Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome

Abstract

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.

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…However, if ERS is prolonged or too severe, the UPR may result in the activation of apoptosis [77] . SMCs synthesize most of the inter- [78] . Pedruzzi et al [79] reported that the 7-ketocholesterol (7-Kchol)-activating pathway induced an early triggering of ERS in SMCs, as assessed by transient intracellular Ca 2+ oscillations and IRE-1, JNK, and AP-1 expression.…”

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

“…During atherogenesis, a maladaptive inflammatory response is initiated by the deposition of cholesterol-rich lipoproteins in the subendothelial layer of arterial walls (6). Signs of ER stress are most prominent in the atherosclerosis-prone regions of vascular lesions, such as the branching points of arteries, and typically observed in macrophages-among other immune cells-infiltrating these regions (7,8). Chronic, irremediable ER stress triggers apoptosis in macrophages, contributing to the growth of the necrotic core Significance Endoplasmic reticulum (ER) stress is linked to the development of complex metabolic diseases, including diabetes, obesity, and atherosclerosis.…”

“…Work over the last decade has pinpointed ER stress as a driving force for atherosclerosis progression (5,(7)(8)(9)(10). For example, inhibiting the apoptotic signaling downstream of ER stress through genetic deletion of the proapoptotic transcription factor CCAAT box binding enhancer homologous protein (CHOP) or the signal transducer c-jun N-terminal kinase (JNK) blocks atherosclerosis progression (5,(11)(12)(13).…”

“…First, a profound increase in IRE1 phosphorylation and XBP1s expression is observed in atherosclerotic plaques of mice and humans (8,10). Second, mechanical sheer stresses activate IRE1, whereas cardiovascular disease risk factors, such as oxidized phospholipids and homocysteine, induce both IRE1 and PERK (5,(25)(26)(27)(28)(29).…”

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

“…7 In advanced atherosclerotic plaques, the presence of oxidized lipids, inflammation, and metabolic stress induces ER stress and activates UPR. 8 ER stress is also related to cardiac damage and vascular endothelial dysfunction in angiotensin II (Ang II)-induced hypertension. 9 Whether ER stress and UPR are causal to defects of cardiovascular phenotypes under the disease conditions, however, are not fully understood.…”