International Journal of Molecular Sciences

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Special Issue: New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases

by Sonia Benitez and José Luis Sánchez-Quesada

Int. J. Mol. Sci. 2023, 24(13), 10659; https://doi.org/10.3390/ijms241310659 - 26 Jun 2023

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Abstract

Lipids and lipoproteins play a key role in cardiovascular diseases (CVD), mainly in the development of atherosclerosis [...] Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

Research

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15 pages, 1106 KiB

Open AccessArticle

PCSK9 Inhibitors Have Apolipoprotein C-III-Related Anti-Inflammatory Activity, Assessed by 1H-NMR Glycoprotein Profile in Subjects at High or very High Cardiovascular Risk

by Pere Rehues, Josefa Girona, Montse Guardiola, Núria Plana, Roberto Scicali, Salvatore Piro, Ovidio Muñiz-Grijalvo, José Luis Díaz-Díaz, Lluís Recasens, Marta Pinyol, Roser Rosales, Yaiza Esteban, Núria Amigó, Lluís Masana, Daiana Ibarretxe and Josep Ribalta

Int. J. Mol. Sci. 2023, 24(3), 2319; https://doi.org/10.3390/ijms24032319 - 24 Jan 2023

Cited by 9 | Viewed by 2370

Abstract

Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of [...] Read more.

Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of systemic inflammation such as high-sensitivity C-reactive protein (hsCRP). Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation, and their role as inflammatory biomarkers is under clinical evaluation. In this observational study, we evaluate the effects of iPCSK9 on glycoproteins (Glyc) A, B and F. Thirty-nine patients eligible for iPCSK9 therapy were enrolled. One sample before and after one to six months of iPCSK9 therapy with alirocumab was obtained from each patient. Lipids, apolipoproteins, hsCRP and PCSK9 levels were measured by biochemical analyses, and the lipoprotein and glycoprotein profiles were measured by 1H nuclear magnetic resonance (1H-NMR). The PCSK9 inhibitor reduced total (36.27%, p < 0.001), LDL (55.05%, p < 0.001) and non-high-density lipoprotein (HDL) (45.11%, p < 0.001) cholesterol, apolipoprotein (apo) C-III (10%, p < 0.001), triglycerides (9.92%, p < 0.001) and glycoprotein signals GlycA (11.97%, p < 0.001), GlycB (3.83%, p = 0.017) and GlycF (7.26%, p < 0.001). It also increased apoA-I (2.05%, p = 0.043) and HDL cholesterol levels (11.58%, p < 0.001). Circulating PCSK9 levels increased six-fold (626.28%, p < 0.001). The decrease in Glyc signals positively correlated with the decrease in triglycerides and apoC-III. In conclusion, in addition to LDL cholesterol, iPCSK9 therapy also induces a reduction in systemic inflammation measured by 1H-NMR glycoprotein signals, which correlates with a decrease in triglycerides and apoC-III. Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

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18 pages, 1671 KiB

Open AccessArticle

Associations between Endothelial Lipase, High-Density Lipoprotein, and Endothelial Function Differ in Healthy Volunteers and Metabolic Syndrome Patients

by Iva Klobučar, Julia T. Stadler, Lucija Klobučar, Margarete Lechleitner, Matias Trbušić, Gudrun Pregartner, Andrea Berghold, Hansjörg Habisch, Tobias Madl, Gunther Marsche, Saša Frank and Vesna Degoricija

Int. J. Mol. Sci. 2023, 24(3), 2073; https://doi.org/10.3390/ijms24032073 - 20 Jan 2023

Cited by 7 | Viewed by 1916

Abstract

Metabolic syndrome (MS) is characterized by endothelial- and high-density lipoprotein (HDL) dysfunction and increased endothelial lipase (EL) serum levels. We examined the associations between EL serum levels, HDL (serum levels, lipid content, and function), and endothelial function in healthy volunteers (HV) and MS [...] Read more.

Metabolic syndrome (MS) is characterized by endothelial- and high-density lipoprotein (HDL) dysfunction and increased endothelial lipase (EL) serum levels. We examined the associations between EL serum levels, HDL (serum levels, lipid content, and function), and endothelial function in healthy volunteers (HV) and MS patients. Flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), serum levels of HDL subclasses (measured by nuclear magnetic resonance (NMR) spectroscopy), and EL serum levels differed significantly between HV and MS patients. The serum levels of triglycerides in large HDL particles were significantly positively correlated with FMD and NMD in HV, but not in MS patients. Cholesterol (C) and phospholipid (PL) contents of large HDL particles, calculated as HDL1-C/HDL1-apoA-I and HDL1-PL/HDL1-apoA-I, respectively, were significantly negatively correlated with FMD in HV, but not in MS patients. Cholesterol efflux capacity and arylesterase activity of HDL, as well as EL, were correlated with neither FMD nor NMD. EL was significantly negatively correlated with HDL-PL/HDL-apoA-I in HV, but not in MS patients, and with serum levels of small dense HDL containing apolipoprotein A-II in MS patients, but not in HV. We conclude that MS modulates the association between HDL and endothelial function, as well as between EL and HDL. HDL cholesterol efflux capacity and arylesterase activity, as well as EL serum levels, are not associated with endothelial function in HV or MS patients. Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

