RGD Reference Report - Losartan improves aortic endothelium-dependent relaxation via proline-rich tyrosine kinase 2/Src/Akt pathway in type 2 diabetic Goto-Kakizaki rats. - Rat Genome Database

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Losartan improves aortic endothelium-dependent relaxation via proline-rich tyrosine kinase 2/Src/Akt pathway in type 2 diabetic Goto-Kakizaki rats.

Authors: Nemoto, S  Kobayashi, T  Taguchi, K  Matsumoto, T  Kamata, K 
Citation: Nemoto S, etal., Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2383-94. doi: 10.1152/ajpheart.00178.2011. Epub 2011 Sep 16.
RGD ID: 10041069
Pubmed: PMID:21926342   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpheart.00178.2011   (Journal Full-text)

In diabetic states, endothelial dysfunction is related to vascular complications. We hypothesized that insulin-induced relaxation and the associated proline-rich tyrosine kinase 2 (Pyk2)/Src/Akt pathway would be abnormal in aortas from the Goto-Kakizaki (GK) type 2 diabetic rat, which exhibits hyperglycemia/insulin resistance, and that losartan treatment of such rats (25 mg.kg(-1).day(-1) for 2 wk) would correct these abnormalities. Endothelium-dependent relaxation was by measuring isometric force in helical strips of aortas from four groups, each of 30 rats: normal Wistar (control), GK (diabetic), losartan-treated normal, and losartan-treated GK. Pyk2, Src, and Akt/endothelial nitric oxide synthase (eNOS) signaling-pathway protein levels and activities were assayed mainly by Western blotting and partly by immunohistochemistry. In GK (vs. age-matched control) aortas, various insulin-stimulated levels [nitric oxide production and the phosphorylations of eNOS at Ser(1177), of Akt at Thr(308), of phosphoinositide-dependent kinase-1 (PDK1) at Ser(241), of Src at Tyr(416), and of Pyk2 at Tyr(579)] were all significantly decreased and unaffected by either Src inhibitor (PP2) or Pyk2 inhibitor (AG17), while the insulin-stimulated levels of insulin receptor substrate (IRS)-1 phosphorylation at Ser(307), total-eNOS, and total-Akt were significantly increased. Losartan treatment normalized these altered levels. The insulin-stimulated phosphorylation levels of Src/PDK1/Akt/eNOS, but not of Pyk2, were decreased by PP2 in control and losartan-treated GK, but not in GK, aortas. These results suggest that in the GK diabetic aorta increased phospho-IRS-1 (at Ser(307)) and decreased Pyk2/Src activity inhibit insulin-induced stimulation of the PDK/Akt/eNOS pathway. The observed increase in phospho-IRS-1 (at Ser(307)) may result from increased angiotensin II activity.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTK2BHumandiabetic angiopathy treatmentISOPtk2b (Rattus norvegicus)associated with Diabetes Mellitus and Type 2RGD 
Ptk2bRatdiabetic angiopathy treatmentIDA associated with Diabetes Mellitus and Type 2RGD 
Ptk2bMousediabetic angiopathy treatmentISOPtk2b (Rattus norvegicus)associated with Diabetes Mellitus and Type 2RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ptk2bRatpositive regulation of nitric oxide biosynthetic process  IMP  RGD 
Ptk2bRatpositive regulation of nitric-oxide synthase activity  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ptk2b  (protein tyrosine kinase 2 beta)

Genes (Mus musculus)
Ptk2b  (PTK2 protein tyrosine kinase 2 beta)

Genes (Homo sapiens)
PTK2B  (protein tyrosine kinase 2 beta)


Additional Information