Simvastatin improves diabetes-induced coronary endothelial dysfunction

Huda El Sayed Tawfik, Azza B. El-Remessy, Suraporn Matragoon, Guochuan Ma, Ruth B Caldwell, Robert William Caldwell

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Abstract

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors decrease cardiovascular morbidity in diabetic patients, but the mechanism is unclear. We studied the actions of simvastatin (SIM) in enhancing NO bioavailability and reducing oxidative stress in coronary vessels from diabetic rats and in rat coronary artery endothelial cells (RCAEC) exposed to high glucose. Coronary arteries isolated from diabetic rats showed decreases in acetylcholine (ACh)-mediated maximal relaxation from 81.0 ± 4.5% in controls to 43.5 ± 7.6% at 4 weeks and 22.3 ± 0.6% at 10 weeks of diabetes. This effect was associated with oxidative stress in coronary vessels as shown by dichlorofluorescein (DCF) imaging and nitrotyrosine labeling. Diabetes also reduced trans-coronary uptake of [3H]L-arginine. Supplemental L-arginine (50 mg/kg/day p.o.) did not improve coronary vasorelaxation to ACh. However, SIM treatment (5 mg/kg/day subcutaneously) improved maximal ACh relaxation to 65.8 ± 5.1% at 4 weeks and 47.1 ± 3.9% at 10 weeks. Coronary arteries from rats treated with both SIM and L-arginine demonstrated the same maximal relaxation to ACh (66.1 ± 3%) as SIM alone. Mevalonate and L-NAME (Nω-nitro-L-arginine methyl ester hydrochloride) inhibited the response to ACh in SIM-treated diabetic rats. Coronary arteries from all groups relaxed similarly to sodium nitroprusside. SIM increased endothelial NO synthase protein levels and blocked diabetes-induced increases in DCF and nitrotyrosine labeling in diabetic coronary vessels. SIM treatment restored normal NO levels in media from high-glucose-treated RCAEC and plasma of diabetic rat. Treatment with SIM or the NADPH oxidase inhibitor apocynin also blocked high-glucose-induced increases in reactive oxygen species and superoxide formation in RCAEC. Taken together, these data suggest that SIM improves diabetes-induced coronary dysfunction by reducing oxidative stress and increasing NO bioavailability.

Original languageEnglish (US)
Pages (from-to)386-395
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume319
Issue number1
DOIs
StatePublished - Oct 2 2006

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Simvastatin
Coronary Vessels
Acetylcholine
Arginine
Oxidative Stress
Endothelial Cells
Glucose
Biological Availability
Hydroxymethylglutaryl CoA Reductases
Mevalonic Acid
NADPH Oxidase
NG-Nitroarginine Methyl Ester
Nitroprusside
Vasodilation
Nitric Oxide Synthase
Superoxides
Reactive Oxygen Species
Morbidity

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Simvastatin improves diabetes-induced coronary endothelial dysfunction. / Tawfik, Huda El Sayed; El-Remessy, Azza B.; Matragoon, Suraporn; Ma, Guochuan; Caldwell, Ruth B; Caldwell, Robert William.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 319, No. 1, 02.10.2006, p. 386-395.

Research output: Contribution to journalArticle

Tawfik, Huda El Sayed ; El-Remessy, Azza B. ; Matragoon, Suraporn ; Ma, Guochuan ; Caldwell, Ruth B ; Caldwell, Robert William. / Simvastatin improves diabetes-induced coronary endothelial dysfunction. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 319, No. 1. pp. 386-395.
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