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13 pages, 1063 KiB

Open AccessArticle

Presence of Ceramidase Activity in Electronegative LDL

by Núria Puig, Jose Rives, Montserrat Estruch, Ana Aguilera-Simon, Noemi Rotllan, Mercedes Camacho, Núria Colomé, Francesc Canals, José Luis Sánchez-Quesada and Sonia Benitez

Int. J. Mol. Sci. 2023, 24(1), 165; https://doi.org/10.3390/ijms24010165 - 22 Dec 2022

Cited by 2 | Viewed by 2179

Abstract

Electronegative low-density lipoprotein (LDL(−)) is a minor modified fraction of human plasma LDL with several atherogenic properties. Among them is increased bioactive lipid mediator content, such as lysophosphatidylcholine (LPC), non-esterified fatty acids (NEFA), ceramide (Cer), and sphingosine (Sph), which are related to the [...] Read more.

Electronegative low-density lipoprotein (LDL(−)) is a minor modified fraction of human plasma LDL with several atherogenic properties. Among them is increased bioactive lipid mediator content, such as lysophosphatidylcholine (LPC), non-esterified fatty acids (NEFA), ceramide (Cer), and sphingosine (Sph), which are related to the presence of some phospholipolytic activities, including platelet-activating factor acetylhydrolase (PAF-AH), phospholipase C (PLC), and sphingomyelinase (SMase), in LDL(−). However, these enzymes’ activities do not explain the increased Sph content, which typically derives from Cer degradation. In the present study, we analyzed the putative presence of ceramidase (CDase) activity, which could explain the increased Sph content. Thin layer chromatography (TLC) and lipidomic analysis showed that Cer, Sph, and NEFA spontaneously increased in LDL(−) incubated alone at 37 °C, in contrast with native LDL(+). An inhibitor of neutral CDase prevented the formation of Sph and, in turn, increased Cer content in LDL(−). In addition, LDL(−) efficiently degraded fluorescently labeled Cer (NBD-Cer) to form Sph and NEFA. These observations defend the existence of the CDase-like activity’s association with LDL(−). However, neither the proteomic analysis nor the Western blot detected the presence of an enzyme with known CDase activity. Further studies are thus warranted to define the origin of the CDase-like activity detected in LDL(−). Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

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10 pages, 4921 KiB

Open AccessArticle

Atherogenic Indices as a Predictor of Aortic Calcification in Prostate Cancer Patients Assessed Using ¹⁸F-Sodium Fluoride PET/CT

by Michelle Dai, Winnie Xu, Helene Chesnais, Nancy Anabaraonye, James Parente, Shampa Chatterjee and Chamith S. Rajapakse

Int. J. Mol. Sci. 2022, 23(21), 13056; https://doi.org/10.3390/ijms232113056 - 27 Oct 2022

Cited by 4 | Viewed by 2119

Abstract

A major pathophysiological cause of cardiovascular disease is vascular plaque calcification. Fluorine 18–Sodium Fluoride (18F-NaF) PET/CT can be used as a sensitive imaging modality for detection of vascular calcification. The aim of this study was to find a non-invasive, cost-efficient, and readily available [...] Read more.

A major pathophysiological cause of cardiovascular disease is vascular plaque calcification. Fluorine 18–Sodium Fluoride (18F-NaF) PET/CT can be used as a sensitive imaging modality for detection of vascular calcification. The aim of this study was to find a non-invasive, cost-efficient, and readily available metric for predicting vascular calcification severity. This retrospective study was performed on 36 participants who underwent 18F-NaF fused PET/CT scans. The mean standard uptake values (SUVs) were calculated from manually sectioned axial sections over the aortic arch and thoracic aorta. Correlation analyses were performed between SUVs and calculated atherogenic indices (AIs). Castelli’s Risk Index I (r = 0.63, p < 0.0001), Castelli’s Risk Index II (r = 0.64, p < 0.0001), Atherogenic Coefficient (r = 0.63, p < 0.0001), Atherogenic Index of Plasma (r = 0.51, p = 0.00152), and standalone high-density lipoprotein (HDL) cholesterol (r = −0.53, p = 0.000786) were associated with aortic calcification. AIs show strong association with aortic arch and thoracic aorta calcifications. AIs are better predictors of vascular calcification compared to standalone lipid metrics, with the exception of HDL cholesterol. Clinical application of AIs provides a holistic metric beneficial for enhancing screening and treatment protocols. Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

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12 pages, 3122 KiB

Open AccessArticle

Lipoprotein Profile in Immunological Non-Responders PLHIV after Antiretroviral Therapy Initiation

by Jenifer Masip, Rosa Jorba, Miguel López-Dupla, Pere Domingo, Yolanda María Pacheco, Graciano García-Pardo, Esteban Martínez, Consuelo Viladés, Sergi Veloso, Verónica Alba, Montserrat Olona, Francesc Vidal, Frederic Gómez-Bertomeu, Joaquim Peraire and Anna Rull

Int. J. Mol. Sci. 2022, 23(15), 8071; https://doi.org/10.3390/ijms23158071 - 22 Jul 2022

Cited by 3 | Viewed by 2095

Abstract

Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular [...] Read more.

Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular dysfunction may be associated with impaired immune function. We previously stated that immunological non-responders (INR) were at higher CV risk than immunological responders (IR) before starting antiretroviral therapy (ART). Using Liposcale^® tests, we characterized the lipoprotein profile from the same cohort of PLHIV at month 12 and month 36 after starting ART, intending to explore what happened with these indicators of CV risk during viral suppression. ART initiation dissipates the differences in lipoprotein-based CV risk markers between INR and IR, and only an increase in the number of HDL-P was found in INR + IR when compared to controls (p = 0.047). Interestingly, CD4⁺ T-cell counts negatively correlated with medium HDL-P concentrations at month 12 in all individuals (ρ = −0.335, p = 0.003). Longitudinal analyses showed an important increase in LDL-P and HDL-P at month 36 when compared to baseline values in both IR and INR. A proper balance between a proatherogenic and atherogenic environment may be related to the reconstitution of CD4⁺ T-cell count in PLHIV. Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

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Review

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15 pages, 764 KiB

Open AccessReview

Can Electronegative LDL Act as a Multienzymatic Complex?

by Sonia Benitez, Núria Puig, José Rives, Arnau Solé and José Luis Sánchez-Quesada

Int. J. Mol. Sci. 2023, 24(8), 7074; https://doi.org/10.3390/ijms24087074 - 11 Apr 2023

Cited by 3 | Viewed by 2101

Abstract

Electronegative LDL (LDL(−)) is a minor form of LDL present in blood for which proportions are increased in pathologies with increased cardiovascular risk. In vitro studies have shown that LDL(−) presents pro-atherogenic properties, including a high susceptibility to aggregation, the ability to induce [...] Read more.

Electronegative LDL (LDL(−)) is a minor form of LDL present in blood for which proportions are increased in pathologies with increased cardiovascular risk. In vitro studies have shown that LDL(−) presents pro-atherogenic properties, including a high susceptibility to aggregation, the ability to induce inflammation and apoptosis, and increased binding to arterial proteoglycans; however, it also shows some anti-atherogenic properties, which suggest a role in controlling the atherosclerotic process. One of the distinctive features of LDL(−) is that it has enzymatic activities with the ability to degrade different lipids. For example, LDL(−) transports platelet-activating factor acetylhydrolase (PAF-AH), which degrades oxidized phospholipids. In addition, two other enzymatic activities are exhibited by LDL(−). The first is type C phospholipase activity, which degrades both lysophosphatidylcholine (LysoPLC-like activity) and sphingomyelin (SMase-like activity). The second is ceramidase activity (CDase-like). Based on the complementarity of the products and substrates of these different activities, this review speculates on the possibility that LDL(−) may act as a sort of multienzymatic complex in which these enzymatic activities exert a concerted action. We hypothesize that LysoPLC/SMase and CDase activities could be generated by conformational changes in apoB-100 and that both activities occur in proximity to PAF-AH, making it feasible to discern a coordinated action among them. Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

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16 pages, 1933 KiB

Open AccessReview

The Oxidized Lipoproteins In Vivo: Its Diversity and Behavior in the Human Circulation

by Hiroyuki Itabe and Takashi Obama

Int. J. Mol. Sci. 2023, 24(6), 5747; https://doi.org/10.3390/ijms24065747 - 17 Mar 2023

Cited by 7 | Viewed by 3742

Abstract

A high concentration of low-density lipoproteins (LDLs) in circulation has been well-known as a major risk factor for cardiovascular diseases. The presence of oxidized LDLs (oxLDLs) in atherosclerotic lesions and circulation was demonstrated using anti-oxLDL monoclonal antibodies. The so-called “oxLDL hypothesis”, as a [...] Read more.

A high concentration of low-density lipoproteins (LDLs) in circulation has been well-known as a major risk factor for cardiovascular diseases. The presence of oxidized LDLs (oxLDLs) in atherosclerotic lesions and circulation was demonstrated using anti-oxLDL monoclonal antibodies. The so-called “oxLDL hypothesis”, as a mechanism for atherosclerosis development, has been attracting attention for decades. However, the oxLDL has been considered a hypothetical particle since the oxLDL present in vivo has not been fully characterized. Several chemically modified LDLs have been proposed to mimic oxLDLs. Some of the subfractions of LDL, especially Lp(a) and electronegative LDL, have been characterized as oxLDL candidates as oxidized phospholipids that stimulate vascular cells. Oxidized high-density lipoprotein (oxHDL) and oxLDL were discovered immunologically in vivo. Recently, an oxLDL-oxHDL complex was found in human plasma, suggesting the involvement of HDLs in the oxidative modification of lipoproteins in vivo. In this review, we summarize our understanding of oxidized lipoproteins and propose a novel standpoint to understand the oxidized lipoproteins present in vivo. Full article

(This article belongs to the Special Issue New Insight into the Molecular Role of Lipids and Lipoproteins in Vascular Diseases)

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