在再灌注心肌梗死小鼠模型中，衰老相关缺陷与不良心脏重塑有关。
Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction.
作者信息
Bujak Marcin, Kweon Hyuk Jung, Chatila Khaled, Li Na, Taffet George, Frangogiannis Nikolaos G
机构信息
Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, Texas 77030, USA.
出版信息
J Am Coll Cardiol. 2008 Apr 8;51(14):1384-92. doi: 10.1016/j.jacc.2008.01.011.
OBJECTIVES
The purpose of this study was to study aging-associated alterations in the inflammatory and reparative response after myocardial infarction (MI) and their involvement in adverse post-infarction remodeling of the senescent heart.
BACKGROUND
Advanced age is a predictor of death and ventricular dilation in patients with MI; however, the cellular mechanisms responsible for increased remodeling of the infarcted senescent heart remain poorly understood.
METHODS
Histomorphometric, molecular, and echocardiographic end points were compared between young and senescent mice undergoing reperfused infarction protocols. The response of young and senescent mouse cardiac fibroblasts to transforming growth factor (TGF)-beta stimulation was examined.
RESULTS
Senescence was associated with decreased and delayed neutrophil and macrophage infiltration, markedly reduced cytokine and chemokine expression in the infarcted myocardium, and impaired phagocytosis of dead cardiomyocytes. Reduced inflammation in senescent mouse infarcts was followed by decreased myofibroblast density and markedly diminished collagen deposition in the scar. The healing defects in senescent animals were associated with enhanced dilative and hypertrophic remodeling and worse systolic dysfunction. Fibroblasts isolated from senescent mouse hearts showed a blunted response to TGF-beta1.
CONCLUSIONS
Although young mice exhibit a robust post-infarction inflammatory response and form dense collagenous scars, senescent mice show suppressed inflammation, delayed granulation tissue formation, and markedly reduced collagen deposition. These defects might contribute to adverse remodeling. These observations suggest that caution is necessary when attempting to therapeutically target the post-infarction inflammatory response in patients with reperfused MI. The injurious potential of inflammatory mediators might have been overstated, owing to extrapolation of experimental findings from young animals to older human patients.
目的
本研究旨在探讨心肌梗死（MI）后炎症和修复反应中与衰老相关的变化，以及它们在衰老心脏梗死后期不良重塑中的作用。
背景
高龄是MI患者死亡和心室扩张的预测因素；然而，导致梗死衰老心脏重塑增加的细胞机制仍知之甚少。
方法
比较接受再灌注梗死方案的年轻和衰老小鼠的组织形态计量学、分子和超声心动图终点。检测年轻和衰老小鼠心脏成纤维细胞对转化生长因子（TGF）-β刺激的反应。
结果
衰老与中性粒细胞和巨噬细胞浸润减少及延迟、梗死心肌中细胞因子和趋化因子表达显著降低、死亡心肌细胞吞噬功能受损有关。衰老小鼠梗死灶炎症减轻后，肌成纤维细胞密度降低，瘢痕中胶原沉积明显减少。衰老动物的愈合缺陷与扩张性和肥厚性重塑增强及收缩功能障碍加重有关。从衰老小鼠心脏分离的成纤维细胞对TGF-β1的反应减弱。
结论
尽管年轻小鼠在梗死后表现出强烈的炎症反应并形成致密的胶原瘢痕，但衰老小鼠表现出炎症抑制、肉芽组织形成延迟和胶原沉积明显减少。这些缺陷可能导致不良重塑。这些观察结果表明，在试图对再灌注MI患者的梗死后炎症反应进行治疗性靶向时，必须谨慎。由于将年轻动物的实验结果外推至老年人类患者，炎症介质的有害潜力可能被高估了。
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