RAGE and modulation of ischemic injury in the diabetic myocardium.
RAGE and modulation of ischemic injury in the diabetic myocardium.
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DOI：
10.2337/db07-0326
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发表时间：
2008-07
期刊：
影响因子：
7.7
通讯作者：
Ramasamy R
中科院分区：
文献类型：
--
作者：
Bucciarelli LG;Ananthakrishnan R;Hwang YC;Kaneko M;Song F;Sell DR;Strauch C;Monnier VM;Yan SF;Schmidt AM;Ramasamy R
目的：与年龄匹配的非糖尿病患者相比，糖尿病患者发生心肌梗死和心力衰竭的风险增加。晚期糖基化终产物受体(RAGE)在糖尿病组织中上调。在本研究中，我们验证了RAGE影响糖尿病心肌缺血/再灌注(I/R)损伤的假说。在糖尿病大鼠心脏，RAGE及其配体的表达增强，并定位于内皮细胞和单核巨噬细胞。研究设计和方法-用链脲佐菌素诱导糖尿病模型，具体分析RAGE、RAGE纯合子缺失小鼠和表达胞浆结构域缺失RAGE(DNRAGE)的转基因(TG)小鼠的影响。结果：RAGE基因缺失的糖尿病小鼠显著免受心脏I/R损伤的不利影响，表现为LDH和低糖氧化产物羧甲基赖氨酸(CML)和戊糖苷的释放减少，功能恢复改善，ATP增加。在内皮细胞或单核巨噬细胞表达DNRAGE的糖尿病TG小鼠，心肌组织中缺血损伤和慢性粒细胞白血病的标志物显著减少，而心肌组织中的ATP水平显著升高。此外，与野生型糖尿病小鼠相比，糖尿病RAGE修饰小鼠的心脏细胞凋亡的关键标志caspase-3活性和细胞色素c释放减少。结论：这些发现表明RAGE在糖尿病心脏I/R损伤中起着新的和关键的作用。
OBJECTIVE—Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues. In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes. RESEARCH DESIGN AND METHODS—To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R. RESULTS—Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R. CONCLUSIONS—These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart.
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影响因子：
20.1
作者：
Kubota, T;McTiernan, CF;Feldman, AM
通讯作者：
Feldman, AM
影响因子：
15.9
作者：
Harja, Evis;Bu, De-Xiu;Schmidt, Ann Marie
通讯作者：
Schmidt, Ann Marie
影响因子：
4.8
作者：
JAFFE, AS;SPADARO, JJ;SOBEL, BE
通讯作者：
SOBEL, BE
影响因子：
11.1
作者：
LEHTO, S;PYORALA, K;LAAKSO, M
通讯作者：
LAAKSO, M
影响因子：
7.7
作者：
Marfella, R;Di Filippo, C;D'Amico, M
通讯作者：
D'Amico, M