Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction
Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction
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DOI：
10.1016/j.jacc.2008.01.011
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发表时间：
2008-04-08
影响因子：
24
通讯作者：
Frangogiannis, Nikolaos G.
中科院分区：
文献类型：
--
作者：
Bujak, Marcin;Kweon, Hyuk Jung;Frangogiannis, Nikolaos G.
目的探讨心肌梗死(MI)后炎症反应和修复反应的增龄变化及其与心肌梗死后心脏重构的关系。背景高龄是心肌梗塞患者死亡和心室扩张的预测因子，但心肌梗死后心肌重构增加的细胞机制尚不清楚。方法比较青年和老年小鼠心肌梗死再灌注后心脏组织学、分子和超声心动图终点。结果衰老过程中中性粒细胞和巨噬细胞浸润减少和延迟，心肌梗死区细胞因子和趋化因子表达明显减少，死亡心肌细胞吞噬功能受损。衰老小鼠梗死后炎症减轻，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以及更严重的收缩功能障碍有关。从衰老小鼠心脏分离的成纤维细胞对转化生长因子-β1的反应迟钝。结论虽然青年小鼠表现出强烈的心肌梗死后炎症反应，并形成致密的胶原瘢痕，但衰老小鼠的炎症反应受到抑制，肉芽组织形成延迟，胶原沉积明显减少。这些缺陷可能导致不利的重塑。这些观察结果表明，在对再灌流心肌梗死患者的心肌梗塞后炎症反应进行靶向治疗时，需要谨慎。炎症介质的潜在伤害性可能被夸大了，因为实验结果从幼年动物推算到年长的人类患者。
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-beta 1.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.