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Molecular Medicine Reports Aug 2024Atherosclerosis (AS) is a chronic inflammatory disease caused by the deposition of lipoproteins and sequent immune responses. Within the atherosclerotic plaque,... (Review)
Review
Atherosclerosis (AS) is a chronic inflammatory disease caused by the deposition of lipoproteins and sequent immune responses. Within the atherosclerotic plaque, macrophages are the most abundant immune cells and play a great part as protagonists and promoters of AS. In the past decade, the concept of 'trained immunity' has emerged, which highlights the memory characteristics of innate immunity, thus opening up a new avenue of research. Evidence suggests that trained immunity may regulate the onset and progression of AS with trained macrophages playing an important and dynamic role in atherogenesis. The present review provided a summary of concepts related to trained immunity and its relationship with AS. Furthermore, different phenotypes of macrophages responding to various stimuli within the atherosclerotic plaque were presented, along with the complex mechanisms of metabolic and epigenetic reprogramming in the cells. Finally, several promising therapeutic approaches for AS cardiovascular disease were discussed, which may shed light on new clinical strategies.
Topics: Atherosclerosis; Humans; Epigenesis, Genetic; Macrophages; Animals; Immunity, Innate; Plaque, Atherosclerotic
PubMed: 38904193
DOI: 10.3892/mmr.2024.13269 -
International Journal of Biological... 2024Shear stress-induced Dickkopf-1 (DKK1) secretion by endothelial cells (ECs) promotes EC dysfunction and accelerates atherosclerosis (AS). However, the paracrine role of...
Shear stress-induced Dickkopf-1 (DKK1) secretion by endothelial cells (ECs) promotes EC dysfunction and accelerates atherosclerosis (AS). However, the paracrine role of endothelial DKK1 in modulating adjacent smooth muscle cells (SMCs) in atherosclerosis remains unclear. This study investigated the role of EC-secreted DKK1 in SMC-derived foam cell formation under shear stress, and . Parallel-plate co-culture flow system was used to explore the cellular communication between ECs and SMCs under shear stress . Endothelium-specific knockout of DKK1 (DKK1/APOE) and endothelium-specific overexpression of DKK1 (DKK1) mice were constructed to investigate the role of endothelial DKK1 in atherosclerosis and SMC-derived foam cell formation . RNA sequencing (RNA-seq) was used to identify the downstream targets of DKK1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot, coimmunoprecipitation (Co-IP) assays and chromatin immunoprecipitation (ChIP) experiments were conducted to explore the underlying regulatory mechanisms. DKK1 is transcriptionally upregulated in ECs under conditions of low shear stress, but not in co-cultured SMCs. However, DKK1 protein in co-cultured SMCs is increased via uptake of low shear stress-induced endothelial DKK1, thereby promoting lipid uptake and foam cell formation in co-cultured SMCs via the post-translational upregulation of scavenger receptor-A (SR-A) verified in parallel-plate co-culture flow system, DKK1 and DKK1 mice. RNA sequencing revealed that DKK1-induced SR-A upregulation in SMCs is dependent on Ubiquitin-specific Protease 53 (USP53), which bound to SR-A via its USP domain and cysteine at position 41, exerting deubiquitination to maintain the stability of the SR-A protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby mediating the effect of DKK1 on lipid uptake in SMCs. Moreover, DKK1 regulates the transcription of USP53 by facilitating the binding of transcription factor CREB to the USP53 promoter. SMC-specific overexpression of USP53 via adeno-associated virus serotype 2 vectors in DKK1/APOE mice reversed the alleviation of atherosclerotic plaque burden, SR-A expression and lipid accumulation in SMCs within plaques resulting from DKK1 deficiency. Our findings demonstrate that, endothelial DKK1, induced by pathological low shear stress, acts as an intercellular mediator, promoted the foam cell formation of SMCs. These results suggest that targeted intervention with endothelial DKK1 may confer beneficial effects on atherosclerosis.
