD. We hypothesized that PGC-1? suppresses mtH2O2 production to reestablish NO-mediated dilation in isolated vessels from patients with CAD. Isolated human adipose arterioles were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the presence of PEG (polyethylene glycol)-catalase (H2O2 scavenger) or L-NAME (NG-nitro-l-arginine methyl ester; NOS inhibitor). In contrast to the exclusively NO- or H2O2-mediated dilation seen in either non-CAD or CAD conditions, respectively, flow-mediated dilation in CAD vessels was sensitive to both L-NAME and PEG-catalase after PGC-1? upregulation using ZLN005 and ?-lipoic acid. PGC-1? overexpression in CAD vessels protected against the vascular dysfunction induced by an acute increase in intraluminal pressure. In contrast, downregulation of PGC-1? in non-CAD vessels produces a CAD-like phenotype characterized by mtH2O2-mediated dilation (no contribution of NO). Loss of PGC-1? may contribute to the shift toward the mtH2O2-mediated dilation observed in vessels from subjects with CAD. Strategies to boost PGC-1? levels may provide a therapeutic option in patients with CAD by shifting away from mtH2O2-mediated dilation, increasing NO bioavailability, and reducing levels of mtH2O2 Furthermore, increased expression of PGC-1? allows for simultaneous contributions of both NO and H2O2 to flow-mediated dilation.

SUBMITTER: Kadlec AO

PROVIDER: S-EPMC5485836 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α) Overexpression in Coronary Artery Disease Recruits NO and Hydrogen Peroxide During Flow-Mediated Dilation and Protects Against Increased Intraluminal Pressure.

Kadlec Andrew O AO Chabowski Dawid S DS Ait-Aissa Karima K Hockenberry Joseph C JC Otterson Mary F MF Durand Matthew J MJ Freed Julie K JK Beyer Andreas M AM Gutterman David D DD

Hypertension (Dallas, Tex. : 1979) 20170522 1

Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide (mtH2O2). Excessive mtH2O2 production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) is implicated in the pathogenesis of CAD. We hypothes ...[more]

PMID: 28533333

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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.

Project description:Hepatic peroxisomes are essential for lipid conversions that include the formation of mature conjugated bile acids, the degradation of branched chain fatty acids, and the synthesis of docosahexaenoic acid. Through unresolved mechanisms, deletion of functional peroxisomes from mouse hepatocytes (L-Pex5(-/-) mice) causes severe structural and functional abnormalities at the inner mitochondrial membrane. We now demonstrate that the peroxisomal and mitochondrial anomalies trigger energy deficits, as shown by increased AMP/ATP and decreased NAD(+)/NADH ratios. This causes suppression of gluconeogenesis and glycogen synthesis and up-regulation of glycolysis. As a consequence, L-Pex5(-/-) mice combust more carbohydrates resulting in lower body weights despite increased food intake. The perturbation of carbohydrate metabolism does not require a long term adaptation to the absence of functional peroxisomes as similar metabolic changes were also rapidly induced by acute elimination of Pex5 via adenoviral administration of Cre. Despite its marked activation, peroxisome proliferator-activated receptor α (PPARα) was not causally involved in these metabolic perturbations, because all abnormalities still manifested when peroxisomes were eliminated in a peroxisome proliferator-activated receptor α null background. Instead, AMP-activated kinase activation was responsible for the down-regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1α was suppressed despite AMP-activated kinase activation, a paradigm not previously reported, and they jointly contributed to impaired gluconeogenesis. In conclusion, lack of functional peroxisomes from hepatocytes results in marked disturbances of carbohydrate homeostasis, which are consistent with adaptations to an energy deficit. Because this is primarily due to impaired mitochondrial ATP production, these L-Pex5-deficient livers can also be considered as a model for secondary mitochondrial hepatopathies.

Project description:ObjectiveThe etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1), which modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, PGC-1α critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test the hypothesis that mitochondrial biogenesis is deficient in human OA chondrocytes and that this deficiency functionally increases chondrocyte procatabolic responses, which are reversed by activation of the AMPK/SIRT-1/PGC-1α pathway.MethodsWe assessed the expression and activity (phosphorylation) of AMPKα, SIRT-1, and PGC-1α in human knee chondrocytes and human and mouse knee cartilage, and we defined and compared the content and function of mitochondria, including oxidative phosphorylation and expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A [TFAM] and nuclear respiratory factors [NRFs]).ResultsHuman knee OA chondrocytes had a decreased mitochondrial biogenesis capacity, which was linked to reduced AMPKα activity and decreased expression of SIRT-1, PGC-1α, TFAM, NRF-1, and NRF-2. Human knee OA and aging mouse knee cartilage had decreased expression of TFAM and ubiquinol-cytochrome c reductase core protein, a subunit of mitochondrial complex III, in situ. Chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced procatabolic responses to interleukin-1β. Finally, activation of AMPK by A-769662 increased PGC-1α expression via SIRT-1 and reversed impairments in mitochondrial biogenesis, oxidative phosphorylation, and intracellular ATP in human knee OA chondrocytes.ConclusionMitochondrial biogenesis is deficient in human OA chondrocytes, and this deficiency promotes chondrocyte procatabolic responses. TFAM-mediated activation of the AMPK/SIRT-1/PGC-1α pathway reverses these effects, suggesting translational potential of pharmacologic AMPK activators to limit OA progression.

Dataset Information

PGC-1? (Peroxisome Proliferator-Activated Receptor ? Coactivator 1-?) Overexpression in Coronary Artery Disease Recruits NO and Hydrogen Peroxide During Flow-Mediated Dilation and Protects Against Increased Intraluminal Pressure.

Publications

PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α) Overexpression in Coronary Artery Disease Recruits NO and Hydrogen Peroxide During Flow-Mediated Dilation and Protects Against Increased Intraluminal Pressure.

Similar Datasets

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