期刊
DIABETES
卷 53, 期 9, 页码 2436-2442出版社
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.53.9.2436
关键词
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资金
- NHLBI NIH HHS [P01 HL68769, P50 HL65203, R01 HL067948, R01 HL59238] Funding Source: Medline
Coronary microvessels generate reactive oxygen species in response to high glucose (HG), resulting in vasodilator defects involving an impaired function of vascular K+ channels. Inhibition of voltage-gated K+ (K-v) channels by peroxynitrite (ONOO-), formed by the interaction of superoxide and nitric oxide, may contribute to impaired dilation. The present study investigated whether HG induces ONOO- formation to mediate nitration and impairment of K-v channels in rat small coronary arteries (RSCAs). Exposure to ONOO- reduced the dilator influence of K-v channels in RSCAs. Patch-clamp studies revealed that ONOO- diminished whole-cell and unitary K-v currents attributable to the K(v)1 gene family in smooth muscle cells. Subsequently, immunohistochemically detected enhancement of nitrotyrosine residues in RSCAs that were cultured in HG (23 mmol/l) compared with normal glucose (5.5 mmol/l) for 24 h correlated with the nitration of K(v)1.2 channel alpha-subunits. HG-induced nitrotyrosine formation was partially reversed by scavenging ONOO-. Finally, RSCAs that were exposed to HG for 24 h showed a loss of K-v channel dilator influence that also was partially restored by the ONOO- scavengers urate and ebselen. We conclude that ONOO- generated by HG impairs K-v channel function in coronary microvessels, possibly by nitrating tyrosine residues in the pore-forming region of the K-v channel protein.
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