International Journal of Molecular Sciences

Editorial

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3 pages, 207 KiB

Open AccessEditorial

Atherosclerosis and Other Related-Arterial Diseases

by Luis M. Blanco-Colio and Jose L. Martín-Ventura

Int. J. Mol. Sci. 2023, 24(13), 10453; https://doi.org/10.3390/ijms241310453 - 21 Jun 2023

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Abstract

Cardiovascular diseases (CVD) are a major cause of morbidity and mortality worldwide, accounting for more than 17 million deaths each year [...] Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

Research

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12 pages, 2255 KiB

Open AccessArticle

FTY720 Reduces Lipid Accumulation by Upregulating ABCA1 through Liver X Receptor and Sphingosine Kinase 2 Signaling in Macrophages

by Koki Tachibana, Kohshi Kusumoto, Mai Ogawa, Hidenori Ando, Taro Shimizu, Yu Ishima, Tatsuhiro Ishida and Keiichiro Okuhira

Int. J. Mol. Sci. 2022, 23(23), 14617; https://doi.org/10.3390/ijms232314617 - 23 Nov 2022

Cited by 5 | Viewed by 2160

Abstract

Formation of foam cells as a result of excess lipid accumulation by macrophages is a pathological hallmark of atherosclerosis. Fingolimod (FTY720) is an immunosuppressive agent used in clinical settings for the treatment of multiple sclerosis and has been reported to inhibit atherosclerotic plaque [...] Read more.

Formation of foam cells as a result of excess lipid accumulation by macrophages is a pathological hallmark of atherosclerosis. Fingolimod (FTY720) is an immunosuppressive agent used in clinical settings for the treatment of multiple sclerosis and has been reported to inhibit atherosclerotic plaque development. However, little is known about the effect of FTY720 on lipid accumulation leading to foam cell formation. In this study, we investigated the effects of FTY720 on lipid accumulation in murine macrophages. FTY720 treatment reduced lipid droplet formation and increased the expression of ATP-binding cassette transporter A1 (ABCA1) in J774 mouse macrophages. FTY720 also enhanced the expression of liver X receptor (LXR) target genes such as FASN, APOE, and ABCG1. In addition, FTY720-induced upregulation of ABCA1 was abolished by knockdown of sphingosine kinase 2 (SphK2) expression. Furthermore, we found that FTY720 treatment induced histone H3 lysine 9 (H3K9) acetylation, which was lost in SphK2-knockdown cells. Taken together, FTY720 induces ABCA1 expression through SphK2-mediated acetylation of H3K9 and suppresses lipid accumulation in macrophages, which provides novel insights into the mechanisms of action of FTY720 on atherosclerosis. Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

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17 pages, 7951 KiB

Open AccessArticle

Differential Response of Ileal and Colonic Microbiota in Rats with High-Fat Diet-Induced Atherosclerosis

by Lingmiao Wen, Wei Xiong, Guihua Wei, Liudai Zhang, Yanjun Liu, Tinglan Zhang, Alvin Altamirano, Qiaozhi Yin, Tiane Zhang and Zhiyong Yan

Int. J. Mol. Sci. 2022, 23(19), 11154; https://doi.org/10.3390/ijms231911154 - 22 Sep 2022

Cited by 4 | Viewed by 1513

Abstract

Growing evidence suggests that gut microbiota are associated with atherosclerosis (AS). However, the functional heterogeneity of each gut segment gives rise to regional differences in gut microbiota. We established a rat model of AS by feeding the rats a high-fat diet for a [...] Read more.

Growing evidence suggests that gut microbiota are associated with atherosclerosis (AS). However, the functional heterogeneity of each gut segment gives rise to regional differences in gut microbiota. We established a rat model of AS by feeding the rats a high-fat diet for a long period. The pathological and microbiota changes in the ileum and colon of the rats were examined, and correlations between AS and microbiota were analyzed. The aortic mesothelium of the experimental rats was damaged. The intima showed evident calcium salt deposition, indicating that the AS rat model was successfully developed. We noted varying degrees of pathological damage in the ileum and colon of the experimental rats. The 16S rDNA high-throughput sequencing showed significant differences in α-diversity, β-diversity, and microbiota comparisons in the ileum and colon. Furthermore, the ileum and colon of AS rats showed varying degrees of intestinal microbiota disturbance. This article contributes to the study of the relationship between the microbiota in different regions of the gut and AS, and provides new approaches in gut microbiota intervention for the treatment of AS. Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

