Editorial

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Open AccessEditorial

The Underlying Pathology of Atherosclerosis: Different Players

by Noemi Rotllan

Int. J. Mol. Sci. 2022, 23(6), 3235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063235 - 17 Mar 2022

Cited by 1 | Viewed by 1103

Cardiovascular diseases (CDVs) are still the leading cause of mortality in the developed world, despite the high number of deaths caused by the COVID pandemic of the last two years [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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15 pages, 1529 KiB

Open AccessArticle

Trimethylamine n-Oxide (TMAO) Modulates the Expression of Cardiovascular Disease-Related microRNAs and Their Targets

by Laura Díez-Ricote, Paloma Ruiz-Valderrey, Víctor Micó, Ruth Blanco-Rojo, João Tomé-Carneiro, Alberto Dávalos, José M. Ordovás and Lidia Daimiel

Int. J. Mol. Sci. 2021, 22(20), 11145; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011145 - 15 Oct 2021

Cited by 18 | Viewed by 2673

Abstract

Diet is a well-known risk factor of cardiovascular diseases (CVDs). Some microRNAs (miRNAs) have been described to regulate molecular pathways related to CVDs. Diet can modulate miRNAs and their target genes. Choline, betaine, and l-carnitine, nutrients found in animal products, are metabolized [...] Read more.

Diet is a well-known risk factor of cardiovascular diseases (CVDs). Some microRNAs (miRNAs) have been described to regulate molecular pathways related to CVDs. Diet can modulate miRNAs and their target genes. Choline, betaine, and l-carnitine, nutrients found in animal products, are metabolized into trimethylamine n-oxide (TMAO), which has been associated with CVD risk. The aim of this study was to investigate TMAO regulation of CVD-related miRNAs and their target genes in cellular models of liver and macrophages. We treated HEPG-2, THP-1, mouse liver organoids, and primary human macrophages with 6 µM TMAO at different timepoints (4, 8, and 24 h for HEPG-2 and mouse liver organoids, 12 and 24 h for THP-1, and 12 h for primary human macrophages) and analyzed the expression of a selected panel of CVD-related miRNAs and their target genes and proteins by real-time PCR and Western blot, respectively. HEPG-2 cells were transfected with anti-miR-30c and syn-miR-30c. TMAO increased the expression of miR-21-5p and miR-30c-5p. PER2, a target gene of both, decreased its expression with TMAO in HEPG-2 and mice liver organoids but increased its mRNA expression with syn-miR-30c. We concluded that TMAO modulates the expression of miRNAs related to CVDs, and that such modulation affects their target genes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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21 pages, 5496 KiB

Open AccessArticle

The Lipid-Modulating Effect of Tangeretin on the Inhibition of Angiopoietin-like 3 (ANGPTL3) Gene Expression through Regulation of LXRα Activation in Hepatic Cells

by Pei-Yi Chen, Tzu-Ya Chao, Hao-Jen Hsu, Chih-Yang Wang, Ching-Yen Lin, Wan-Yun Gao, Ming-Jiuan Wu and Jui-Hung Yen

Int. J. Mol. Sci. 2021, 22(18), 9853; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189853 - 12 Sep 2021

Cited by 14 | Viewed by 2939

Abstract

The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pentamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyperlipidemia, diabetes, and obesity. The aim of [...] Read more.

The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pentamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyperlipidemia, diabetes, and obesity. The aim of this study was to investigate the lipid-modulating effects and the underlying mechanisms of tangeretin action in hepatic cells. Transcriptome and bioinformatics analyses with the Gene Ontology (GO) database showed that tangeretin significantly regulated a set of 13 differentially expressed genes (DEGs) associated with the regulation of lipoprotein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential inhibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly downregulated by tangeretin. We demonstrated that tangeretin significantly inhibited the mRNA expression of ANGPTL3 in HepG2 and Huh-7 cells. Tangeretin treatment of hepatic cells also reduced the levels of both intracellular and secreted ANGPTL3 proteins. Moreover, we found that inhibition of ANGPTL3 production by tangeretin augmented LPL activity. We further demonstrated that the transcriptional activity of the ANGPTL3 promoter was significantly attenuated by tangeretin, and we identified a DNA element located between the −250 and −121 positions that responded to tangeretin. Furthermore, we found that tangeretin did not alter the levels of the nuclear liver X receptor α (LXRα) protein, an essential transcription factor that binds to the tangeretin-responsive element, but it can counteract LXRα-mediated ANGPTL3 transcription. On the basis of molecular docking analysis, tangeretin was predicted to bind to the ligand-binding domain of LXRα, which would result in suppression of LXRα activation. Our findings support the hypothesis that tangeretin exerts a lipid-lowering effect by modulating the LXRα-ANGPTL3-LPL pathway, and thus, it can be used as a potential phytochemical for the prevention or treatment of dyslipidemia. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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11 pages, 4868 KiB

