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Molecular Therapy : the Journal of the... Oct 2022Atherosclerosis is the main underlying pathology for many cardiovascular diseases (CVDs), which are the leading cause of death globally and represent a serious health... (Review)
Review
Atherosclerosis is the main underlying pathology for many cardiovascular diseases (CVDs), which are the leading cause of death globally and represent a serious health crisis. Atherosclerosis is a chronic condition that can lead to myocardial infarction, ischemic cardiomyopathy, stroke, and peripheral arterial disease. Elevated plasma lipids, hypertension, and high glucose are the major risk factors for developing atherosclerotic plaques. To date, most pharmacological therapies aim to control these risk factors, but they do not target the plaque-causing cells themselves. In patients with acute coronary syndromes, surgical revascularization with percutaneous coronary intervention has greatly reduced mortality rates. However, stent thrombosis and neo-atherosclerosis have emerged as major safety concerns of drug eluting stents due to delayed re-endothelialization. This review summarizes the major milestones, strengths, and limitations of current anti-atherosclerotic therapies. It provides an overview of the recent discoveries and emerging game-changing technologies in the fields of nanomedicine, mRNA therapeutics, and gene editing that have the potential to revolutionize CVD clinical practice by steering it toward precision medicine.
Topics: Atherosclerosis; Drug-Eluting Stents; Glucose; Humans; Lipids; RNA, Messenger; Risk Factors; Treatment Outcome
PubMed: 36065464
DOI: 10.1016/j.ymthe.2022.08.024 -
Nature Reviews. Cardiology Sep 2022The AIM2 inflammasome is activated by host and pathogen DNA. Work from the past 5 years indicates that the AIM2 inflammasome has an important role in advanced...
The AIM2 inflammasome is activated by host and pathogen DNA. Work from the past 5 years indicates that the AIM2 inflammasome has an important role in advanced atherosclerosis driven by clonal haematopoiesis and possibly in atherosclerosis accelerated by acute infection. Therefore, the AIM2 inflammasome might be an important target for precision medicine.
Topics: Atherosclerosis; Humans
PubMed: 35882998
DOI: 10.1038/s41569-022-00755-0 -
Cardiovascular Research May 2023CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and...
AIMS
CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice.
METHOD AND RESULTS
Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac-/- compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1).
CONCLUSIONS
We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.
Topics: Animals; Mice; Atherosclerosis; Macrophages; Plaque, Atherosclerotic; Signal Transduction; Aorta; CD40 Antigens
PubMed: 35587037
DOI: 10.1093/cvr/cvac084 -
JCI Insight Sep 2022Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase...
Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet-fed (WD-fed) Ldlr-/- mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.
Topics: Aminopyridines; Animals; Atherosclerosis; Bile Acids and Salts; Diabetes Mellitus, Experimental; Humans; Hypercholesterolemia; I-kappa B Kinase; Mice; Protein Serine-Threonine Kinases
PubMed: 35917178
DOI: 10.1172/jci.insight.155552 -
Frontiers in Bioscience (Scholar... Dec 2023Systemic sclerosis (SSc) is a rare systemic autoimmune disease of unknown etiology, which is characterized by endothelial dysfunction, pathologic vasculopathy, and... (Review)
Review
Systemic sclerosis (SSc) is a rare systemic autoimmune disease of unknown etiology, which is characterized by endothelial dysfunction, pathologic vasculopathy, and increased tissue fibrosis. Traditionally, SSc has been regarded as a prototypical fibrotic disease in the family of systemic autoimmune diseases. Traditionally, emphasis has been placed on the three components of the pathogenesis of SSc: vascular, immune, and mesenchymal. Microvascular lesions, including endothelial dysfunction and smooth muscle cell migration into the intima of vessels in SSc, resemble the atherosclerotic process. Although microvascular disease is a hallmark of SSc, understanding the role of atherosclerotic vascular lesions in patients with SSc remains limited. It is still unknown whether the increased cardiovascular risk in SSc is related to specific cardiac complications (such as myocardial fibrosis) or the accelerated development of atherosclerosis. Different immune cell types appear to be involved in the immunopathogenesis of SSc via the activation of other immune cells, fibrosis, or vascular damage. Macrophages, B cells, T cells, dendritic cells, neutrophils, and endothelial cells have been reported to play the most important role in the pathogenesis of SSc and atherosclerosis. In our article, we reviewed the most significant and recent studies on the pathogenetic links between the development of SSc and the atherosclerotic process.
