期刊
CIRCULATION RESEARCH
卷 102, 期 12, 页码 1575-1583出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.171264
关键词
hypoxic pulmonary vasoconstriction; metallothionein; fluorescence microscopy; endothelial cells
资金
- NCRR NIH HHS [U54 RR022241, 1 U54 RR022241-01] Funding Source: Medline
- NHLBI NIH HHS [HL081421, HL65697, P01 HL070807-020003, HL70807, HL070807, R01 HL081421, P01 HL070807, R37 HL065697, R37 HL065697-01, R01 HL081421-01A1] Funding Source: Medline
- NIGMS NIH HHS [P50 GM053789-080010, P50 GM053789, GM53789] Funding Source: Medline
The metal binding protein metallothionein (MT) is a target for nitric oxide (NO), causing release of bound zinc that affects myogenic reflex in systemic resistance vessels. Here, we investigate a role for NO-induced zinc release in pulmonary vasoregulation. We show that acute hypoxia causes reversible constriction of intraacinar arteries (<50 mu m/L) in isolated perfused mouse lung (IPL). We further demonstrate that isolated pulmonary (but not aortic) endothelial cells constrict in hypoxia. Hypoxia also causes NO-dependent increases in labile zinc in mouse lung endothelial cells and endothelium of IPL. The latter observation is dependent on MT because it is not apparent in IPL of MT-/- mice. Data from NO-sensitive fluorescence resonance energy transfer-based reporters support hypoxia-induced NO production in pulmonary endothelium. Furthermore, hypoxic constriction is blunted in IPL of MT-/- mice and in wild-type mice, or rats, treated with the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), suggesting a role for chelatable zinc in modulating HPV. Finally, the NO donor DETAnonoate causes further vasoconstriction in hypoxic IPL in which NO vasodilatory pathways are inhibited. Collectively, these data suggest that zinc thiolate signaling is a component of the effects of acute hypoxia-mediated NO biosynthesis and that this pathway may contribute to constriction in the pulmonary vasculature.
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