Topics: Animals; Atherosclerosis; Mice; Intercellular Signaling Peptides and Proteins; Foam Cells; Myocytes, Smooth Muscle; Endothelial Cells; Humans; Ubiquitination; Male; Coculture Techniques; Mice, Knockout; Ubiquitin-Specific Proteases; Mice, Inbred C57BL
PubMed: 38904030
DOI: 10.7150/ijbs.91957 -
International Journal of Pharmaceutics Jun 2024Atherosclerosis is a chronic multifactorial cardiovascular disease. To combat atherosclerosis effectively, it is necessary to develop precision and targeted therapy in...
Atherosclerosis is a chronic multifactorial cardiovascular disease. To combat atherosclerosis effectively, it is necessary to develop precision and targeted therapy in the early stages of plaque formation. In this study, a simvastatin (SV)-containing prodrug micelle SPCPV was developed by incorporating a peroxalate ester bond (PO). SPCPV could specifically target VCAM-1 overexpressed at atherosclerotic lesions. SPCPV contains a carrier (CP) composed of cyclodextrin (CD) and polyethylene glycol (PEG). At the lesions, CP and SV exerted multifaceted anti-atherosclerotic effects. In vitro studies demonstrated that intracellular reactive oxygen species (ROS) could induce the release of SV from SPCPV. The uptake of SPCPV was higher in inflammatory cells than in normal cells. Furthermore, in vitro experiments showed that SPCPV effectively reduced ROS levels, possessed anti-inflammatory properties, inhibited foam cell formation, and promoted cholesterol efflux. In vivo studies using atherosclerotic rats showed that SPCPV reduced the thickness of the vascular wall and low-density lipoprotein (LDL). This study developed a drug delivery strategy that could target atherosclerotic plaques and treat atherosclerosis by integrating the carrier with SV. The findings demonstrated that SPCPV possessed high stability and safety and had great therapeutic potential for treating early-stage atherosclerosis.
PubMed: 38901540
DOI: 10.1016/j.ijpharm.2024.124352 -
Nature Nanotechnology Jun 2024The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being...
The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being major drivers of plaque progression. Nanotherapeutics that can resolve inflammation and scavenge ROS have the potential to treat atherosclerosis. Here we demonstrate the potential of black phosphorus nanosheets (BPNSs) as a therapeutic agent for the treatment of atherosclerosis. BPNSs can effectively scavenge a broad spectrum of ROS and suppress atherosclerosis-associated pro-inflammatory cytokine production in lesional macrophages. We also demonstrate ROS-responsive, targeted-peptide-modified BPNS-based carriers for the delivery of resolvin D1 (an inflammation-resolving lipid mediator) to lesional macrophages, which further boosts the anti-atherosclerotic efficacy. The targeted nanotherapeutics not only reduce plaque areas but also substantially improve plaque stability in high-fat-diet-fed apolipoprotein E-deficient mice. This study presents a therapeutic strategy against atherosclerosis, and highlights the potential of BPNS-based therapeutics to treat other inflammatory diseases.
PubMed: 38898135
DOI: 10.1038/s41565-024-01687-1 -
Journal of the American College of... Jun 2024Some autoimmune diseases carry elevated risk for atherosclerotic cardiovascular disease (ASCVD), yet the underlying mechanism and the influence of traditional risk...
BACKGROUND
Some autoimmune diseases carry elevated risk for atherosclerotic cardiovascular disease (ASCVD), yet the underlying mechanism and the influence of traditional risk factors remain unclear.
OBJECTIVES
This study sought to determine whether autoimmune diseases independently correlate with coronary atherosclerosis and ASCVD risk and whether traditional cardiovascular risk factors modulate the risk.
METHODS
The study included 85,512 patients from the Western Denmark Heart Registry undergoing coronary computed tomography angiography. A diagnosis of 1 of 18 autoimmune diseases was assessed. Adjusted OR (aOR) for any plaque, any coronary artery calcification (CAC), CAC of >90th percentile, and obstructive coronary artery disease as well as adjusted HR (aHR) for ASCVD were calculated.
