Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus.

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Research Abstract Details 

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Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Abstract Text:

Philip Wenzel,Andreas Daiber,Matthias Oelze,Moritz Brandt,Ellen Closs,Jian Xu,Thomas Thum,Johann Bauersachs,Georg Ertl,Ming-Hui Zou,Ulrich ,Thomas ,Philip Wenzel,Andreas Daiber,Matthias Oelze,Moritz Brandt,Ellen Closs,Jian Xu,Thomas Thum,Johann Bauersachs,Georg Ertl,Ming-Hui Zou,Ulrich ,Thomas ,

OBJECTIVE: HMG-CoA reductase inhibitors have been shown to upregulate GTP cyclohydrolase I (GTPCH-I), the key enzyme for tetrahydrobiopterin de novo synthesis and to normalize tetrahydrobiopterin levels in hyperglycemic endothelial cells. We sought to determine whether in vivo treatment with the HMG-CoA reductase inhibitor atorvastatin is able to upregulate the GTPCH-I, to recouple eNOS and to normalize endothelial dysfunction in an experimental model of diabetes mellitus. METHODS AND RESULTS: In male Wistar rats, diabetes was induced by streptozotocin (STZ, 60mg/kg). In STZ rats, atorvastatin feeding (20mg/kg/d, 7 weeks), normalized vascular dysfunction as analyzed by isometric tension studies, levels of circulating endothelial progenitor cells (FACS-analysis), superoxide formation (assessed by lucigenin-enhanced chemiluminescence and dihydroethidium staining), vascular levels of the phosphorylated vasodilator-stimulated phosphoprotein (P-VASP), tyrosine nitration of the prostacyclin synthase, expression of GTPCH-I, dihydrofolate reductase and eNOS, translocation of regulatory NADPH oxidase subunits rac1, p47phox and p67phox (assessed by Western blot) and vascular tetrahydrobiopterin levels as measured by HPLC. Dihydroethidine staining revealed that the reduction of vascular superoxide was at least in part due to eNOS recoupling. CONCLUSION: HMG-CoA reductase inhibition normalizes endothelial function and reduces oxidative stress in diabetes by inhibiting activation of the vascular NADPH oxidase and by preventing eNOS uncoupling due to an upregulation of the key enzyme of tetrahydrobiopterin synthesis, GTPCH-I.

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Publishing Authors By Initials

P Wenzel,A Daiber,M Oelze,M Brandt,E Closs,J Xu,T Thum,J Bauersachs,G Ertl,MH Zou,U ,T ,P Wenzel,A Daiber,M Oelze,M Brandt,E Closs,J Xu,T Thum,J Bauersachs,G Ertl,MH Zou,U ,T ,

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Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Atherosclerosis

VOLUME: 198

Page Numbers: 65-76

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ISSN: 1879-1484

DAY: 3

MONTH: 12

YEAR: 2007

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Information

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LANGUAGE: eng

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MEDLINETA: Atherosclerosis

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