p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload
p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload
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DOI：
10.1016/j.yjmcc.2015.06.001
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发表时间：
2015-08-01
影响因子：
5
通讯作者：
Minamino, Tohru
中科院分区：
文献类型：
--
作者：
Yoshida, Yohko;Shimizu, Ippei;Minamino, Tohru
严重心力衰竭导致的死亡率和残疾率仍然高得令人无法接受。有证据表明，无菌炎症反应在衰竭心脏的心脏重塑进展中发挥着关键作用。 p53 信号通路与心力衰竭有关，但 p53 与衰竭心脏炎症之间的病理联系在很大程度上尚不清楚。在这里，我们证明了 p53 诱导的炎症在心力衰竭中的关键作用。压力超负荷时，心脏内皮细胞和骨髓细胞中 p53 的表达增加，导致内皮细胞的细胞间粘附分子 1 (ICAM1) 表达上调，骨髓细胞的整合素表达上调。内皮细胞或骨髓细胞中 p53 的缺失分别显着降低了 ICAM1 或整合素的表达，并减少了心脏炎症并改善了压力超负荷期间的收缩功能障碍。相反，骨髓细胞中 p53 的过度表达会导致整合素表达增加和心脏炎症，从而降低收缩功能。去甲肾上腺素显着增加内皮细胞和巨噬细胞中p53的表达。减少内皮细胞或骨髓细胞中β(2)-肾上腺素能受体的表达可减轻心脏炎症并改善压力超负荷期间的收缩功能障碍。这些结果表明，交感神经系统的激活通过 p53 信号传导上调 ICAM1 和整合素表达，从而加剧心脏功能障碍，从而促进心脏炎症。抑制p53诱导的炎症可能是心力衰竭的一种新的治疗策略。 (C) 2015 Elsevier Ltd. 保留所有权利。
The rates of death and disability caused by severe heart failure are still unacceptably high. There is evidence that the sterile inflammatory response has a critical role in the progression of cardiac remodeling in the failing heart. The p53 signaling pathway has been implicated in heart failure, but the pathological link between p53 and inflammation in the failing heart is largely unknown. Here we demonstrate a critical role of p53-induced inflammation in heart failure. Expression of p53 was increased in cardiac endothelial cells and bone marrow cells in response to pressure overload, leading to up-regulation of intercellular adhesion molecule-1 (ICAM1) expression by endothelial cells and integrin expression by bone marrow cells. Deletion of p53 from endothelial cells or bone marrow cells significantly reduced ICAM1 or integrin expression, respectively, as well as decreasing cardiac inflammation and ameliorating systolic dysfunction during pressure overload. Conversely, overexpression of p53 in bone marrow cells led to an increase of integrin expression and cardiac inflammation that reduced systolic function. Norepinephrine markedly increased p53 expression in endothelial cells and macrophages. Reducing beta(2)-adrenergic receptor expression in endothelial cells or bone marrow cells attenuated cardiac inflammation and improved systolic dysfunction during pressure overload. These results suggest that activation of the sympathetic nervous system promotes cardiac inflammation by up-regulating ICAM1 and integrin expression via p53 signaling to exacerbate cardiac dysfunction. Inhibition of p53-induced inflammation may be a novel therapeutic strategy for heart failure. (C) 2015 Elsevier Ltd. All rights reserved.