International Journal of Molecular Sciences

Editorial

4 pages, 219 KiB

Open AccessEditorial

Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity to New Therapeutic Approaches

by Shifa Jebari-Benslaiman, Asier Larrea-Sebal, Asier Benito-Vicente and César Martín

Int. J. Mol. Sci. 2023, 24(8), 7659; https://doi.org/10.3390/ijms24087659 - 21 Apr 2023

Cited by 1 | Viewed by 1216

Abstract

This Special Issue, “Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity to New Therapeutic Approaches”, contributes to advancing our knowledge of the molecular mechanisms that drive cardiovascular disease, atherosclerosis and familial hypercholesterolemia and the development of state-of-the-art research in the [...] Read more.

This Special Issue, “Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity to New Therapeutic Approaches”, contributes to advancing our knowledge of the molecular mechanisms that drive cardiovascular disease, atherosclerosis and familial hypercholesterolemia and the development of state-of-the-art research in the field [...] Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

Research

Jump to: Editorial, Review, Other

12 pages, 3244 KiB

Open AccessArticle

Functional Characterization of p.(Arg160Gln) PCSK9 Variant Accidentally Found in a Hypercholesterolemic Subject

by Asier Larrea-Sebal, Chiara Trenti, Shifa Jebari-Benslaiman, Stefano Bertolini, Sebastiano Calandra, Emanuele A. Negri, Efrem Bonelli, Asier Benito-Vicente, Leire Uraga-Gracianteparaluceta, César Martín and Tommaso Fasano

Int. J. Mol. Sci. 2023, 24(4), 3330; https://doi.org/10.3390/ijms24043330 - 7 Feb 2023

Cited by 2 | Viewed by 1596

Abstract

Familial hypercholesterolaemia (FH) is an autosomal dominant dyslipidaemia, characterised by elevated LDL cholesterol (LDL-C) levels in the blood. Three main genes are involved in FH diagnosis: LDL receptor (LDLr), Apolipoprotein B (APOB) and Protein convertase subtilisin/kexin type 9 (PCSK9) with genetic mutations that [...] Read more.

Familial hypercholesterolaemia (FH) is an autosomal dominant dyslipidaemia, characterised by elevated LDL cholesterol (LDL-C) levels in the blood. Three main genes are involved in FH diagnosis: LDL receptor (LDLr), Apolipoprotein B (APOB) and Protein convertase subtilisin/kexin type 9 (PCSK9) with genetic mutations that led to reduced plasma LDL-C clearance. To date, several PCSK9 gain-of-function (GOF) variants causing FH have been described based on their increased ability to degrade LDLr. On the other hand, mutations that reduce the activity of PCSK9 on LDLr degradation have been described as loss-of-function (LOF) variants. It is therefore important to functionally characterise PCSK9 variants in order to support the genetic diagnosis of FH. The aim of this work is to functionally characterise the p.(Arg160Gln) PCSK9 variant found in a subject suspected to have FH. Different techniques have been combined to determine efficiency of the autocatalytic cleavage, protein expression, effect of the variant on LDLr activity and affinity of the PCSK9 variant for the LDLr. Expression and processing of the p.(Arg160Gln) variant had a result similar to that of WT PCSK9. The effect of p.(Arg160Gln) PCSK9 on LDLr activity is lower than WT PCSK9, with higher values of LDL internalisation (13%) and p.(Arg160Gln) PCSK9 affinity for the LDLr is lower than WT, EC50 8.6 ± 0.8 and 25.9 ± 0.7, respectively. The p.(Arg160Gln) PCSK9 variant is a LOF PCSK9 whose loss of activity is caused by a displacement of the PCSK9 P’ helix, which reduces the stability of the LDLr-PCSK9 complex. Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

► Show Figures

Figure 1

9 pages, 638 KiB

Open AccessArticle

Decreased Epicardial CTRP3 mRNA Levels in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease Undergoing Elective Cardiac Surgery: A Possible Association with Coronary Atherosclerosis

by Zdenek Matloch, Milos Mraz, Barbora Judita Kasperova, Helena Kratochvilova, Petr Svoboda, Iveta Pleyerova, Katerina Reznickova, Sarah Norman, Daniel Hlavacek, Jakub Mahrik, Peter Ivak, Zdenka Lacinova, Ivan Netuka and Martin Haluzik

Int. J. Mol. Sci. 2022, 23(17), 9988; https://doi.org/10.3390/ijms23179988 - 1 Sep 2022

Cited by 4 | Viewed by 1811

Abstract

(1) Background: C1q TNF-related protein 3 (CTRP3) is an adipokine with anti-inflammatory and cardioprotective properties. In our study, we explored changes in serum CTRP3 and its gene expression in epicardial (EAT) and subcutaneous (SAT) adipose tissue in patients with and without coronary artery [...] Read more.

