Reduced ischemia/reperfusion injury via glutathione-initiated nitric oxide-releasing dendrimers

被引：55

作者：

Johnson, Timothy A. ^{[1
]}

Stasko, Nathan A. ^{[2
]}

Matthews, Jessica L. ^{[3
]}

Cascio, Wayne E. ^{[3
]}

Holmuhamedov, Ekhson L. ^{[4
]}

Johnson, C. Bryce ^{[4
]}

Schoenfisch, Mark H. ^{[2
]}

机构：

[1] Virginia Tech, Carilion Sch Med, Dept Basic Sci, Roanoke, VA 24016 USA

[2] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA

[3] E Carolina Univ, Dept Cardiovasc Sci, Greenville, NC USA

[4] Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC USA

来源：

NITRIC OXIDE-BIOLOGY AND CHEMISTRY | 2010年 / 22卷 / 01期

关键词：

Nitric oxide; Dendrimer; Nitrosothiol; Glutathione; Ischemia/reperfusion injury; BIOMEDICAL APPLICATIONS; MYOCARDIAL-ISCHEMIA; DENDRITIC POLYMERS; CHEMISTRY; TRANSPORT; KINETICS; DELIVERY; HEART;

D O I：

10.1016/j.niox.2009.11.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We report the therapeutic potential of S-nitroso-N-acetylpenicillamine-derivatized generation-4 polyamidoamine dendrimers (G4-SNAP) for reducing ischemia/reperfusion (I/R) injury in an isolated, perfused rat heart. The use of this dendrimer scaffold to deliver the nitrosothiol therapeutic did not inhibit NO donor activity as the required dose of G4-SNAP to minimize I/R injury (31 nM corresponding to 2 mu M SNAP) was consistent with the optimum concentration of small molecule SNAP alone. An exploration of G4-SNAP NO release kinetics in the presence of physiologically relevant concentrations of glutathione (GSH) indicated enhanced NO release (t[NO] = 1.28 mu M NO/mg) at 500 mu M GSH. Reperfusion experiments conducted with 500 mu M GSH further lowered the optimal therapeutic G4-SNAP dose to 230 pM (i.e., 15 nM SNAP). The unique combination of G4-SNAP dendrimer and glutathione trigger represents a novel strategy with possible clinical relevance toward salvaging ischemic tissue. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：30 / 36

页数：7

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