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Inflammation Research : Official... Jan 2024Atherosclerosis, characterized by abnormal arterial lipid deposition, is an age-dependent inflammatory disease and contributes to elevated morbidity and mortality....
BACKGROUND
Atherosclerosis, characterized by abnormal arterial lipid deposition, is an age-dependent inflammatory disease and contributes to elevated morbidity and mortality. Senescent foamy macrophages are considered to be deleterious at all stages of atherosclerosis, while the underlying mechanisms remain largely unknown. In this study, we aimed to explore the senescence-related genes in macrophages diagnosis for atherosclerotic plaque progression.
METHODS
The atherosclerosis-related datasets were retrieved from the Gene Expression Omnibus (GEO) database, and cellular senescence-associated genes were acquired from the CellAge database. R package Limma was used to screen out the differentially expressed senescence-related genes (DE-SRGs), and then three machine learning algorithms were applied to determine the hub DE-SRGs. Next, we established a nomogram model to further confirm the clinical significance of hub DE-SRGs. Finally, we validated the expression of hub SRG ABI3 by Sc-RNA seq analysis and explored the underlying mechanism of ABI3 in THP-1-derived macrophages and mouse atherosclerotic lesions.
RESULTS
A total of 15 DE-SRGs were identified in macrophage-rich plaques, with five hub DE-SRGs (ABI3, CAV1, NINJ1, Nox4 and YAP1) were further screened using three machine learning algorithms. Subsequently, a nomogram predictive model confirmed the high validity of the five hub DE-SRGs for evaluating atherosclerotic plaque progression. Further, the ABI3 expression was upregulated in macrophages of advanced plaques and senescent THP-1-derived macrophages, which was consistent with the bioinformatics analysis. ABI3 knockdown abolished macrophage senescence, and the NF-κB signaling pathway contributed to ABI3-mediated macrophage senescence.
CONCLUSION
We identified five cellular senescence-associated genes for atherogenesis progression and unveiled that ABI3 might promote macrophage senescence via activation of the NF-κB pathway in atherogenesis progression, which proposes new preventive and therapeutic strategies of senolytic agents for atherosclerosis.
Topics: Animals; Mice; Atherosclerosis; Macrophages; NF-kappa B; Plaque, Atherosclerotic; Signal Transduction
PubMed: 38062164
DOI: 10.1007/s00011-023-01817-w -
Molecules (Basel, Switzerland) Aug 2023Atherosclerosis is a multifactorial, progressive, chronic inflammatory disease. Ultrasound and magnetic resonance imaging are the most accurate predictors of...
Atherosclerosis is a multifactorial, progressive, chronic inflammatory disease. Ultrasound and magnetic resonance imaging are the most accurate predictors of atherosclerotic plaque instability (MRI). Cytokines such as osteopontin, osteoprotegerin, and metalloproteinase 9 could be used as the most recent markers to identify and track the efficacy of anti-atherosclerotic therapy. Patients with USG and MRI-verified unstable atherosclerotic plaque were included in the study. Biomarker concentrations were measured and compared before and after PCSK9 inhibitor therapy. Additionally, concentrations prior to treatment were correlated with MRI images of the carotid artery. After treatment with alirocumab, the concentrations of MMP-9 ( < 0.01) and OPN, OPG ( < 0.05) decreased significantly. Furthermore, the results of OPN, OPG, and MMP 9 varied significantly depending on the type of atherosclerotic plaque in the MRI assay. In stable atherosclerotic plaques, the concentrations of OPN and OPG were greater ( < 0.01), whereas the concentration of MMP9 correlated with the instability of the plaque ( < 0.05). We demonstrated, probably for the first time, that alirocumab therapy significantly decreased the serum concentration of atherosclerotic plaque markers. In addition, we demonstrated the relationship between the type of atherosclerotic plaque as determined by carotid MRI and the concentration of these markers.
