scholarly journals Protective Functions of Liver X Receptor α in Established Vulnerable Plaques: Involvement of Regulating Endoplasmic Reticulum–Mediated Macrophage Apoptosis and Efferocytosis

2021 ◽  
Author(s):  
Xinyu Che ◽  
Qingqing Xiao ◽  
Wei Song ◽  
Hengyuan Zhang ◽  
Beibei Sun ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Apolipoprotein E ◽  
Plaque Rupture ◽  
Liver X Receptor ◽  
Intraplaque Hemorrhage ◽  
Vehicle Group ◽  
Lesion Volume ◽  
Genetic Ablation ◽  
Vulnerable Plaques

Background Liver X receptor (LXR) belongs to the metabolic nuclear receptor superfamily, which plays a critical regulatory role in vascular physiology/pathology. However, effects of systemic LXR activation on established vulnerable plaques and the potential isotype‐specific role involved remain unclear. Methods and Results The 8‐week‐old male apolipoprotein E −/− mice went through carotid branch ligation and renal artery constriction, combined with a high‐fat diet. Plaques in the left carotid artery acquired vulnerable features 4 weeks later, confirmed by magnetic resonance imaging scans and histological analysis. From that time on, mice were injected intraperitoneally daily with PBS or GW3965 (10 mg/kg per day) for an additional 4 weeks. Treatment with LXR agonists reduced the lesion volume by 52.61%, compared with the vehicle group. More important, a profile of less intraplaque hemorrhage detection and necrotic core formation was found. These actions collectively attenuated the incidence of plaque rupture. Mechanistically, reduced lesional apoptosis, enhanced efferocytosis, and alleviated endoplasmic reticulum stress are involved in the process. Furthermore, genetic ablation of LXRα, but not LXRβ, blunted the protective effects of LXR on the endoplasmic reticulum stress–elicited C/EBP‐homologous protein pathway in peritoneal macrophages. In concert with the LXRα‐predominant role in vitro, activated LXR failed to stabilize vulnerable plaques and correct the acquired cellular anomalies in LXRα −/− apolipoprotein E −/− mice. Conclusions Our results revealed that LXRα mediates the capacity of LXR activation to stabilize vulnerable plaques and prevent plaque rupture via amelioration of macrophage endoplasmic reticulum stress, lesional apoptosis, and defective efferocytosis. These findings might expand the application scenarios of LXR therapeutics for atherosclerosis.

Influence of Microcalcifications on Stress Development Within a Vulnerable Plaque’s Cap

2011 ◽  
Author(s):  
Ze’ev Aronis ◽  
Erez Kanka ◽  
Eyass Massarwa ◽  
Rami Haj-Ali ◽  
Shmuel Einav
Keyword(s):  
Mechanical Characteristics ◽  
Plaque Rupture ◽  
Intraplaque Hemorrhage ◽  
Rapid Progression ◽  
Stress Concentrations ◽  
Coronary Syndrome ◽  
Vulnerable Plaques ◽  
Material Fatigue ◽  
Mechanical Factors ◽  
As Stress

Vulnerable plaques are inflamed, active, and growing lesions which are prone to complications such as rupture, luminal and mural thrombosis, intraplaque hemorrhage, and rapid progression to stenosis. Despite major advances in the prevention and treatment of this disease, it remains the leading cause of morbidity and mortality worldwide, accounting for 30% of all deaths globally [1]. The importance of stress/strain distribution is now well recognized in vascular pathophysiology, specifically in the mechanisms of plaque rupture. Finite element modeling (FEM) and advanced fluid structure interaction (FSI) studies can better characterize coronary stenosis coupling constitutive equations. Mechanical factors such as stress concentrations within a plaque (material fatigue), lesion characteristic (location, size, and composition), and flow patterns are involved in rupture of plaques. Assessment of local mechanical characteristics caused by plaque structure is important for identifying vulnerable plaques and may improve final estimation of the risk for coronary syndrome.

scholarly journals Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

2015 ◽  
Vol 291 (3) ◽  
pp. 1115-1122 ◽  
Author(s):  
Xiaowei Sun ◽  
Mary E. Haas ◽  
Ji Miao ◽  
Abhiruchi Mehta ◽  
Mark J. Graham ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Liver X Receptor

Stress Concentrations of Vulnerable Plaques With a Composite Variable Core

2010 ◽  
Author(s):  
Eyass Massarwa ◽  
Aronis Ze’ev ◽  
Rami Eliasy ◽  
Rami Haj-Ali ◽  
Shmuel Einav
Keyword(s):  
Plaque Rupture ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Plaque Morphology ◽  
Rapid Progression ◽  
Stress Concentrations ◽  
Coronary Syndrome ◽  
Fibrous Cap ◽  
Vulnerable Plaques ◽  
Life Threatening

Vulnerable plaques are inflamed, active, and growing lesions which are prone to complications such as rupture, luminal and mural thrombosis, intraplaque hemorrhage, and rapid progression to stenosis. It remains difficult to assess what factors influence the biomechanical stability of vulnerable plaques and promote some of them to rupture while others remain intact. The rupture of thin fibrous cap overlying the necrotic core of a vulnerable plaque is the principal cause of acute coronary syndrome. The mechanism or mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to a life threatening athero-thrombotic lesion are not fully understood. It has been widely assumed that plaque morphology is the major determinant of clinical outcome [1, 2]. Thin-cap fibroatheroma with a large necrotic core and a fibrous cap of < 65μm was describes as a more specific precursor of plaque rupture due to tissue stress.