Open AccessArticle

Sustained Elevated Blood Pressure Accelerates Atherosclerosis Development in a Preclinical Model of Disease

by Andrés Gonzalez-Guerra, Marta Roche-Molina, Nieves García-Quintáns, Cristina Sánchez-Ramos, Daniel Martín-Pérez, Mariya Lytvyn, Javier de Nicolás-Hernández, José Rivera-Torres, Diego F. Arroyo, David Sanz-Rosa and Juan A. Bernal

Int. J. Mol. Sci. 2021, 22(16), 8448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168448 - 06 Aug 2021

Cited by 8 | Viewed by 2396

Abstract

The continuous relationship between blood pressure (BP) and cardiovascular events makes the distinction between elevated BP and hypertension based on arbitrary cut-off values for BP. Even mild BP elevations manifesting as high-normal BP have been associated with cardiovascular risk. We hypothesize that persistent [...] Read more.

The continuous relationship between blood pressure (BP) and cardiovascular events makes the distinction between elevated BP and hypertension based on arbitrary cut-off values for BP. Even mild BP elevations manifesting as high-normal BP have been associated with cardiovascular risk. We hypothesize that persistent elevated BP increases atherosclerotic plaque development. To evaluate this causal link, we developed a new mouse model of elevated BP based on adeno-associated virus (AAV) gene transfer. We constructed AAV vectors to support transfer of the hRenin and hAngiotensinogen genes. A single injection of AAV-Ren/Ang (10¹¹ total viral particles) induced sustained systolic BP increase (130 ± 20 mmHg, vs. 110 ± 15 mmHg in controls; p = 0.05). In ApoE^−/− mice, AAV-induced mild BP elevation caused larger atherosclerotic lesions evaluated by histology (10-fold increase vs. normotensive controls). In this preclinical model, atheroma plaques development was attenuated by BP control with a calcium channel blocker, indicating that a small increase in BP within a physiological range has a substantial impact on plaque development in a preclinical model of atherosclerosis. These data support that non-optimal BP represents a risk for atherosclerosis development. Earlier intervention in elevated BP may prevent or delay morbidity and mortality associated with atherosclerosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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Review

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13 pages, 1036 KiB

Open AccessReview

Epigenetic Regulation by microRNAs in Hyperhomocysteinemia-Accelerated Atherosclerosis

by Raquel Griñán, Joan Carles Escolà-Gil, Josep Julve, Sonia Benítez and Noemí Rotllan

Int. J. Mol. Sci. 2022, 23(20), 12452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012452 - 18 Oct 2022

Cited by 8 | Viewed by 2234

Abstract

Increased serum levels of homocysteine (Hcy) is a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature such as atherosclerosis. However, the precise mechanisms by which Hcy contributes to this condition remain elusive. During the development of [...] Read more.

Increased serum levels of homocysteine (Hcy) is a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature such as atherosclerosis. However, the precise mechanisms by which Hcy contributes to this condition remain elusive. During the development of atherosclerosis, epigenetic modifications influence gene expression. As such, epigenetic modifications are an adaptive response to endogenous and exogenous factors that lead to altered gene expression by methylation and acetylation reactions of different substrates and the action of noncoding RNA including microRNAs (miRNAs). Epigenetic remodeling modulates cell biology in both physiological and physiopathological conditions. DNA and histone modification have been identified to have a crucial role in the progression of atherosclerosis. However, the potential role of miRNAs in hyperHcy (HHcy)-related atherosclerosis disease remains poorly explored and might be essential as well. There is no review available yet summarizing the contribution of miRNAs to hyperhomocystein-mediated atherogenicity or their potential as therapeutic targets even though their important role has been described in numerous studies. Specifically, downregulation of miR-143 or miR-125b has been shown to regulate VSCMs proliferation in vitro. In preclinical studies, downregulation of miR-92 or miR195-3p has been shown to increase the accumulation of cholesterol in foam cells and increase macrophage inflammation and atherosclerotic plaque formation, respectively. Another preclinical study found that there is a reciprocal regulation between miR-148a/152 and DNMT1 in Hcy-accelerated atherosclerosis. Interestingly, a couple of studies have shown that miR-143 or miR-217 may be used as potential biomarkers in patients with HHcy that may develop atherosclerosis. Moreover, the current review will also update current knowledge on miRNA-based therapies, their challenges, and approaches to deal with Hcy-induced atherosclerosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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17 pages, 1399 KiB