Topics: Humans; Plaque, Atherosclerotic; Proprotein Convertase 9; Atherosclerosis; Ultrasonography
PubMed: 37570897
DOI: 10.3390/molecules28155928 -
European Journal of Pharmacology Dec 2017Acute cardiovascular events, due to rupture or erosion of an atherosclerotic plaque, represent the major cause of morbidity and mortality in patients. Growing evidence... (Review)
Review
Acute cardiovascular events, due to rupture or erosion of an atherosclerotic plaque, represent the major cause of morbidity and mortality in patients. Growing evidence suggests that plaque neovascularization is an important contributor to plaque growth and instability. The vessels' immaturity, with profound structural and functional abnormalities, leads to recurrent intraplaque hemorrhage. This review discusses new insights of atherosclerotic neovascularization, including the effects of leaky neovessels on intraplaque hemorrhage, both in experimental models and humans. Furthermore, modalities for in vivo imaging and therapeutic interventions to target plaque angiogenesis will be discussed.
Topics: Animals; Hemorrhage; Humans; Molecular Imaging; Neovascularization, Pathologic; Plaque, Atherosclerotic
PubMed: 28435093
DOI: 10.1016/j.ejphar.2017.04.028 -
Current Atherosclerosis Reports Aug 2016Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification... (Review)
Review
Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification is a more active process, involving complex signaling pathways and bone-like genetic programs. Initially, imaging of atherosclerotic calcification was limited to gross assessment of calcium burden, which is associated with total atherosclerotic burden and risk of cardiovascular mortality and of all cause mortality. More recently, sophisticated molecular imaging studies of the various processes involved in calcification have begun to elucidate information about plaque calcium composition and consequent vulnerability to rupture, leading to hard cardiovascular events like myocardial infarction. As such, there has been renewed interest in imaging calcification to advance risk assessment accuracy in an evolving era of precision medicine. Here we summarize recent advances in our understanding of the biologic process of atherosclerotic calcification as well as some of the molecular imaging tools used to assess it.
Topics: Animals; Calcinosis; Humans; Molecular Imaging; Plaque, Atherosclerotic; Precision Medicine
PubMed: 27339750
DOI: 10.1007/s11883-016-0601-6 -
Cell Death & Disease May 2021Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture...
Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE) mice. Six-week IMD infusion significantly reduced atherosclerotic lesion size. Of note, IMD lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD administration prevented ERS activation in aortic lesions of ApoE mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE mice. IMD decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.
Topics: Animals; Apoptosis; Humans; Inflammasomes; Macrophages; Mice; Neuropeptides; Peptide Fragments; Plaque, Atherosclerotic
PubMed: 33934111
DOI: 10.1038/s41419-021-03712-w -
Biomedicine & Pharmacotherapy =... Jun 2021With the aging population, coronary syndrome is one of the leading causes of mortality. Atherosclerosis is the pathophysiological basis of coronary syndrome, which is...
With the aging population, coronary syndrome is one of the leading causes of mortality. Atherosclerosis is the pathophysiological basis of coronary syndrome, which is caused by plaque rupture and predisposed or aggravated by many perioperative complications. Parecoxib is one of the most widely used nonsteroidal anti-inflammatory perioperative drugs. This study aims to evaluate the potential benefits of parecoxib on atherosclerosis progression. Apolipoprotein E-deficient (Apo E-/-) mice were intraperitoneally injected by parecoxib (par group) or saline (control group) and, meanwhile, were given a western diet for 12 weeks. The aorta and aortic root were examined by oil red O (ORO) staining for atherosclerotic lesions. The expression level of matrix metalloproteinases (MMPs), was investigated using immunofluorescence and western blot. Macrophage inflammation was investigated by Q-PCR. Parecoxib treatment increased the number of vascular smooth muscle cells (VSMC) and amount of collagen, while and decreased the number of macrophages in murine aortic walls. The expression of MMP1, 2, 9, and 13 as well as IL- 1β and IL-6 were also decreased in the par group. However, there was no statistical difference in lipid infiltration between the two groups. Parecoxib could improve plaque stability by suppressing inflammation and inhibiting MMPs production.