Topics: Humans; Endothelial Cells; Scleroderma, Systemic; Fibrosis; Atherosclerosis; Biomarkers
PubMed: 38163957
DOI: 10.31083/j.fbs1504016 -
Current Opinion in Lipidology Aug 2019Acute phase serum amyloid A (SAA) is persistently elevated in chronic inflammatory conditions, and elevated levels predict cardiovascular risk in humans. More recently,... (Review)
Review
PURPOSE OF REVIEW
Acute phase serum amyloid A (SAA) is persistently elevated in chronic inflammatory conditions, and elevated levels predict cardiovascular risk in humans. More recently, murine studies have demonstrated that over-expression of SAA increases and deficiency/suppression of SAA attenuates atherosclerosis. Thus, beyond being a biomarker, SAA appears to play a causal role in atherogenesis. The purpose of this review is to summarize the data supporting SAA as a key player in atherosclerosis development.
RECENT FINDINGS
A number of pro-inflammatory and pro-atherogenic activities have been ascribed to SAA. However, the literature is conflicted, as recombinant SAA, and/or lipid-free SAA, used in many of the earlier studies, do not reflect the activity of native human or murine SAA, which exists largely lipid-associated. Recent literatures demonstrate that SAA activates the NLRP3 inflammasome, alters vascular function, affects HDL function, and increases thrombosis. Importantly, SAA activity appears to be regulated by its lipid association, and HDL may serve to sequester and limit SAA activity.
SUMMARY
SAA has many pro-inflammatory and pro-atherogenic activities, is clearly demonstrated to affect atherosclerosis development, and may be a candidate target for clinical trials in cardiovascular diseases.
Topics: Animals; Atherosclerosis; Blood Vessels; Humans; Lipoproteins; Serum Amyloid A Protein; Thrombosis
PubMed: 31135596
DOI: 10.1097/MOL.0000000000000616 -
Reviews in Cardiovascular Medicine Sep 2021As a potential causative factor in various cardiovascular diseases, the gut microbe-generated metabolite trimethylamine N-oxide (TMAO) has courted considerable research... (Review)
Review
As a potential causative factor in various cardiovascular diseases, the gut microbe-generated metabolite trimethylamine N-oxide (TMAO) has courted considerable research interest as a potential biomarker. TMAO is a small molecule considered to be beneficial for the health of deep-water animals due to its ability to protect proteins against hydrostatic pressure stress. However, it may cause deleterious effects in humans as mounting evidence suggests that TMAO may enhance atherosclerosis, independent of traditional risk factors. This may be mediated by its capacity to enhance inflammation, platelet activation and thrombosis, and inhibit reverse cholesterol transport. In humans, circulating levels of TMAO have been found to be associated with increased risk of developing atherosclerotic diseases such as carotid atherosclerosis, coronary atherosclerotic heart disease, stroke, and peripheral arteriosclerosis. This review aims to discuss the current role of TMAO in the atherosclerosis process, using animal models and clinical studies, with special attention to determining whether TMAO could be used as a marker for monitoring severity and prognosis in atherosclerosis and to evaluate evidence for its role as a mediator in the pathogenesis of atherosclerotic vascular disease.
Topics: Animals; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Humans; Methylamines
PubMed: 34565077
DOI: 10.31083/j.rcm2203085 -
Drug Design, Development and Therapy 2022To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism.
PURPOSE
To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism.
METHODS
Blood glucose, blood lipid, oxidative stress response and inflammatory cytokines were examined by intraperitoneal glucose tolerance test and ELISA assay. HE and Oil Red O staining were used to estimate the extent of hepatic steatosis and atherosclerosis. RNA-seq and qRT-PCR were used to further investigate the potential mechanism. The effects of canagliflozin on autophagy were detected using transmission electron microscopy and Western blotting. The endothelial function-related markers were determined by qRT-PCR.
RESULTS
Canagliflozin notably alleviated the elevation in blood glucose and insulin resistance in western diet-fed ApoE-/- mice. In ApoE-/-+Cana group, ApoE-/- mice had lower levels of TG, TC, LDL-C, TNF-α, IL-6, IL-1β, and MCP-1. HE and Oil Red O staining presented that canagliflozin restrained the atherosclerotic plaque development and lipid accumulation. RNA-seq showed that 87 DEGs were relevant to improvement of hepatic steatosis and atherosclerosis by canagliflozin. Among them, CPS1, ASS1, ASL, ARG1, MATLA, GLS2, GOT1, SREBP1, Plin5, Retreg1, and C/EBPβ were verified. KEGG enrichment analysis indicated that DEGs were mainly involved in amino acid metabolism. Besides, we observed that canagliflozin reduced the contents of aspartic acid and citrulline in liver. Western blotting showed that ASS1 and p-AMPK/AMPK was remarkably elevated after administration of canagliflozin. Correspondingly, canagliflozin down-regulated SREBP1, FAS, ACC1, HMGCR, p-mTOR/m-TOR, p-ULK1/ULK1 and p62, but up-regulated CPT1, Beclin 1 and LC3 II/LC3I. TEM showed that canagliflozin reduced the number of lipid droplets and increased the autophagosomes. Moreover, we found that canagliflozin elevated the aortic endothelial function-associated markers including ASS1, ASL and eNOS.
CONCLUSION
Canagliflozin may attenuate hepatic steatosis by improving lipid metabolism, enhancing autophagy, and reducing inflammatory response through ASS1/AMPK pathway. Besides, canagliflozin further effectively improves the aortic endothelial function, thereby suppressing atherosclerosis development.
Topics: Mice; Animals; Mice, Knockout, ApoE; Canagliflozin; Diet, Western; Atherosclerosis; Fatty Liver; Mice, Inbred C57BL
PubMed: 36510490
DOI: 10.2147/DDDT.S388823 -
Arteriosclerosis, Thrombosis, and... Jul 2024Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in... (Review)
Review
Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in atherosclerosis is relatively well established, we are only beginning to understand how bidirectional T-cell/B-cell interactions can exert prominent atheroprotective and proatherogenic functions. In this review, we will focus on these T-cell/B-cell interactions and how we could use them to therapeutically target the adaptive immune response in atherosclerosis.
Topics: Humans; Atherosclerosis; Animals; Cell Communication; T-Lymphocytes; B-Lymphocytes; Adaptive Immunity; Signal Transduction
PubMed: 38813700
DOI: 10.1161/ATVBAHA.124.319845 -
Current Opinion in Lipidology Oct 2022To highlight recent conceptual and technological advances that have positioned the field to interrogate the cellular and molecular mechanisms contributing to the... (Review)
Review
PURPOSE OF REVIEW
To highlight recent conceptual and technological advances that have positioned the field to interrogate the cellular and molecular mechanisms contributing to the initiation of atherosclerosis, including intimal lipid accumulation, inflammation, and lesion growth.
RECENT FINDINGS
Advances in the understanding of endothelial LDL transcytosis and rapid lipid uptake by intimal macrophages provide mechanistic insights into intimal LDL accumulation and the initiation of atherogenesis. Recent studies have used unbiased single-cell approaches, such as single-cell RNA sequencing and CyTOF, to characterize the cellular components of the normal intima and atherosclerotic lesions. In-vitro studies and high-resolution transcriptomic analysis of aortic intimal lipid-loaded versus lipid-poor myeloid populations in vivo suggest that lipid-loaded macrophages may not be the primary drivers of inflammation in atherosclerotic lesions.
SUMMARY
A new perspective on the complex cellular landscape of the aorta, specifically the atherosclerosis-prone regions, confirm that intimal accumulation of lipid, monocyte recruitment, and macrophage accumulation are key events in atherogenesis triggered by hypercholesterolemia. Targeting these early events may prove to be a promising strategy for the attenuation of lesion development; however, the specific details of how hypercholesterolemia acts to initiate early inflammatory events remain to be fully elucidated.
Topics: Aorta; Atherosclerosis; Humans; Hypercholesterolemia; Inflammation; Lipids
PubMed: 35979994
DOI: 10.1097/MOL.0000000000000843