Open AccessReview

The Paradigm Change of IL-33 in Vascular Biology

by Svitlana Demyanets, Stefan Stojkovic, Kurt Huber and Johann Wojta

Int. J. Mol. Sci. 2021, 22(24), 13288; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413288 - 10 Dec 2021

Cited by 10 | Viewed by 2782

Abstract

In this review, we focus on the actual understanding of the role of IL-33 in vascular biology in the context of the historical development since the description of IL-33 as a member of IL-1 superfamily and the ligand for ST2 receptor in 2005. [...] Read more.

In this review, we focus on the actual understanding of the role of IL-33 in vascular biology in the context of the historical development since the description of IL-33 as a member of IL-1 superfamily and the ligand for ST2 receptor in 2005. We summarize recent data on the biology, structure and signaling of this dual-function factor with both nuclear and extracellular cytokine properties. We describe cellular sources of IL-33, particularly within vascular wall, changes in its expression in different cardio-vascular conditions and mechanisms of IL-33 release. Additionally, we summarize the regulators of IL-33 expression as well as the effects of IL-33 itself in cells of the vasculature and in monocytes/macrophages in vitro combined with the consequences of IL-33 modulation in models of vascular diseases in vivo. Described in murine atherosclerosis models as well as in macrophages as an atheroprotective cytokine, extracellular IL-33 induces proinflammatory, prothrombotic and proangiogenic activation of human endothelial cells, which are processes known to be involved in the development and progression of atherosclerosis. We, therefore, discuss that IL-33 can possess both protective and harmful effects in experimental models of vascular pathologies depending on experimental conditions, type and dose of administration or method of modulation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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12 pages, 1591 KiB

Open AccessReview

Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia

by Pei-Yi Chen, Wan-Yun Gao, Je-Wen Liou, Ching-Yen Lin, Ming-Jiuan Wu and Jui-Hung Yen

Int. J. Mol. Sci. 2021, 22(14), 7310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147310 - 07 Jul 2021

Cited by 28 | Viewed by 6525

Abstract

Dyslipidemia is characterized by increasing plasma levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides (TGs) and TG-rich lipoproteins (TGRLs) and is a major risk factor for the development of atherosclerotic cardiovascular disorders (ASCVDs). It is important to understand the metabolic mechanisms underlying dyslipidemia to develop [...] Read more.

Dyslipidemia is characterized by increasing plasma levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides (TGs) and TG-rich lipoproteins (TGRLs) and is a major risk factor for the development of atherosclerotic cardiovascular disorders (ASCVDs). It is important to understand the metabolic mechanisms underlying dyslipidemia to develop effective strategies against ASCVDs. Angiopoietin-like 3 (ANGPTL3), a member of the angiopoietin-like protein family exclusively synthesized in the liver, has been demonstrated to be a critical regulator of lipoprotein metabolism to inhibit lipoprotein lipase (LPL) activity. Genetic, biochemical, and clinical studies in animals and humans have shown that loss of function, inactivation, or downregulated expression of ANGPTL3 is associated with an obvious reduction in plasma levels of TGs, LDL-C, and high-density lipoprotein-cholesterol (HDL-C), atherosclerotic lesions, and the risk of cardiovascular events. Therefore, ANGPTL3 is considered an alternative target for lipid-lowering therapy. Emerging studies have focused on ANGPTL3 inhibition via antisense oligonucleotides (ASOs) and monoclonal antibody-based therapies, which have been carried out in mouse or monkey models and in human clinical studies for the management of dyslipidemia and ASCVDs. This review will summarize the current literature on the important role of ANGPTL3 in controlling lipoprotein metabolism and dyslipidemia, with an emphasis on anti-ANGPTL3 therapies as a potential strategy for the treatment of dyslipidemia and ASCVDs. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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27 pages, 1959 KiB

Open AccessReview

Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs

by Amin Javadifar, Sahar Rastgoo, Maciej Banach, Tannaz Jamialahmadi, Thomas P. Johnston and Amirhossein Sahebkar

Int. J. Mol. Sci. 2021, 22(5), 2529; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052529 - 03 Mar 2021

Cited by 43 | Viewed by 4858

Abstract

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper [...] Read more.

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis)

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