scholarly journals An Inhibitor of Grp94 Inhibits OxLDL-Induced Autophagy and Apoptosis in VECs and Stabilized Atherosclerotic Plaques

2021 ◽  
Vol 8 ◽  
Author(s):  
Qun Wei ◽  
Hui Ren ◽  
Jun Zhang ◽  
Wen Yao ◽  
Baoxiang Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endothelial Cell ◽  
Endoplasmic Reticulum Stress ◽  
Apolipoprotein E ◽  
Atherosclerotic Plaque ◽  
Vascular Endothelial Cell ◽  
Atherosclerotic Lesion ◽  
Vascular Endothelial ◽  
Inflammatory Macrophages

Background: Oxidized low-density lipoprotein (oxLDL) induces vascular endothelial cell (VEC) injury and atherosclerosis through activating endoplasmic reticulum stress. Expression of glucose-regulated protein 94 (Grp94) is induced by endoplasmic reticulum stress and Grp94 is involved in cardiovascular diseases. This study aimed to determine the role of Grp94 in oxLDL-induced vascular endothelial cell injury and atherosclerosis.Methods and Results: An inhibitor of Grp94, HCP1, was used to investigate the role of Grp94 in oxLDL-induced VEC injury in human umbilical vein endothelial cells and atherosclerosis in apolipoprotein E−/− mice. Results showed that HCP1 inhibited autophagy and apoptosis induced by oxLDL in VECs. And we found that Grp94 might interact with adenosine monophosphate-activated protein kinase (AMPK) and activate its activity. HCP1 inhibited AMPK activity and overexpression of Grp94 blocked the effect of HCP1. Besides, HCP1 activated the activity of mechanistic target of rapamycin complex 1 (mTORC1), co-treatment with AMPK activator acadesine eliminated the effect of HCP1 on mTORC1 activity as well as autophagy. In apolipoprotein E−/− mice, HCP1 suppressed autophagy and apoptosis of atherosclerotic plaque endothelium. In addition, HCP1 increased the content of collagen, smooth muscle cells, and anti-inflammatory macrophages while reducing the activity of MMP-2/9 and pro-inflammatory macrophages in the atherosclerotic lesion.Conclusion: HCP1 inhibited oxLDL-induced VEC injury and promoted the stabilization of atherosclerotic plaque in apoE−/− mice. Grp94 might be a potential therapeutic target in the clinical treatment of atherosclerosis.

Abstract 38: Endoplasmic Reticulum Stress Pathway-mediated Apoptosis is Involved in Ang II Induced Abdominal Aortic Aneurysm

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Yanwen Qin ◽  
Xu Cao ◽  
Ou Liu ◽  
Huihua Li ◽  
Hongjia Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Apolipoprotein E ◽  
Er Stress ◽  
Aortic Aneurysms ◽  
Aortic Diameter ◽  
Ang Ii ◽  
Caspase 12 ◽  
Abdominal Aortic ◽  
Deficient Mice

Backgroud— Abdominal aortic aneurysms (AAA) represent a unique and dramatic example of vessel wall remodeling characterized by degeneration of the elastic media. Apoptosis of vascular smooth muscle cells plays an important role in the pathogenesis of AAA. However, the potential mechanism remains poorly understood. Endoplasmic reticulum stress (ER stress)-induced apoptosis has been proved to be one of the important pathogenesis of cardiovascular disease. However, whether ER stress is involved in AAA is still not known. We assessed the hypothesis that ER-associated apoptosis is involved in Angiotensin II (Ang II)-induced AAA in apolipoprotein E-deficient mice. Methods and Results— Mice were infused with Ang II (1000 ng/kg per minute) with or without ER stress inhibitor (taurine-conjugated ursodeoxycholic acid) for 4 weeks. Mice infused with Ang II displayed an increase in aortic diameter. Detection of apoptosis was performed with the TUNEL assay. We performed Western blot and Real-time PCR to analyze indicators of ER molecule chaperone and ER-associated apoptosis. Glucose Regulated Proteins 78 and 94 (GRP78/BiP and GRP94), the ER chaperone, were up-regulated significantly in AAA compared to control. Furthermore, the hallmarks of ER-associated apoptosis, C/EBP homologous protein (CHOP), caspase-12 and PERK-eIF2-ATF4 signaling pathway were found to have activated in the AAA. The inhibition of ER stress significantly decreased maximal aortic diameter by 31% and abdominal aortic weight by 35% ( P <0.05, respectively). ER stress inhibitor also reduced GRP 78, CHOP and caspase-12 expression ( P <0.05, respectively). Taken together, these results suggested that apoptosis induced by ER stress may contribute to the development of AAA. Conclusions— ER stress response is involved in the pathogenesis of Ang II induced AAA in apolipoprotein E-deficient mice. ER stress inhibition attenuates AAA formation during Ang II infusion in apolipoprotein E-deficient mice. Therefore, ER stress could be a potential target for AAA.

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