Mechanism of reversal of high glucose-induced endothelial nitric oxide synthase uncoupling by tanshinone IIA in human endothelial cell line EA.hy926

Zhi Wei Zhou, Xiao Liang Xie, Shu Feng Zhou, Chun Guang Li

Research output: Contribution to journalArticlepeer-review

Abstract

Endothelial nitric oxide synthase (eNOS) uncoupling plays a causal role in endothelial dysfunction in many cardiovascular and metabolic diseases. Tanshinone IIA (Tan IIA), an active compound from Salvia miltiorrhiza, has been used to treat cardiovascular and metabolic diseases. However, the effects of Tan IIA on eNOS uncoupling have not been reported. We hypothesize that Tan IIA can regulate eNOS uncoupling in endothelium cells under oxidative stress. The results showed that eNOS-mediated NO generation was significantly decreased, accompanied by increased superoxide production and NOX4 expression. The ratio of eNOS dimer to monomer and NOS cofactor tetrahydrobiopterin (BH4) to 7,8-dihydrobiopterin (BH2) as well as expressions of heat-shock protein of 90 kDa (HSP90), GTP cyclohydrolase-1 (GTPCH1) and dihydrofolate reductase (DHFR) were significantly decreased. Tan IIA significantly inhibited superoxide production and expression of NOX4, and increased NO generation and eNOS homodimerization, as well as expressions of HSP90, GTPCH1 and DHFR in a concentration-dependent manner. The ratio of BH4 to BH2 was also elevated by Tan IIA. In addition, Tan IIA significantly inhibited the increase in expression of PI3K in high glucose treated cells. Wortmannin, a PI3K inhibitor, significantly inhibited the high glucose induced NOX4 expression. The results demonstrated that Tan IIA restored eNOS uncoupling induced by high glucose by targeting NADPH oxidase, HSP90, GTPCH1 and DHFR, and PI3K pathway, which leads to reduced intracellular oxidative stress and increased NO generation. Tan IIA may be used as a prototype agent to restore eNOS coupling under certain cardiovascular and metabolic diseases.

Original languageEnglish (US)
Pages (from-to)97-105
Number of pages9
JournalEuropean Journal of Pharmacology
Volume697
Issue number1-3
DOIs
StatePublished - Dec 15 2012
Externally publishedYes

Keywords

  • Endothelial dysfunction
  • Endothelial nitric oxide synthase uncoupling
  • NADPH oxidase
  • Tanshinone IIA
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Pharmacology

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