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18 pages, 2837 KiB

Open AccessArticle

A microRNA Signature for the Diagnosis of Statins Intolerance

by Alipio Mangas, Alexandra Pérez-Serra, Fernando Bonet, Ovidio Muñiz, Francisco Fuentes, Aurora Gonzalez-Estrada, Oscar Campuzano, Juan Sebastian Rodriguez Roca, Elena Alonso-Villa and Rocio Toro

Int. J. Mol. Sci. 2022, 23(15), 8146; https://doi.org/10.3390/ijms23158146 - 24 Jul 2022

Cited by 2 | Viewed by 1914

Abstract

Atherosclerotic cardiovascular diseases (ASCVD) are the leading cause of morbidity and mortality in Western societies. Statins are the first-choice therapy for dislipidemias and are considered the cornerstone of ASCVD. Statin-associated muscle symptoms are the main reason for dropout of this treatment. There is [...] Read more.

Atherosclerotic cardiovascular diseases (ASCVD) are the leading cause of morbidity and mortality in Western societies. Statins are the first-choice therapy for dislipidemias and are considered the cornerstone of ASCVD. Statin-associated muscle symptoms are the main reason for dropout of this treatment. There is an urgent need to identify new biomarkers with discriminative precision for diagnosing intolerance to statins (SI) in patients. MicroRNAs (miRNAs) have emerged as evolutionarily conserved molecules that serve as reliable biomarkers and regulators of multiple cellular events in cardiovascular diseases. In the current study, we evaluated plasma miRNAs as potential biomarkers to discriminate between the SI vs. non-statin intolerant (NSI) population. It is a multicenter, prospective, case-control study. A total of 179 differentially expressed circulating miRNAs were screened in two cardiovascular risk patient cohorts (high and very high risk): (i) NSI (n = 10); (ii) SI (n = 10). Ten miRNAs were identified as being overexpressed in plasma and validated in the plasma of NSI (n = 45) and SI (n = 39). Let-7c-5p, let-7d-5p, let-7f-5p, miR-376a-3p and miR-376c-3p were overexpressed in the plasma of SI patients. The receiver operating characteristic curve analysis supported the discriminative potential of the diagnosis. We propose a three-miRNA predictive fingerprint (let-7f, miR-376a-3p and miR-376c-3p) and several clinical variables (non-HDLc and years of dyslipidemia) for SI discrimination; this model achieves sensitivity, specificity and area under the receiver operating characteristic curve (AUC) of 83.67%, 88.57 and 89.10, respectively. In clinical practice, this set of miRNAs combined with clinical variables may discriminate between SI vs. NSI subjects. This multiparametric model may arise as a potential diagnostic biomarker with clinical value. Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

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15 pages, 4768 KiB

Open AccessArticle

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium

by Mireia López-Riera, Rebeca Ortega, Luisa Hueso, María Carmen Montesinos, Mari Carmen Gomez-Cabrera, María Jesús Sanz, José T. Real and Laura Piqueras

Int. J. Mol. Sci. 2021, 22(17), 9267; https://doi.org/10.3390/ijms22179267 - 27 Aug 2021

Cited by 3 | Viewed by 2089

Abstract

Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can [...] Read more.

Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes. Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

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Review

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14 pages, 2000 KiB

Open AccessReview

Vascular Calcification: Key Roles of Phosphate and Pyrophosphate

by Ricardo Villa-Bellosta

Int. J. Mol. Sci. 2021, 22(24), 13536; https://doi.org/10.3390/ijms222413536 - 17 Dec 2021

Cited by 48 | Viewed by 6712

Abstract

Cardiovascular complications due to accelerated arterial stiffening and atherosclerosis are the leading cause of morbimortality in Western society. Both pathologies are frequently associated with vascular calcification. Pathologic calcification of cardiovascular structures, or vascular calcification, is associated with several diseases (for example, genetic diseases, [...] Read more.