Topics: Animals; Cells, Cultured; Cyclooxygenase 2 Inhibitors; Inflammation Mediators; Isoxazoles; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic
PubMed: 33740522
DOI: 10.1016/j.biopha.2021.111423 -
Journal of Atherosclerosis and... Jul 2016
Topics: Disease Susceptibility; Gelatinases; Humans; Plaque, Atherosclerotic; Risk Factors
PubMed: 27237102
DOI: 10.5551/jat.ED048 -
British Journal of Pharmacology Mar 2022The rupture of unstable atherosclerotic plaques is the major cause of cardiovascular mortality and morbidity. Despite significant limitations in our understanding and... (Review)
Review
The rupture of unstable atherosclerotic plaques is the major cause of cardiovascular mortality and morbidity. Despite significant limitations in our understanding and ability to identify unstable plaque pathology and prevent plaque rupture, most atherosclerosis research utilises preclinical animal models exhibiting stable atherosclerosis. Here, we introduce the tandem stenosis (TS) mouse model that reflects plaque instability and rupture, as seen in patients. The TS model involves dual ligation of the right carotid artery, leading to locally predefined unstable atherosclerosis in hypercholesterolaemic mice. It exhibits key characteristics of human unstable plaques, including plaque rupture, luminal thrombosis, intraplaque haemorrhage, large necrotic cores, thin or ruptured fibrous caps and extensive immune cell accumulation. Altogether, the TS model represents an ideal preclinical tool for improving our understanding of human plaque instability and rupture, for the development of imaging technologies to identify unstable plaques, and for the development and testing of plaque-stabilising treatments for the prevention of atherosclerotic plaque rupture. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
Topics: Animals; Atherosclerosis; Constriction, Pathologic; Disease Models, Animal; Humans; Mice; Plaque, Atherosclerotic
PubMed: 33368184
DOI: 10.1111/bph.15356 -
Journal of the American College of... May 2011Cardiovascular diseases are still the primary causes of mortality in the United States and in Western Europe. Arterial thrombosis is triggered by a ruptured... (Review)
Review
Cardiovascular diseases are still the primary causes of mortality in the United States and in Western Europe. Arterial thrombosis is triggered by a ruptured atherosclerotic plaque and precipitates an acute vascular event, which is responsible for the high mortality rate. These rupture-prone plaques are called "vulnerable plaques." During the past decades, much effort has been put toward accurately detecting the presence of vulnerable plaques with different imaging techniques. In this review, we provide an overview of the currently available invasive and noninvasive imaging modalities used to detect vulnerable plaques. We will discuss the upcoming challenges in translating these techniques into clinical practice and in assigning them their exact place in the decision-making process.
Topics: Animals; Diagnostic Imaging; Humans; Plaque, Atherosclerotic; Thrombosis; Ultrasonography, Interventional
PubMed: 21565634
DOI: 10.1016/j.jacc.2011.02.018 -
Journal of Ultrasound Sep 2022The aim of the proposed study was to conduct a feasibility study using a flat rectangular (2 × 10 mm) transducer operating at 4.0 MHz for creating thermal lesions...
PURPOSE
The aim of the proposed study was to conduct a feasibility study using a flat rectangular (2 × 10 mm) transducer operating at 4.0 MHz for creating thermal lesions in an arterial atherosclerotic plaque phantom. The proposed method can be used in the future for treating atherosclerotic plaques in human arteries.
MATERIALS AND METHODS
The flat rectangular transducer was firstly assessed in agar/silica evaporated milk phantom, polyacrylamide phantom and freshly excised turkeytissue phantom. Then, the same transducer was assessed in an arterial atherosclerotic plaque phantom which was created in the laboratory with a very low cost. The recipe of the atherosclerotic plaque phantom was 4% w/v agar, 1% w/v gypsum, 2% w/v butter and 93% water. The amount of plaque removal was evaluated visually and using an X-Ray system.
RESULTS
It was shown that the flat rectangular transducer can create thermal lesions on the agar/silica evaporated milk phantom, polyacrylamide phantom and in excised tissue. The size of the lesions matches the geometry of the transducer. Moreover, this transducer destroyed 27.1% of the atherosclerotic plaque phantom with 8 W acoustical power and 30 s duration.
CONCLUSIONS
This feasibility study demonstrated that atherosclerotic plaque can be destroyed using a very small flat rectangular (2 × 10 mm) transducer in a very small time interval of 30 s. In future clinical trials the transducer will be incorporated in a catheter which will be inserted intravascular (1-3 mm) wide and can be used to treat atherosclerotic plaques in the coronary arteries.
Topics: Agar; Coronary Vessels; Humans; Phantoms, Imaging; Plaque, Atherosclerotic; Silicon Dioxide
PubMed: 35098435
DOI: 10.1007/s40477-022-00658-3