Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Canada.
Circ Res. 2010 Jan 8;106(1):93-101. doi: 10.1161/CIRCRESAHA.109.195834. Epub 2009 Nov 12.
Post-myocardial infarction ventricular remodeling is associated with the expression of a variety of factors including S100B that can potentially modulate myocyte apoptosis.
This study was undertaken to investigate the expression and function of S100B and its receptor, the receptor for advanced glycation end products (RAGE) in both postinfarction myocardium and in a rat neonatal myocyte culture model.
In a rat model of myocardial infarction following coronary artery ligation, we demonstrate in periinfarct myocytes, upregulation of RAGE, induction of S100B, and release into plasma with consequent myocyte apoptosis. Using a coimmunoprecipitation strategy, we demonstrate a direct interaction between S100B and RAGE. In rat neonatal cardiac myocyte cultures, S100B at concentrations > or = 50 nmol/L induced myocyte apoptosis, as evidenced by increased terminal DNA fragmentation, TUNEL, cytochrome c release from mitochondria to cytoplasm, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p53, increased expression and activity of proapoptotic caspase-3, and decreased expression of antiapoptotic Bcl-2. Transfection of a full-length cDNA of RAGE or a dominant-negative mutant of RAGE resulted in increased or attenuated S100B-induced myocyte apoptosis, respectively. Inhibition of ERK1/2 by U0126/PD-98059 or overexpression of a dominant negative p53 comparably inhibited S100B-induced myocyte apoptosis.
These results suggest that interaction of RAGE and its ligand S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53 signaling. This receptor-mediated mechanism is uniquely amenable to therapeutic intervention.
心肌梗死后心室重构与多种因子的表达有关，包括 S100B，它可能调节心肌细胞凋亡。
本研究旨在探讨 S100B 及其受体，即晚期糖基化终产物受体（RAGE）在心肌梗死后和大鼠乳鼠心肌细胞培养模型中的表达和功能。
在冠状动脉结扎后的大鼠心肌梗死模型中，我们在梗死周边心肌细胞中观察到 RAGE 的上调、S100B 的诱导以及随之而来的血浆中 S100B 的释放和随后的心肌细胞凋亡。通过共免疫沉淀策略，我们证明了 S100B 和 RAGE 之间存在直接相互作用。在大鼠乳鼠心肌细胞培养中，浓度≥50 nmol/L 的 S100B 诱导心肌细胞凋亡，表现为末端 DNA 片段化增加、TUNEL、线粒体细胞色素 c 释放到细胞质、细胞外信号调节激酶（ERK）1/2 和 p53 的磷酸化、促凋亡 caspase-3 的表达和活性增加，以及抗凋亡 Bcl-2 的表达减少。RAGE 的全长 cDNA 转染或 RAGE 的显性失活突变转染分别导致 S100B 诱导的心肌细胞凋亡增加或减弱。U0126/PD-98059 抑制 ERK1/2 或过表达显性失活 p53 均可抑制 S100B 诱导的心肌细胞凋亡。
这些结果表明，心肌梗死后 RAGE 与其配体 S100B 的相互作用可能通过激活 ERK1/2 和 p53 信号通路在心肌细胞凋亡中发挥作用。这种受体介导的机制特别适合于治疗干预。