RESULTS
During 5.3 years (Q1-Q3: 2.8-8.2 years) of follow-up, 3,832 ASCVD events occurred. A total of 4,064 patients had a diagnosis of autoimmune disease, which was associated with both presence of any plaque (aOR: 1.29; 95% CI: 1.20-1.40), any CAC (aOR: 1.28; 95% CI: 1.19-1.37), and severe CAC of >90th percentile (aOR: 1.53; 95% CI: 1.39-1.68), but not with having obstructive coronary artery disease (aOR: 1.04; 95% CI: 0.91-1.17). Patients with autoimmune diseases had a 46% higher risk (aHR: 1.46; 95% CI: 1.29-1.65) for ASCVD. Traditional cardiovascular risk factors were strongly associated with future ASCVD events, and a favorable cardiovascular risk factor profile in autoimmune patients was associated with ∼54% lower risk compared to patients with presence of risk factors (aHR: 0.46; 95% CI: 0.27-0.81).
CONCLUSIONS
Autoimmune diseases were independently associated with higher burden of coronary atherosclerosis and higher risk for future ASCVD events, with risk accentuated by traditional cardiovascular risk factors. These findings suggest that autoimmune diseases increase risk through accelerated atherogenesis and that cardiovascular risk factor control is key for improving prognosis in patients with autoimmune diseases.
Topics: Humans; Coronary Artery Disease; Male; Female; Autoimmune Diseases; Middle Aged; Aged; Denmark; Severity of Illness Index; Registries; Computed Tomography Angiography; Coronary Angiography; Risk Factors; Myocardial Ischemia; Follow-Up Studies
PubMed: 38897674
DOI: 10.1016/j.jacc.2024.04.030 -
Biochemical and Biophysical Research... Jun 2024Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells...
BACKGROUND
Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis.
METHODS
We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis.
RESULTS
Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK.
CONCLUSION
Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis.
PubMed: 38897039
DOI: 10.1016/j.bbrc.2024.150236 -
Inflammation Research : Official... Jun 2024Macrophage-mediated cleaning up of dead cells is a crucial determinant in reducing coronary artery inflammation and maintaining vascular homeostasis. However, this...
BACKGROUND
Macrophage-mediated cleaning up of dead cells is a crucial determinant in reducing coronary artery inflammation and maintaining vascular homeostasis. However, this process also leads to programmed death of macrophages. So far, the role of macrophage death in the progression of atherosclerosis remains controversial. Also, the underlying mechanism by which transcriptional regulation and reprogramming triggered by macrophage death pathways lead to changes in vascular inflammation and remodeling are still largely unknown. TRIM25-mediated RIG-I signaling plays a key role in regulation of macrophages fate, however the role of TRIM25 in macrophage death-mediated atherosclerotic progression remains unclear. This study aims to investigate the relationship between TRIM25 and macrophage death in atherosclerosis.
METHODS
A total of 34 blood samples of patients with coronary stent implantation, including chronic total occlusion (CTO) leisions (n = 14) or with more than 50% stenosis of a coronary artery but without CTO leisions (n = 20), were collected, and the serum level of TRIM25 was detected by ELISA. Apoe mice with or without TRIM25 gene deletion were fed with the high-fat diet (HFD) for 12 weeks and the plaque areas, necrotic core size, aortic fibrosis and inflammation were investigated. TRIM25 wild-type and deficient macrophages were isolated, cultured and stimulated with ox-LDL, RNA-seq, real-time PCR, western blot and FACS experiments were used to screen and validate signaling pathways caused by TRIM25 deletion.
RESULTS
Downregulation of TRIM25 was observed in circulating blood of CTO patients and also in HFD-induced mouse aortas. After HFD for 12 weeks, TRIM25ApoeE mice developed smaller atherosclerotic plaques, less inflammation, lower collagen content and aortic fibrosis compared with TRIM25ApoeE mice. By RNA-seq and KEGG enrichment analysis, we revealed that deletion of TRIM25 mainly affected pyroptosis and necroptosis pathways in ox-LDL-induced macrophages, and the expressions of PARP1 and RIPK3, were significantly decreased in TRIM25 deficient macrophages. Overexpression of TRIM25 promoted M1 polarization and necroptosis of macrophages, while inhibition of PARP1 reversed this process. Further, we observed that XRCC1, a repairer of DNA damage, was significantly upregulated in TRIM25 deficient macrophages, inhibiting PARP1 activity and PARP1-mediated pro-inflammatory change, M1 polarization and necroptosis of macrophages. By contrast, TRIM25 overexpression mediated ubiquitination of XRCC1, and the inhibition of XRCC1 released PARP1, and activated macrophage M1 polarization and necroptosis, which accelerated aortic inflammation and atherosclerotic plaque progression.
CONCLUSIONS
Our study has uncovered a crucial role of the TRIM25-XRCC1-PARP1-RIPK3 axis in regulating macrophage death during atherosclerosis, and we highlight the potential therapeutic significance of macrophage reprogramming regulation in preventing the development of atherosclerosis.
PubMed: 38896288
DOI: 10.1007/s00011-024-01906-4 -
Frontiers in Medicine 2024[This corrects the article DOI: 10.3389/fmed.2024.1284199.].
[This corrects the article DOI: 10.3389/fmed.2024.1284199.].
PubMed: 38895189
DOI: 10.3389/fmed.2024.1416622 -
Diagnostics (Basel, Switzerland) May 2024The aim of the study was to assess the relationship between the presence of atherosclerotic lesions in the carotid arteries detected by ultrasound and the occurrence of...
The aim of the study was to assess the relationship between the presence of atherosclerotic lesions in the carotid arteries detected by ultrasound and the occurrence of atherosclerosis in the coronary arteries determined by computed tomography (CT) in patients with arterial hypertension (HTA). A total of 83 patients with HTA were qualified for the study (age: 71.3 ± 8.5 years). All subjects underwent carotid arteries ultrasound and coronary arteries CT. The carotid plaque score was assessed using ultrasound. The studied group was divided into two subgroups: a subgroup with the carotid plaque score ≤ 1 (A) and a subgroup with carotid plaque score ≥2 (B). Coronary arteries CT assessed coronary artery calcium score (CACS) and degree of coronary stenosis based on CAD-RADS. In subgroup B, a significantly higher CACS (411.3 ± 70.1 vs. 93.5 ± 31.8) and significantly higher grade in the CAD-RADS classification were demonstrated than in subgroup A (CAD-RADS ≥ 3: 21.8 vs. 6.0%). The regression analysis showed that carotid plaque score and age are independent risk factors for the severity of atherosclerotic lesions in the coronary arteries. In summary, ultrasound assessment of the carotid plaque score in patients with HTA could be considered as surrogate indicator of the risk and severity of atherosclerotic changes in the coronary arteries, but further studies are necessary to corroborate these results.
PubMed: 38893628
DOI: 10.3390/diagnostics14111101 -
Diagnostics (Basel, Switzerland) May 2024Atherosclerotic plaque buildup in the coronary and carotid arteries is pivotal in the onset of acute myocardial infarctions or cerebrovascular events, leading to... (Review)
Review
Atherosclerotic plaque buildup in the coronary and carotid arteries is pivotal in the onset of acute myocardial infarctions or cerebrovascular events, leading to heightened levels of illness and death. Atherosclerosis is a complex and multistep disease, beginning with the deposition of low-density lipoproteins in the arterial intima and culminating in plaque rupture. Modern technology favors non-invasive imaging techniques to assess atherosclerotic plaque and offer insights beyond mere artery stenosis. Among these, computed tomography stands out for its widespread clinical adoption and is prized for its speed and accessibility. Nonetheless, some limitations persist. The introduction of photon-counting computed tomography (PCCT), with its multi-energy capabilities, enhanced spatial resolution, and superior soft tissue contrast with minimal electronic noise, brings significant advantages to carotid and coronary artery imaging, enabling a more comprehensive examination of atherosclerotic plaque composition. This narrative review aims to provide a comprehensive overview of the main concepts related to PCCT. Additionally, we aim to explore the existing literature on the clinical application of PCCT in assessing atherosclerotic plaque. Finally, we will examine the advantages and limitations of this recently introduced technology.
PubMed: 38893593
DOI: 10.3390/diagnostics14111065