(1) Background: C1q TNF-related protein 3 (CTRP3) is an adipokine with anti-inflammatory and cardioprotective properties. In our study, we explored changes in serum CTRP3 and its gene expression in epicardial (EAT) and subcutaneous (SAT) adipose tissue in patients with and without coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) undergoing elective cardiac surgery. (2) Methods: SAT, EAT, and blood samples were collected at the start and end of surgery from 34 patients: (i) 11 without CAD or T2DM, (ii) 14 with CAD and without T2DM, and (iii) 9 with both CAD and T2DM. mRNA levels of CTRP3 were assessed by quantitative reverse transcription PCR. Circulating levels of CTRP3 and other factors were measured using ELISA and Luminex Multiplex commercial kits. (3) Results: Baseline plasma levels of TNF-α and IL6 did not differ among the groups and increased at the end of surgery. Baseline circulating levels of CTRP3 did not differ among the groups and decreased after surgery. In contrast, baseline CTRP3 mRNA levels in EAT were significantly decreased in CAD/T2DM group, while no differences were found for TNF-α and IL6 gene expression. (4) Conclusions: Our data suggest that decreased EAT mRNA levels of CTRP3 could contribute to higher risk of atherosclerosis in patients with CAD and T2DM. Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

► Show Figures

Figure 1

14 pages, 1725 KiB

Open AccessArticle

Investigation of the Associations of Novel Inflammatory Biomarkers—Systemic Inflammatory Index (SII) and Systemic Inflammatory Response Index (SIRI)—With the Severity of Coronary Artery Disease and Acute Coronary Syndrome Occurrence

by Ewelina A. Dziedzic, Jakub S. Gąsior, Agnieszka Tuzimek, Justyna Paleczny, Adam Junka, Marek Dąbrowski and Piotr Jankowski

Int. J. Mol. Sci. 2022, 23(17), 9553; https://doi.org/10.3390/ijms23179553 - 23 Aug 2022

Cited by 61 | Viewed by 15550

Abstract

Atherosclerosis, the underlying cause of coronary artery disease (CAD), has a significant inflammatory component. White blood cell count is an affordable and accessible way to assess the systemic immune response, as it comprises many subgroups with distinct and complex functions. Considering their multidirectional [...] Read more.

Atherosclerosis, the underlying cause of coronary artery disease (CAD), has a significant inflammatory component. White blood cell count is an affordable and accessible way to assess the systemic immune response, as it comprises many subgroups with distinct and complex functions. Considering their multidirectional effect on atherosclerosis, new biomarkers integrating various leukocyte subgroups, the Systemic Inflammatory Index (SII) and the Systemic Inflammatory Response Index (SIRI), were recently devised to describe the balance between inflammation and immune reaction. This research aimed to evaluate the relationship of the intensity of inflammation measured by these biomarkers with the severity of CAD assessed with coronary angiography and with the diagnosis of acute coronary syndrome (ACS) or stable CAD in 699 patients. SIRI, but not SII, was associated with the diagnosis, having the highest values for patients with ACS (STEMI), significantly higher than in patients with stable CAD (p < 0.01). The highest SII and SIRI values were observed in patients with three-vessel CAD. SII and SIRI require further in-depth and well-designed research to evaluate their potential in a clinical setting. Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

► Show Figures

Figure 1

12 pages, 884 KiB

Open AccessArticle

Non-Fasting Hypertriglyceridemia Burden as a Residual Risk of the Progression of Carotid Artery Stenosis

by Yoichi Miura, Ryuta Yasuda, Naoki Toma and Hidenori Suzuki

Int. J. Mol. Sci. 2022, 23(16), 9197; https://doi.org/10.3390/ijms23169197 - 16 Aug 2022

Cited by 3 | Viewed by 1393

Abstract

The relationships between repeated non-fasting triglyceride (TG) measurements and carotid stenosis progression during follow-ups have never been investigated. In 111 consecutive carotid arteries of 88 patients with ≥50% atherosclerotic stenosis on at least one side, who had ≥3 blood samples taken during ≥one-year [...] Read more.

The relationships between repeated non-fasting triglyceride (TG) measurements and carotid stenosis progression during follow-ups have never been investigated. In 111 consecutive carotid arteries of 88 patients with ≥50% atherosclerotic stenosis on at least one side, who had ≥3 blood samples taken during ≥one-year follow-ups, clinical variables were compared between carotid arteries with and without subsequent stenosis progression. To evaluate non-fasting TG burden, a new parameter area [TG ≥ 175] was calculated by integrating non-fasting TG values ≥ 175 mg/dL (i.e., TG values minus 175) with the measurement intervals (year). Carotid stenosis progression occurred in 22 arteries (19.8%) during the mean follow-up period of 1185 days. Younger age, symptomatic stenosis, higher mean values of TG during follow-ups, the area [TG ≥ 175], mean TG values ≥ 175 mg/dL and maximum TG values ≥175 mg/dL were significant factors related to the progression on univariate analyses. The cut-off value of the area [TG ≥ 175] to discriminate carotid stenosis progression was 6.35 year-mg/dL. Multivariate analyses demonstrated that symptomatic stenosis and the area [TG ≥ 175] ≥ 6.35 year-mg/dL were independently related to carotid stenosis progression. In conclusion, the area [TG ≥ 175] was an independent risk factor for carotid stenosis progression, and this study suggests the importance to continuously control non-fasting TG levels < 175 mg/dL during follow-ups to prevent carotid stenosis progression. Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

