-
Pharmacology & Therapeutics Apr 2019Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid...
Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic "writers", "readers", and "erasers". Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics.
Topics: Animals; Atherosclerosis; Epigenesis, Genetic; Humans; Immunity; RNA, Untranslated; Risk Factors
PubMed: 30439455
DOI: 10.1016/j.pharmthera.2018.11.003 -
BMC Biology Feb 2023Immune cells that infiltrate lesions are important for atherosclerosis progression and immunotherapies. This study was aimed at gaining important new insights into the...
BACKGROUND
Immune cells that infiltrate lesions are important for atherosclerosis progression and immunotherapies. This study was aimed at gaining important new insights into the heterogeneity of these cells by integrating the sequencing results of multiple samples and using an enhanced single-cell sequencing workflow to overcome the limitations of a single study.
RESULTS
Integrative analyses identified 28 distinct subpopulations based on gene expression profiles. Further analysis demonstrated that these cells manifested high heterogeneity at the levels of tissue preferences, genetic perturbations, functional variations, immune dynamics, transcriptional regulators, metabolic changes, and communication patterns. Of the T cells, interferon-induced CD8 T cells were involved in the progression of atherosclerosis. In contrast, proinflammatory CD4 CD28 T cells predicted a poor outcome in atherosclerosis. Notably, we identified two subpopulations of foamy macrophages that exhibit contrasting phenotypes. Among them, TREM2SPP1 foamy macrophages were preferentially distributed in the hypoxic core of plaques. These glycolytic metabolism-enriched cells, with impaired cholesterol metabolism and robust pro-angiogenic capacity, were phenotypically regulated by CSF1 secreted by co-localised mast cells. Moreover, combined with deconvolution of the bulk datasets, we revealed that these dysfunctional cells had a higher proportion of ruptured and haemorrhagic lesions and were significantly associated with poor atherosclerosis prognoses.
CONCLUSIONS
We systematically explored atherosclerotic immune heterogeneity and identified cell populations underlying atherosclerosis progression and poor prognosis, which may be valuable for developing new and precise immunotherapies.
Topics: Humans; Atherosclerosis; Biological Transport; CD8-Positive T-Lymphocytes; Immunotherapy
PubMed: 36855107
DOI: 10.1186/s12915-023-01540-2 -
Oncotarget Aug 2015
Topics: Adaptor Proteins, Vesicular Transport; Animals; Atherosclerosis; Humans; Mice
PubMed: 26305723
DOI: 10.18632/oncotarget.5098 -
Circulation Research Jun 2022miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to...
BACKGROUND
miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis.
METHODS
We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics.
RESULTS
The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes (, etc) and tissue inhibitor of metalloproteinase 3 () and downregulation of in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33.
CONCLUSIONS
This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
Topics: Antagomirs; Atherosclerosis; Humans; Macrophages; MicroRNAs; Plaque, Atherosclerotic
PubMed: 35534923
DOI: 10.1161/CIRCRESAHA.121.320296 -
International Journal of Molecular... Feb 2022Atherosclerosis has been known in medicine for several centuries. As early as 1755, the Swedish anatomist Albrecht von Haller used the term "atheroma" to describe... (Review)
Review
Atherosclerosis has been known in medicine for several centuries. As early as 1755, the Swedish anatomist Albrecht von Haller used the term "atheroma" to describe vascular lesions. Atherosclerosis may originate from an unbalanced diet or bad habits, and is mainly found in developed countries. Clinical trials have been conducted to establish the causes of atherosclerosis, and also to develop treatments for this disease. However, prevention of the disease has always been better than treatment, so vaccination may be the key to saving thousands of lives. The creation of a vaccine may be directly related to the study of autoimmune processes occurring in the body, immunity. This review considers the issues related to the involvement of the immune response in the development of atherosclerotic lesions. Modern concepts of atherogenesis, immune inflammation in atherosclerosis, and potential vaccine targets are also discussed. There is a particular focus on experimental and clinical data supporting the development of immune therapies to reduce cardiovascular risk.
Topics: Adaptive Immunity; Atherosclerosis; Drug Development; Humans; Vaccination
PubMed: 35269559
DOI: 10.3390/ijms23052417 -
Archives of Cardiovascular Diseases Dec 2016Atherosclerosis is an inflammatory disease within the arterial wall that is responsible for several important adverse vascular events, including coronary artery disease,... (Review)
Review
Atherosclerosis is an inflammatory disease within the arterial wall that is responsible for several important adverse vascular events, including coronary artery disease, myocardial infraction, stroke and peripheral artery disease. Both innate and adaptive immunity play important roles in the development of atherosclerosis. In particular, monocytes/macrophages, which are the surrogate cells of innate immunity, have important proatherogenic effects. In addition, adaptive immune responses effected by T cells play important roles in atherosclerosis. While the T-helper cell type 1 (Th1) response has a potent proatherogenic effect, the pathogenic roles of other T cell subsets, such as the Th2 and Th17 pathways, remain controversial. However, the antiatherosclerotic protective roles of regulatory T cells and some Th2-related cytokines, such as interleukin-5, have been clearly established. In light of numerous data in animal models showing the importance of inflammatory cells in atherosclerosis and its complications, treatment of cardiovascular diseases with anti-inflammatory drugs may be an attractive strategy. However, future randomized placebo-controlled trials are required to test this possibility, to evaluate the proper effect of anti-inflammatory drugs as cardiovascular therapeutic agents without confounding effects.
Topics: Adaptive Immunity; Animals; Atherosclerosis; Humans; Inflammation; Inflammation Mediators
PubMed: 27595467
DOI: 10.1016/j.acvd.2016.04.002 -
Vascular Health and Risk Management 2023Multiple lines of evidence confirm that the cumulative burden of low-density lipoprotein cholesterol (LDL-C) is causally related to the development of atherosclerotic... (Review)
Review
Multiple lines of evidence confirm that the cumulative burden of low-density lipoprotein cholesterol (LDL-C) is causally related to the development of atherosclerotic cardiovascular disease (ASCVD). As such, lowering LDL-C is a central tenet in all ASCVD prevention guidelines, which recommend matching the intensity of LDL-C lowering with the absolute risk of the patient. Unfortunately, issues such as difficulty with long-term adherence to statin therapy and inability to achieve desired LDL-C thresholds with statins alone results in residual elevated ASCVD risk. Non-statin therapies generally provide similar risk reduction per mmol/L of LDL-C reduction and are included by major society guidelines as part of the treatment algorithm for managing LDL-C. Per the 2022 American College of Cardiology Expert Consensus Decision Pathway, patients with ASCVD are recommended to achieve both an LDL-C reduction ≥50% and an LDL-C threshold of <55 mg/dL in patients at very high-risk and <70 mg/dL in those not at very high risk. Patients with familial hypercholesterolemia (FH) but without ASCVD should lower LDL-C to <100 mg/dL. For patients who remain above LDL-C thresholds with maximally tolerated statin therapy plus lifestyle changes, non-statin therapy warrants strong consideration. While several non-statin therapies have been granted FDA approval for managing hypercholesterolemia (eg, ezetimibe, Proprotein Convertase Subtilisin/Kexin 9 [PCSK9] monoclonal antibodies, and bempedoic acid), the focus of the current review is on inclisiran, a novel small interfering RNA therapy that inhibits the production of the PCSK9 protein. Inclisiran is currently FDA approved as an adjunct to statin therapy in patients with clinical ASCVD or heterozygous FH who require additional LDL-lowering. The drug is administered by subcutaneous injection twice a year, after an initial baseline and 3 month dose. In this review, we sought to provide an overview of the use of inclisiran, review current trial data, and outline an approach to potential patient selection.
Topics: Humans; Proprotein Convertase 9; Cholesterol, LDL; Cardiovascular Diseases; RNA, Small Interfering; Atherosclerosis; Hyperlipoproteinemia Type II
PubMed: 37434791
DOI: 10.2147/VHRM.S338424 -
Advanced Science (Weinheim,... Dec 2023With the changing disease spectrum, atherosclerosis has become increasingly prevalent worldwide and the associated diseases have emerged as the leading cause of death.... (Review)
Review
With the changing disease spectrum, atherosclerosis has become increasingly prevalent worldwide and the associated diseases have emerged as the leading cause of death. Due to their fascinating physical, chemical, and biological characteristics, nanomaterials are regarded as a promising tool to tackle enormous challenges in medicine. The emerging discipline of nanomedicine has filled a huge application gap in the atherosclerotic field, ushering a new generation of diagnosis and treatment strategies. Herein, based on the essential pathogenic contributors of atherogenesis, as well as the distinct composition/structural characteristics, synthesis strategies, and surface design of nanoplatforms, the three major application branches (nanodiagnosis, nanotherapy, and nanotheranostic) of nanomedicine in atherosclerosis are elaborated. Then, state-of-art studies containing a sequence of representative and significant achievements are summarized in detail with an emphasis on the intrinsic interaction/relationship between nanomedicines and atherosclerosis. Particularly, attention is paid to the biosafety of nanomedicines, which aims to pave the way for future clinical translation of this burgeoning field. Finally, this comprehensive review is concluded by proposing unresolved key scientific issues and sharing the vision and expectation for the future, fully elucidating the closed loop from atherogenesis to the application paradigm of nanomedicines for advancing the early achievement of clinical applications.
Topics: Humans; Nanomedicine; Atherosclerosis; Nanostructures
PubMed: 37897322
DOI: 10.1002/advs.202304294 -
Arteriosclerosis, Thrombosis, and... Apr 2020The immune system's role in atherosclerosis has long been an important research topic and is increasingly investigated for therapeutic and diagnostic purposes.... (Review)
Review
The immune system's role in atherosclerosis has long been an important research topic and is increasingly investigated for therapeutic and diagnostic purposes. Therefore, noninvasive imaging of hematopoietic organs and immune cells will undoubtedly improve atherosclerosis phenotyping and serve as a monitoring method for immunotherapeutic treatments. Among the available imaging techniques, positron emission tomography's unique features make it an ideal tool to quantitatively image the immune response in the context of atherosclerosis and afford reliable readouts to guide medical interventions in cardiovascular disease. Here, we summarize the state of the art in the field of atherosclerosis positron emission tomography immunoimaging and provide an outlook on current and future applications.
Topics: Atherosclerosis; Hematopoietic System; Humans; Nanoparticles; Phagocytes; Plaque, Atherosclerotic; Positron-Emission Tomography; Radioimmunodetection; Radiopharmaceuticals
PubMed: 32078338
DOI: 10.1161/ATVBAHA.119.313455 -
Current Opinion in Lipidology Oct 2018The immune system plays a critical role in the development and modulation of atherosclerosis. New high-parameter technologies, including mass cytometry (CyTOF) and... (Review)
Review
PURPOSE OF REVIEW
The immune system plays a critical role in the development and modulation of atherosclerosis. New high-parameter technologies, including mass cytometry (CyTOF) and single-cell RNA sequencing (scRNAseq), allow for an encompassing analysis of immune cells. Unexplored marker combinations and transcriptomes can define new immune cell subsets and suggest their functions. Here, we review recent advances describing the immune cells in the artery wall of mice with and without atherosclerosis. We compare technologies and discuss limitations and advantages.
RECENT FINDINGS
Both CyTOF and scRNAseq on leukocytes from digested aortae show 10-30 immune cell subsets. Myeloid, T, B and natural killer cells were confirmed. Although cellular functions can be inferred from RNA-Seq data, some subsets cannot be identified based on current knowledge, suggesting they may be new cell types. CyTOF and scRNAseq each identified four B-cell subsets and three macrophage subsets in the atherosclerotic aorta. Limitations include cell death caused by enzymatic digestion and the limited depth of the scRNAseq transcriptomes.
SUMMARY
High-parameter methods are powerful tools for uncovering leukocyte diversity. CyTOF is currently more powerful at discerning leukocyte subsets in the atherosclerotic aorta, whereas scRNAseq provides more insight into their likely functions.
Topics: Animals; Atherosclerosis; Humans; Prognosis; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 30020199
DOI: 10.1097/MOL.0000000000000537