Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome
Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome
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DOI：
10.1161/circulationaha.106.682054
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发表时间：
2007-09-11
期刊：
影响因子：
37.8
通讯作者：
Kitakaze, Masafumi
中科院分区：
文献类型：
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作者：
Myoishi, Masafumi;Hao, Hiroyuki;Kitakaze, Masafumi
背景 - 内质网 (ER) 通过上调 ER 伴侣来响应各种应激，但长期的 ER 应激最终会导致细胞凋亡。尽管细胞凋亡被认为对于动脉粥样硬化斑块的进展和破裂至关重要，但内质网应激和细胞凋亡对不稳定冠状动脉斑块破裂的影响仍不清楚。方法和结果 - 尸检时获得 71 名患者的冠状动脉段，并从 40 名患者获得斑块切除标本。薄帽粥样斑块和破裂斑块的纤维帽中的平滑肌细胞和巨噬细胞，而不是厚帽粥样斑块的纤维帽中的平滑肌细胞和巨噬细胞，显示出ER伴侣蛋白表达和凋亡细胞的显着增加。 ER 伴侣在不稳定型心绞痛患者的斑块切除标本中也表现出比稳定型心绞痛患者的标本更高的表达。与厚帽粥样斑块相比，薄帽动脉粥样硬化纤维帽中 7-酮胆固醇的表达增加。用 7-酮胆固醇处理培养的冠状动脉平滑肌细胞或 THP-1 细胞会诱导 ER 伴侣的上调和细胞凋亡，而抗氧化剂可以阻止这些变化。我们还研究了 ER 引发的细胞凋亡的可能信号通路，发现 CHOP（ER 应激诱导的转录因子）依赖性通路在不稳定斑块中被激活。此外，通过小干扰RNA敲低CHOP表达可减少培养的冠状动脉平滑肌细胞和THP-1细胞的内质网应激依赖性死亡。结论 - 不稳定斑块中发生内质网应激增加。我们的研究结果表明，内质网应激诱导的平滑肌细胞和巨噬细胞凋亡可能导致斑块脆弱性。
Background - The endoplasmic reticulum ( ER) responds to various stresses by upregulation of ER chaperones, but prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear. Methods and Results - Coronary artery segments were obtained at autopsy from 71 patients, and atherectomy specimens were obtained from 40 patients. Smooth muscle cells and macrophages in the fibrous caps of thin-cap atheroma and ruptured plaques, but not in the fibrous caps of thick-cap atheroma and fibrous plaques, showed a marked increase of ER chaperone expression and apoptotic cells. ER chaperones also showed higher expression in atherectomy specimens from patients with unstable angina pectoris than in specimens from those with stable angina. Expression of 7-ketocholesterol was increased in the fibrous caps of thin-cap atheroma compared with thick-cap atheroma. Treatment of cultured coronary artery smooth muscle cells or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, whereas these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP ( a transcription factor induced by ER stress)- dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by small interfering RNA decreased ER stress-dependent death of cultured coronary artery smooth muscle cells and THP-1 cells. Conclusions - Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of smooth muscle cells and macrophages may contribute to plaque vulnerability.