Cardiovascular complications due to accelerated arterial stiffening and atherosclerosis are the leading cause of morbimortality in Western society. Both pathologies are frequently associated with vascular calcification. Pathologic calcification of cardiovascular structures, or vascular calcification, is associated with several diseases (for example, genetic diseases, diabetes, and chronic kidney disease) and is a common consequence of aging. Calcium phosphate deposition, mainly in the form of hydroxyapatite, is the hallmark of vascular calcification and can occur in the medial layer of arteries (medial calcification), in the atheroma plaque (intimal calcification), and cardiac valves (heart valve calcification). Although various mechanisms have been proposed for the pathogenesis of vascular calcification, our understanding of the pathogenesis of calcification is far from complete. However, in recent years, some risk factors have been identified, including high serum phosphorus concentration (hyperphosphatemia) and defective synthesis of pyrophosphate (pyrophosphate deficiency). The balance between phosphate and pyrophosphate, strictly controlled by several genes, plays a key role in vascular calcification. This review summarizes the current knowledge concerning phosphate and pyrophosphate homeostasis, focusing on the role of extracellular pyrophosphate metabolism in aortic smooth muscle cells and macrophages. Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

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23 pages, 2223 KiB

Open AccessReview

NR4A3: A Key Nuclear Receptor in Vascular Biology, Cardiovascular Remodeling, and Beyond

by José Martínez-González, Laia Cañes, Judith Alonso, Carme Ballester-Servera, Antonio Rodríguez-Sinovas, Irene Corrales and Cristina Rodríguez

Int. J. Mol. Sci. 2021, 22(21), 11371; https://doi.org/10.3390/ijms222111371 - 21 Oct 2021

Cited by 17 | Viewed by 3853

Abstract

The mechanisms committed in the activation and response of vascular and inflammatory immune cells play a major role in tissue remodeling in cardiovascular diseases (CVDs) such as atherosclerosis, pulmonary arterial hypertension, and abdominal aortic aneurysm. Cardiovascular remodeling entails interrelated cellular processes (proliferation, survival/apoptosis, [...] Read more.

The mechanisms committed in the activation and response of vascular and inflammatory immune cells play a major role in tissue remodeling in cardiovascular diseases (CVDs) such as atherosclerosis, pulmonary arterial hypertension, and abdominal aortic aneurysm. Cardiovascular remodeling entails interrelated cellular processes (proliferation, survival/apoptosis, inflammation, extracellular matrix (ECM) synthesis/degradation, redox homeostasis, etc.) coordinately regulated by a reduced number of transcription factors. Nuclear receptors of the subfamily 4 group A (NR4A) have recently emerged as key master genes in multiple cellular processes and vital functions of different organs, and have been involved in a variety of high-incidence human pathologies including atherosclerosis and other CVDs. This paper reviews the major findings involving NR4A3 (Neuron-derived Orphan Receptor 1, NOR-1) in the cardiovascular remodeling operating in these diseases. Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

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Other

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15 pages, 3561 KiB

Open AccessCase Report

The Double Mutation DSG2-p.S363X and TBX20-p.D278X Is Associated with Left Ventricular Non-Compaction Cardiomyopathy: Case Report

by Roman Myasnikov, Andreas Brodehl, Alexey Meshkov, Olga Kulikova, Anna Kiseleva, Greta Marie Pohl, Evgeniia Sotnikova, Mikhail Divashuk, Marina Klimushina, Anastasia Zharikova, Maria Pokrovskaya, Sergey Koretskiy, Maria Kharlap, Elena Mershina, Valentin Sinitsyn, Elena Basargina, Leila Gandaeva, Vladimir Barskiy, Sergey Boytsov, Hendrik Milting and Oxana Drapkina Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(13), 6775; https://doi.org/10.3390/ijms22136775 - 24 Jun 2021

Cited by 9 | Viewed by 2497

Abstract

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk [...] Read more.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2-p.S363X and TBX20-p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein–2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant (DSG2-p.S363X) is localized in the extracellular domain of DSG2, we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2-p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC. Full article

(This article belongs to the Special Issue Atherosclerosis and Other Related-Arterial Diseases)

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