RGD Reference Report - Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. - Rat Genome Database

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Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation.

Authors: Du, Xueliang  Edelstein, Diane  Obici, Silvana  Higham, Ninon  Zou, Ming-Hui  Brownlee, Michael 
Citation: Du X, etal., J Clin Invest. 2006 Apr;116(4):1071-80. doi: 10.1172/JCI23354. Epub 2006 Mar 9.
RGD ID: 401960098
Pubmed: PMID:16528409   (View Abstract at PubMed)
PMCID: PMC1395482   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI23354   (Journal Full-text)

Insulin resistance markedly increases cardiovascular disease risk in people with normal glucose tolerance, even after adjustment for known risk factors such as LDL, triglycerides, HDL, and systolic blood pressure. In this report, we show that increased oxidation of FFAs in aortic endothelial cells without added insulin causes increased production of superoxide by the mitochondrial electron transport chain. FFA-induced overproduction of superoxide activated a variety of proinflammatory signals previously implicated in hyperglycemia-induced vascular damage and inactivated 2 important antiatherogenic enzymes, prostacyclin synthase and eNOS. In 2 nondiabetic rodent models--insulin-resistant, obese Zucker (fa/fa) rats and high-fat diet-induced insulin-resistant mice--inactivation of prostacyclin synthase and eNOS was prevented by inhibition of FFA release from adipose tissue; by inhibition of the rate-limiting enzyme for fatty acid oxidation in mitochondria, carnitine palmitoyltransferase I; and by reduction of superoxide levels. These studies identify what we believe to be a novel mechanism contributing to the accelerated atherogenesis and increased cardiovascular disease risk occurring in people with insulin resistance.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumanInsulin Resistance  ISOPtgis (Rattus norvegicus)protein:decreased activity:aorta (rat)RGD 
PtgisRatInsulin Resistance  IEP protein:decreased activity:aorta (rat)RGD 
PtgisMouseInsulin Resistance  ISOPtgis (Rattus norvegicus)protein:decreased activity:aorta (rat)RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumantriglyceride decreases activityISOPtgis (Rattus norvegicus)Triglyceride decreases activity of Ptgis protein in the aortaRGD 
PtgisRattriglyceride decreases activityEXP Triglyceride decreases activity of Ptgis protein in the aortaRGD 
PtgisMousetriglyceride decreases activityISOPtgis (Rattus norvegicus)Triglyceride decreases activity of Ptgis protein in the aortaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ptgis  (prostaglandin I2 synthase)

Genes (Mus musculus)
Ptgis  (prostaglandin I2 (prostacyclin) synthase)

Genes (Homo sapiens)
PTGIS  (prostaglandin I2 synthase)


Additional Information