Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis

被引：95

作者：

Small, GR ^{[1
]}

Hadoke, PWF ^{[1
]}

Sharif, I ^{[1
]}

Dover, AR ^{[1
]}

Armour, D ^{[1
]}

Kenyon, CJ ^{[1
]}

Gray, GA ^{[1
]}

Walker, BR ^{[1
]}

机构：

[1] Univ Edinburgh, Queens Med Res Inst, Ctr Cardiovasc Sci, Edinburgh EH16 4TJ, Midlothian, Scotland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2005年 / 102卷 / 34期

基金：

英国惠康基金;

关键词：

myocardial infarction; wound healing;

D O I：

10.1073/pnas.0500641102

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Angiogenesis restores blood flow to healing tissues, a process that is inhibited by high doses of glucocorticoids. However, the role of endogenous glucocorticoids and the potential for antiglucocorticoid therapy to enhance angiogenesis is unknown. Using in vitro and in vivo models of angiogenesis in mice, we examined effects of (i) endogenous glucocorticoids, (h) blocking endogenous glucocorticoid action with the glucocorticoid receptor antagonist RU38486, and (iii) abolishing local regeneration of glucocorticoids by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1). Glucocorticoids, administered at physiological concentrations, inhibited angiogenesis in an in vitro aortic ring model and in vivo in polyurethane sponges implanted s.c. RU38486-enhanced angiogenesis in s.c. sponges, in healing surgical wounds, and in the myocardium of mice 7 days after myocardial infarction induced by coronary artery ligation. 11 beta HSD1 knockout mice showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. Endogenous glucocorticoids, including those generated locally by 11 beta HSD1, exert tonic inhibition of angiogenesis. Inhibition of 11 beta HSD1 in liver and adipose has been advocated to reduce cardiovascular risk in the metabolic syndrome: these data suggest that 11 beta HSD1 inhibition offers a previously uncharacterized therapeutic approach to improve healing of ischemic or injured tissue.

引用

页码：12165 / 12170

页数：6

共 51 条

[21] Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs [J].