► Show Figures

Figure 1

15 pages, 3726 KiB

Open AccessArticle

The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice

by Eu Jeong Ku, Bo-Rahm Kim, Jee-In Lee, Yun Kyung Lee, Tae Jung Oh, Hak C. Jang and Sung Hee Choi

Int. J. Mol. Sci. 2022, 23(9), 4906; https://doi.org/10.3390/ijms23094906 - 28 Apr 2022

Cited by 15 | Viewed by 2599

Abstract

Interleukin (IL)-1β plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE^–/–) mice. ApoE^–/– mice (8-week male) were treated [...] Read more.

Interleukin (IL)-1β plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE^–/–) mice. ApoE^–/– mice (8-week male) were treated with saline (control), anakinra 10, 25, and 50 mg/kg, respectively (n = 10 in each group). Mice were fed a standard chow (4 weeks) followed by an atherogenic diet (35kcal% fat, 1.25% cholesterol, 12 weeks). Atheromatous plaques in ApoE^–/– mice and the expression of inflammatory genes and signaling pathways in human umbilical vein endothelial cells (HUVECs), rat aortic smooth muscle cells (RAOSMCs), and 3T3-L1 adipocytes were assessed. Anakinra reduced the plaque size of the aortic arch (30.6% and 25.2% at the 25 mg/kg and 50 mg/kg doses, both p < 0.05) and serum triglyceride in ApoE^–/– mice and suppressed inflammatory genes (IL-1β and IL-6) expressions in HUVECs and RAOSMCs (all p < 0.05). In RAOSMCs, anakinra reduced metalloproteinase-9 expression in a dose-dependent manner and inhibited cell migration. Anakinra-treated mice exhibited trends of lower CD68+ macrophage infiltration in visceral fat and monocyte chemoattractant protein-1 expression was reduced in 3T3-L1 adipocytes. Anakinra could be a useful component for complementary treatment with a standard regimen to reduce the residual cardiovascular risk. Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research, Other

38 pages, 3394 KiB

Open AccessReview

Pathophysiology of Atherosclerosis

by Shifa Jebari-Benslaiman, Unai Galicia-García, Asier Larrea-Sebal, Javier Rekondo Olaetxea, Iraide Alloza, Koen Vandenbroeck, Asier Benito-Vicente and César Martín

Int. J. Mol. Sci. 2022, 23(6), 3346; https://doi.org/10.3390/ijms23063346 - 20 Mar 2022

Cited by 223 | Viewed by 49494

Abstract

Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and [...] Read more.

Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. The resultant atheroma plaque, along with these processes, results in cardiovascular complications. This review focuses on the different stages of atherosclerosis development, ranging from endothelial dysfunction to plaque rupture. In addition, the post-transcriptional regulation and modulation of atheroma plaque by microRNAs and lncRNAs, the role of microbiota, and the importance of sex as a crucial risk factor in atherosclerosis are covered here in order to provide a global view of the disease. Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

► Show Figures

Figure 1

Other

Jump to: Editorial, Research, Review

10 pages, 286 KiB

Open AccessHypothesis

Mitochondrial Genetic Background May Impact Statins Side Effects and Atherosclerosis Development in Familial Hypercholesterolemia

by Eduardo Ruiz-Pesini, María Pilar Bayona-Bafaluy, Teresa Sanclemente, José Puzo, Julio Montoya and David Pacheu-Grau

Int. J. Mol. Sci. 2023, 24(1), 471; https://doi.org/10.3390/ijms24010471 - 28 Dec 2022

Cited by 3 | Viewed by 1611

Abstract

Heredity of familial hypercholesterolemia (FH) can present as a dominant monogenic disorder of polygenic origin or with no known genetic cause. In addition, the variability of the symptoms among individuals or within the same families evidence the potential contribution of additional factors than [...] Read more.

Heredity of familial hypercholesterolemia (FH) can present as a dominant monogenic disorder of polygenic origin or with no known genetic cause. In addition, the variability of the symptoms among individuals or within the same families evidence the potential contribution of additional factors than monogenic mutations that could modulate the development and severity of the disease. In addition, statins, the lipid-lowering drugs which constitute the first-line therapy for the disease, cause associated muscular symptoms in a certain number of individuals. Here, we analyze the evidence of the mitochondrial genetic variation with a special emphasis on the role of CoQ₁₀ to explain this variability found in both disease symptoms and statins side effects. We propose to use mtDNA variants and copy numbers as markers for the cardiovascular disease development of FH patients and to predict potential statin secondary effects and explore new mechanisms to identify new markers of disease or implement personalized medicine strategies for FH therapy. Full article

(This article belongs to the Special Issue Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0)

Journal Menu

Journal Browser

Cardiovascular Disease, Atherosclerosis and Familial Hypercholesterolemia: From Molecular Mechanisms Causing Pathogenicity till New Therapeutic Approaches 2.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Editorial

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI