Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction - Possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis
Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction - Possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis
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DOI：
10.1161/01.cir.0000137836.95625.d4
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发表时间：
2004-08-10
期刊：
影响因子：
37.8
通讯作者：
Kitakaze, M
中科院分区：
文献类型：
--
作者：
Okada, K;Minamino, T;Kitakaze, M
背景-内质网（ER）被认为是参与折叠分泌蛋白和膜蛋白的细胞器。内质网通过上调内质网伴侣来应对应激，但长期和/或过度的内质网应激会导致细胞凋亡。然而，内质网应激在心脏病理生理学中的潜在作用仍不清楚。方法和结果-对小鼠进行横主动脉缩窄术(TAC)或假手术。超声心动图分析表明，TAC 后 1 周和 4 周的小鼠分别出现心脏肥大和衰竭。 TAC 后 1 周和 4 周，心脏中 ER 伴侣的表达显着增加，表明 TAC 造成的压力超负荷导致了长时间的 ER 应激。此外，末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记 (TUNEL) 阳性细胞的数量增加，并且在衰竭心脏中 caspase-3 被裂解。血管紧张素 II 1 型受体的拮抗作用可防止 ER 伴侣的上调和衰竭心脏中的细胞凋亡。另一方面，血管紧张素 II 上调 ER 伴侣并诱导培养的成年大鼠心肌细胞凋亡。我们还研究了 ER 引发的细胞凋亡的可能信号通路。 TAC 在衰竭的心脏中激活了 CHOP（一种由 ER 应激诱导的转录因子）依赖性途径，但不激活 JNK 或 caspase-12 依赖性途径。药理学 ER 应激诱导剂上调 ER 伴侣并诱导培养的心肌细胞凋亡。最后，在脑钠肽水平升高的衰竭心脏中，ER 伴侣的 mRNA 水平显着增加。结论 - 这些发现表明，TAC 的压力超负荷会诱导延长的 ER 应激，这可能导致心肌肥大到衰竭进展过程中的心肌细胞凋亡。
Background-The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear.Methods and Results-Mice were subjected to transverse aortic constriction (TAC) or sham operation. Echocardiographic analysis demonstrated that mice 1 and 4 weeks after TAC had cardiac hypertrophy and failure, respectively. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after TAC, indicating that pressure overload by TAC induced prolonged ER stress. In addition, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells increased, and caspase-3 was cleaved in failing hearts. The antagonism of angiotensin II type 1 receptor prevented upregulation of ER chaperones and apoptosis in failing hearts. On the other hand, angiotensin II upregulated ER chaperones and induced apoptosis in cultured adult rat cardiac myocytes. We also investigated possible signaling pathways for ER-initiated apoptosis. The CHOP-(a transcription factor induced by ER stress), but not JNK- or caspase-12-, dependent pathway was activated in failing hearts by TAC. Pharmacological ER stress inducers upregulated ER chaperones and induced apoptosis in cultured cardiac myocytes. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients with elevated brain natriuretic peptide levels.Conclusions-These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure.