Biomolecules

Editorial

5 pages, 181 KiB

Open AccessEditorial

Understanding the Key Determinants of Cardiovascular and Metabolic Disease Progression to Develop Effective Therapeutic Strategies

by Adriana Georgescu

Biomolecules 2024, 14(10), 1281; https://doi.org/10.3390/biom14101281 - 11 Oct 2024

Viewed by 690

Abstract

Cardiovascular disease (CVD) is a general term that is used to describe a range of conditions affecting the cardiovascular system [...] Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

Research

Jump to: Editorial, Review

16 pages, 7694 KiB

Open AccessArticle

Apolipoprotein E (ApoE) Rescues the Contractile Smooth Muscle Cell Phenotype in Popliteal Artery Aneurysm Disease

by Jessica Pauli, Tessa Reisenauer, Greg Winski, Nadja Sachs, Ekaterina Chernogubova, Hannah Freytag, Christoph Otto, Christian Reeps, Hans-Henning Eckstein, Claus-Jürgen Scholz, Lars Maegdefessel and Albert Busch

Biomolecules 2023, 13(7), 1074; https://doi.org/10.3390/biom13071074 - 4 Jul 2023

Cited by 3 | Viewed by 2178

Abstract

Popliteal artery aneurysm (PAA) is the most frequent peripheral aneurysm, primarily seen in male smokers with a prevalence below 1%. This exploratory study aims to shed light on cellular mechanisms involved in PAA progression. Sixteen human PAA and eight non-aneurysmatic popliteal artery samples, [...] Read more.

Popliteal artery aneurysm (PAA) is the most frequent peripheral aneurysm, primarily seen in male smokers with a prevalence below 1%. This exploratory study aims to shed light on cellular mechanisms involved in PAA progression. Sixteen human PAA and eight non-aneurysmatic popliteal artery samples, partially from the same patients, were analyzed by immunohistochemistry, fluorescence imaging, Affymetrix mRNA expression profiling, qPCR and OLink proteomics, and compared to atherosclerotic (n = 6) and abdominal aortic aneurysm (AAA) tissue (n = 19). Additionally, primary cell culture of PAA-derived vascular smooth muscle cells (VSMC) was established for modulation and growth analysis. Compared to non-aneurysmatic popliteal arteries, VSMCs lose the contractile phenotype and the cell proliferation rate increases significantly in PAA. Array analysis identified APOE higher expressed in PAA samples, co-localizing with VSMCs. APOE stimulation of primary human PAA VSMCs significantly reduced cell proliferation. Accordingly, contractile VSMC markers were significantly upregulated. A single case of osseous mechanically induced PAA with a non-diseased VSMC profile emphasizes these findings. Carefully concluded, PAA pathogenesis shows similar features to AAA, yet the mechanisms involved might differ. APOE is specifically higher expressed in PAA tissue and could be involved in VSMC phenotype rescue. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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22 pages, 1062 KiB

Open AccessArticle

Socio-Demographic, Lifestyle, and Cardiometabolic Characteristics Associated with Low-Grade Systemic Inflammation in Russian Adult Population

by Olga Mirolyubova, Kamila Kholmatova, Anna Postoeva, Galina Kostrova, Sofia Malyutina and Alexander V. Kudryavtsev

Biomolecules 2023, 13(5), 835; https://doi.org/10.3390/biom13050835 - 14 May 2023

Cited by 2 | Viewed by 2063

Abstract

Mortality from cardiovascular diseases (CVDs) is higher in Russia compared to other European countries. High-sensitivity C-reactive protein (hs-CRP) is a biomarker of inflammation, and its elevated levels indicate increased CVD risks. We aim to describe the prevalence of low-grade systemic inflammation (LGSI) and [...] Read more.

Mortality from cardiovascular diseases (CVDs) is higher in Russia compared to other European countries. High-sensitivity C-reactive protein (hs-CRP) is a biomarker of inflammation, and its elevated levels indicate increased CVD risks. We aim to describe the prevalence of low-grade systemic inflammation (LGSI) and the associated factors in a Russian population. The Know Your Heart cross-sectional study was conducted in Arkhangelsk, Russia in 2015–2017 with a population sample aged 35–69 years (n = 2380). LGSI was defined as hs-CRP ≥ 2 and <10 mg/L, and its associations with socio-demographic, lifestyle, and cardiometabolic characteristics were analyzed. The prevalence of LGSI (age-standardized to European Standard Population 2013) was 34.1% (33.5% in men and 36.1% in women). In the total sample, the increased odds ratios (ORs) of LGSI were associated with abdominal obesity (2.1), smoking (1.9), dyslipidemia (1.5), pulmonary diseases (1.4), and hypertension (1.3); the decreased ORs were in women (0.6) and in married participants (0.6). In men, the ORs were higher with abdominal obesity (2.1), smoking (2.0), CVDs (1.5), and hazardous drinking (1.5); in women—with abdominal obesity (4.4) and pulmonary diseases (1.5). In conclusion, one-third of the adult population in Arkhangelsk had LGSI. Abdominal obesity was the strongest LGSI correlate in both sexes, while the profiles of other associated factors were different between men and women. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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22 pages, 3111 KiB

Open AccessArticle

Oscillating Glucose Induces the Increase in Inflammatory Stress through Ninjurin-1 Up-Regulation and Stimulation of Transport Proteins in Human Endothelial Cells

by Laura Toma, Gabriela M. Sanda, Camelia S. Stancu, Loredan S. Niculescu, Mina Raileanu and Anca V. Sima

Biomolecules 2023, 13(4), 626; https://doi.org/10.3390/biom13040626 - 30 Mar 2023

Cited by 4 | Viewed by 3009

Abstract

Clinical data implicate fluctuations of high levels of plasma glucose in cardiovascular diseases. Endothelial cells (EC) are the first cells of the vessel wall exposed to them. Our aim was to evaluate the effects of oscillating glucose (OG) on EC function and to [...] Read more.

Clinical data implicate fluctuations of high levels of plasma glucose in cardiovascular diseases. Endothelial cells (EC) are the first cells of the vessel wall exposed to them. Our aim was to evaluate the effects of oscillating glucose (OG) on EC function and to decipher new molecular mechanisms involved. Cultured human ECs (EA.hy926 line and primary cells) were exposed to OG (5/25 mM alternatively at 3 h), constant HG (25 mM) or physiological concentration (5 mM, NG) for 72 h. Markers of inflammation (Ninj-1, MCP-1, RAGE, TNFR1, NF-kB, and p38 MAPK), oxidative stress (ROS, VPO1, and HO-1), and transendothelial transport proteins (SR-BI, caveolin-1, and VAMP-3) were assessed. Inhibitors of ROS (NAC), NF-kB (Bay 11-7085), and Ninj-1 silencing were used to identify the mechanisms of OG-induced EC dysfunction. The results revealed that OG determined an increased expression of Ninj-1, MCP-1, RAGE, TNFR1, SR-B1, and VAMP-3 andstimulated monocyte adhesion. All of these effects were induced bymechanisms involving ROS production or NF-kB activation. NINJ-1 silencing inhibited the upregulation of caveolin-1 and VAMP-3 induced by OG in EC. In conclusion, OG induces increased inflammatory stress, ROS production, and NF-kB activation and stimulates transendothelial transport. To this end, we propose a novel mechanism linking Ninj-1 up-regulation to increased expression of transendothelial transport proteins. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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17 pages, 3426 KiB

Open AccessArticle

Metabolomic Profiling in Patients with Different Hemodynamic Subtypes of Severe Aortic Valve Stenosis

by Philipp Bengel, Manar Elkenani, Bo E. Beuthner, Maik Pietzner, Belal A. Mohamed, Beatrix Pollok-Kopp, Ralph Krätzner, Karl Toischer, Miriam Puls, Andreas Fischer, Lutz Binder, Gerd Hasenfuß and Moritz Schnelle

Biomolecules 2023, 13(1), 95; https://doi.org/10.3390/biom13010095 - 3 Jan 2023

Cited by 1 | Viewed by 2684

Abstract

Severe aortic stenosis (AS) is a common pathological condition in an ageing population imposing significant morbidity and mortality. Based on distinct hemodynamic features, i.e., ejection fraction (EF), transvalvular gradient and stroke volume, four different AS subtypes can be distinguished: (i) normal EF and [...] Read more.

Severe aortic stenosis (AS) is a common pathological condition in an ageing population imposing significant morbidity and mortality. Based on distinct hemodynamic features, i.e., ejection fraction (EF), transvalvular gradient and stroke volume, four different AS subtypes can be distinguished: (i) normal EF and high gradient, (ii) reduced EF and high gradient, (iii) reduced EF and low gradient, and (iv) normal EF and low gradient. These subtypes differ with respect to pathophysiological mechanisms, cardiac remodeling, and prognosis. However, little is known about metabolic changes in these different hemodynamic conditions of AS. Thus, we carried out metabolomic analyses in serum samples of 40 AS patients (n = 10 per subtype) and 10 healthy blood donors (controls) using ultrahigh-performance liquid chromatography–tandem mass spectroscopy. A total of 1293 biochemicals could be identified. Principal component analysis revealed different metabolic profiles in all of the subgroups of AS (All-AS) vs. controls. Out of the determined biochemicals, 48% (n = 620) were altered in All-AS vs. controls (p < 0.05). In this regard, levels of various acylcarnitines (e.g., myristoylcarnitine, fold-change 1.85, p < 0.05), ketone bodies (e.g., 3-hydroxybutyrate, fold-change 11.14, p < 0.05) as well as sugar metabolites (e.g., glucose, fold-change 1.22, p < 0.05) were predominantly increased, whereas amino acids (e.g., leucine, fold-change 0.8, p < 0.05) were mainly reduced in All-AS. Interestingly, these changes appeared to be consistent amongst all AS subtypes. Distinct differences between AS subtypes were found for metabolites belonging to hemoglobin metabolism, diacylglycerols, and dihydrosphingomyelins. These findings indicate that relevant changes in substrate utilization appear to be consistent for different hemodynamic subtypes of AS and may therefore reflect common mechanisms during AS-induced heart failure. Additionally, distinct metabolites could be identified to significantly differ between certain AS subtypes. Future studies need to define their pathophysiological implications. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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16 pages, 3451 KiB

Open AccessEditor’s ChoiceArticle

Thrombin-Mediated Formation of Globular Adiponectin Promotes an Increase in Adipose Tissue Mass

by Peter Zahradka, Carla G. Taylor, Leslee Tworek, Raissa Perrault, Sofia M’Seffar, Megha Murali, Tara Loader and Jeffrey T. Wigle

Biomolecules 2023, 13(1), 30; https://doi.org/10.3390/biom13010030 - 23 Dec 2022

Cited by 4 | Viewed by 2490

Abstract

A decrease in the circulating levels of adiponectin in obesity increases the risk of metabolic complications, but the role of globular adiponectin, a truncated form produced by proteolytic cleavage, has not been defined. The objective of this investigation was to determine how globular [...] Read more.

A decrease in the circulating levels of adiponectin in obesity increases the risk of metabolic complications, but the role of globular adiponectin, a truncated form produced by proteolytic cleavage, has not been defined. The objective of this investigation was to determine how globular adiponectin is generated and to determine whether this process impacts obesity. The cleavage of recombinant full-length adiponectin into globular adiponectin by plasma in vitro was used to identify Gly-93 as the N-terminal residue after proteolytic processing. The amino acid sequence of the cleavage site suggested thrombin was the protease responsible for cleavage, and inhibitors confirmed its likely involvement. The proteolytic site was modified, and this thrombin-resistant mutant protein was infused for 4 weeks into obese adiponectin-knockout mice that had been on a high-fat diet for 8 weeks. The mutation of the cleavage site ensured that globular adiponectin was not generated, and thus did not confound the actions of the full-length adiponectin. Mice infused with the mutant adiponectin accumulated less fat and had smaller adipocytes compared to mice treated with globular adiponectin, and concurrently had elevated fasting glucose. The data demonstrate that generation of globular adiponectin through the action of thrombin increases both adipose tissue mass and adipocyte size, but it has no effect on fasting glucose levels in the context of obesity. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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18 pages, 4211 KiB

Open AccessEditor’s ChoiceArticle

Semicarbazide-Sensitive Amine Oxidase (SSAO) and Lysyl Oxidase (LOX) Association in Rat Aortic Vascular Smooth Muscle Cells

by Vesna Manasieva, Shori Thakur, Lisa A. Lione, Jessal Patel, Anwar Baydoun and John Skamarauskas

Biomolecules 2022, 12(11), 1563; https://doi.org/10.3390/biom12111563 - 26 Oct 2022

Cited by 5 | Viewed by 2433

Abstract

Vascular smooth muscle cells (VSMCs) are the main stromal cells in the medial layer of the vascular wall. These cells produce the extracellular matrix (ECM) and are involved in many pathological changes in the vascular wall. Semicarbazide-sensitive amine oxidase (SSAO) and lysyl oxidase [...] Read more.

Vascular smooth muscle cells (VSMCs) are the main stromal cells in the medial layer of the vascular wall. These cells produce the extracellular matrix (ECM) and are involved in many pathological changes in the vascular wall. Semicarbazide-sensitive amine oxidase (SSAO) and lysyl oxidase (LOX) are vascular enzymes associated with the development of atherosclerosis. In the vascular smooth muscle cells, increased SSAO activity elevates reactive oxygen species (ROS) and induces VSMCs death; increased LOX induces chemotaxis through hydrogen peroxide dependent mechanisms; and decreased LOX contributes to endothelial dysfunction. This study investigates the relationship between SSAO and LOX in VSMCs by studying their activity, protein, and mRNA levels during VSMCs passaging and after silencing the LOX gene, while using their respective substrates and inhibitors. At the basal level, LOX activity decreased with passage and its protein expression was maintained between passages. βAPN abolished LOX activity (** p < 0.01 for 8 vs. 3 and * p < 0.05 for 5 vs. 8) and had no effect on LOX protein and mRNA levels. MDL72527 reduced LOX activity at passage 3 and 5 (^## p < 0.01) and had no effect on LOX protein, and mRNA expression. At the basal level, SSAO activity also decreased with passage, and its protein expression was maintained between passages. MDL72527 abolished SSAO activity (**** p < 0.0001 for 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 5 (** p < 0.01) and 8 (**** p < 0.0001), and Aoc3 mRNA levels at passage 8 (* p < 0.05). βAPN inhibited SSAO activity (**** p < 0.0001 for 5 vs. 3 and 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 3 (* p < 0.05), and Aoc3 mRNA levels at passage 3 (* p < 0.05). Knockdown of the LOX gene (**** p < 0.0001 for Si6 vs. Sictrl and *** p < 0.001 for Si8 vs. Sictrl) and LOX protein (** p < 0.01 for Si6 and Si8 vs. Sictrl) in VSMCs at passage 3 resulted in a reduction in Aoc3 mRNA (^#### p < 0.0001 for Si6 vs. Sictrl and ^### p < 0.001 for Si8 vs. Sictrl) and VAP-1 protein (^# p < 0.05 for Si8 vs. Sictrl). These novel findings demonstrate a passage dependent decrease in LOX activity and increase in SSAO activity in rat aortic VSMCs and show an association between both enzymes in early passage rat aortic VSMCs, where LOX was identified as a regulator of SSAO activity, protein, and mRNA expression. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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19 pages, 3335 KiB

Open AccessArticle

High-Intensity Exercise Training Improves Basal Platelet Prostacyclin Sensitivity and Potentiates the Response to Dual Anti-Platelet Therapy in Postmenopausal Women

by Kate A. Wickham, Line B. Nørregaard, Martina H. Lundberg Slingsby, Stephen S. Cheung and Ylva Hellsten

Biomolecules 2022, 12(10), 1501; https://doi.org/10.3390/biom12101501 - 17 Oct 2022

Cited by 4 | Viewed by 1984

Abstract

The risk of thrombotic events dramatically increases with age and may be accelerated in women by the cessation of endogenous estrogen production at menopause. Patients at risk of thrombosis are prescribed dual anti-platelet therapy (DAPT; aspirin and a P2Y₁₂ antagonist) and are [...] Read more.

The risk of thrombotic events dramatically increases with age and may be accelerated in women by the cessation of endogenous estrogen production at menopause. Patients at risk of thrombosis are prescribed dual anti-platelet therapy (DAPT; aspirin and a P2Y₁₂ antagonist) and are encouraged to participate in regular physical activity, as these modalities improve nitric oxide and prostacyclin-mediated inhibition of platelet aggregation. Methods: We assessed prostacyclin sensitivity as well as basal platelet reactivity with and without in vitro DAPT before and after an 8-week high-intensity exercise training program in 13 healthy, sedentary postmenopausal women. The training intervention consisted of three 1 h sessions per week. Isolated platelets were analyzed for thromboxane A₂ receptor, thromboxane A₂ synthase, cyclooxygenase-1, and prostacyclin receptor protein expression. Additionally, plasma 6-keto prostaglandin F₁_α and thromboxane B₂ levels were determined. Results: Exercise training made platelets more sensitive to the inhibitory effects of prostacyclin on thromboxane-, collagen-, and adenosine 5′-diphosphate (ADP)-induced aggregation, as well as thrombin-receptor activator peptide 6- and ADP-induced aggregation with DAPT. However, there was no change in protein expression from isolated platelets or plasma thromboxane B₂ and prostacyclin levels following training. Conclusion: Together, these findings emphasize the importance of promoting physical activity as a tool for reducing thrombotic risk in postmenopausal women and suggest that training status should be considered when prescribing DAPT in this cohort. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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9 pages, 281 KiB

Open AccessArticle

The Paradoxical Role of Circulating Ketone Bodies in Glycemic Control of Individuals with Type 2 Diabetes: High Risk, High Reward?

by Amarens van der Vaart, Martine G. E. Knol, Martin H. de Borst, Stephan J. L. Bakker, Margery A. Connelly, Erwin Garcia, Henk J. G. Bilo, Peter R. van Dijk and Robin P. F. Dullaart

Biomolecules 2022, 12(9), 1318; https://doi.org/10.3390/biom12091318 - 18 Sep 2022

Cited by 8 | Viewed by 2292

Abstract

Introduction: Fasting plasma ketone bodies (KB) are elevated in individuals with type 2 diabetes (T2D) and could affect glycemic control and disease progression. Prolonged KB exposure may result in adaptive beneficial responses, counteracting glycemic dysregulation. In the current proof-of-concept study in adults with [...] Read more.

Introduction: Fasting plasma ketone bodies (KB) are elevated in individuals with type 2 diabetes (T2D) and could affect glycemic control and disease progression. Prolonged KB exposure may result in adaptive beneficial responses, counteracting glycemic dysregulation. In the current proof-of-concept study in adults with T2D, we hypothesized that fasting plasma KB are cross-sectionally associated with poorer glycemic control but prospectively with better glycemic control. Materials and Methods: Fasting plasma KB were measured via nuclear magnetic resonance spectroscopy in patients with T2D treated in primary care (Zodiac cohort; The Netherlands). We analyzed the associations between KB and HbA1c at baseline using linear regression analyses and HbA1c changes over time using linear mixed models. We adjusted for potential confounders, including risk factors for poor glycemic control. Individuals with T2D participating in the general population-based PREVEND study were used as a replication cohort. Results: We included 271 individuals with T2D with a total of 859 HbA1c measurements during a follow-up period of 3.0 (2.0–3.2) years. At baseline, the total amount of fasting plasma KB was independently and positively associated with HbA1c levels (regression coefficient in the fully adjusted analysis = 0.31; 95% CI 0.06–0.57, per doubling of KB; p = 0.02). In contrast, in the longitudinal analyses, fasting plasma KB were associated with a yearly HbA1c (%) decrease of −0.10 (95% CI −0.19 to −0.00 per doubling baseline KB; p = 0.05). Results were replicated in 387 individuals with T2D from a general population cohort with a total of 1115 glucose measurements during a follow-up period of 7.5 (7.2–8.0) years. A yearly decrease in fasting plasma glucose (mmol/L) of 0.09 was found per doubling of baseline KB. Conclusions: This study is the first to suggest a paradoxical role of circulating KB on glycemic control in T2D: elevated KB are associated with cross-sectionally poorer glycemic control but longitudinally with better long-term glycemic control. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

12 pages, 861 KiB

Open AccessArticle

Effects of RIPC on the Metabolome in Patients Undergoing Vascular Surgery: A Randomized Controlled Trial

by Kadri Eerik, Teele Kasepalu, Karl Kuusik, Jaan Eha, Mare Vähi, Kalle Kilk, Mihkel Zilmer and Jaak Kals

Biomolecules 2022, 12(9), 1312; https://doi.org/10.3390/biom12091312 - 16 Sep 2022

Cited by 3 | Viewed by 2334

Abstract

Background: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC [...] Read more.

Background: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC affects the metabolome and to assess whether metabolomic changes correlate with heart and kidney injury markers after vascular surgery. Methods: a randomized sham-controlled, double-blinded trial was conducted at Tartu University Hospital. Patients undergoing elective open vascular surgery were recruited and RIPC was applied before operation. Blood was collected preoperatively and 24 h postoperatively. The metabolome was analyzed using the AbsoluteIDQ p180 Kit. Results: final analysis included 45 patients from the RIPC group and 47 from the sham group. RIPC did not significantly alter metabolites 24 h postoperatively. There was positive correlation of change in the kynurenine/tryptophan ratio with change in hs-troponin T (r = 0.570, p < 0.001), NT-proBNP (r = 0.552, p < 0.001), cystatin C (r = 0.534, p < 0.001) and beta-2-microglobulin (r = 0.504, p < 0.001) only in the RIPC group. Conclusions: preoperative RIPC did not significantly affect the metabolome 24 h after vascular surgery. The positive linear correlation of kynurenine/tryptophan ratio with heart and kidney injury markers suggests that the kynurenine–tryptophan pathway can play a role in RIPC-associated cardio- and nephroprotective effects. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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15 pages, 4900 KiB

Open AccessArticle

Adenine-Induced Nephropathy Reduces Atherosclerosis in ApoE Knockout Mice

by Laeticia Scherler, Sofia N. Verouti, Daniel Ackermann, Bruno Vogt and Geneviève Escher

Biomolecules 2022, 12(8), 1147; https://doi.org/10.3390/biom12081147 - 19 Aug 2022

Cited by 3 | Viewed by 2908

Abstract

Background: Cardiovascular events are the main cause of death in patients with chronic kidney disease. We hypothesize that the protective effects of renal cholesterol and vitamin D₃ metabolism are lost under this condition. Nephropathy was induced by adenine in Apolipoprotein E knockout [...] Read more.

Background: Cardiovascular events are the main cause of death in patients with chronic kidney disease. We hypothesize that the protective effects of renal cholesterol and vitamin D₃ metabolism are lost under this condition. Nephropathy was induced by adenine in Apolipoprotein E knockout mice. The atherosclerotic phenotype was compared to mice with normal renal function. Methods: Mice were fed a western diet ±0.15% adenine. Urine and feces were collected to assess renal function and fecal output. Atherosclerosis, serum lipoprotein composition and functionality, hepatic lipids, and expression of genes involved in lipid metabolism, vitamin D₃ and Na⁺ homeostasis, were assessed. Bones were analyzed by microCT. Results: Mice fed with adenine showed enhanced urinary Na⁺, Ca²⁺, and Pi excretion, reduced urinary pH, Urea_Urine/Urea_Serum, and Creatinine_Urine/Creatinine_Serum ratios. They developed less atherosclerosis. Lipoproteins in serum and hepatic lipids remained unchanged. Cholesterol efflux increased. Fecal output of cholesteryl ester and triglycerides increased. In the liver, mRNA levels of Cyp27a1, Cyp7a1, and Scarb1 increased; in the kidneys, Slc9a3, Slc12a3, Vdr, and Cyp24a1 decreased. Adenine increased cholesterol efflux in vitro. Tibias were shorter. Conclusion: Adenine induced tubular damage and was athero-protective because of enhanced cholesterol efflux and lipids elimination in feces. Bone growth was also affected. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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15 pages, 6939 KiB

Open AccessEditor’s ChoiceArticle

Extracellular Vesicles from Steatotic Hepatocytes Provoke Pro-Fibrotic Responses in Cultured Stellate Cells

by Maria Teresa Koenen, Elisa Fabiana Brandt, Dawid Marcin Kaczor, Tim Caspers, Alexandra Catharina Anna Heinzmann, Petra Fischer, Daniel Heinrichs, Theresa Hildegard Wirtz, Christian Trautwein, Rory R Koenen and Marie-Luise Berres

Biomolecules 2022, 12(5), 698; https://doi.org/10.3390/biom12050698 - 13 May 2022

Cited by 7 | Viewed by 3178

Abstract

Hepatic steatosis and chronic hepatocyte damage ultimately lead to liver fibrosis. Key pathophysiological steps are the activation and transdifferentiation of hepatic stellate cells. We assessed the interplay between hepatocytes and hepatic stellate cells under normal and steatotic conditions. We hypothesized that hepatocyte-derived extracellular [...] Read more.

Hepatic steatosis and chronic hepatocyte damage ultimately lead to liver fibrosis. Key pathophysiological steps are the activation and transdifferentiation of hepatic stellate cells. We assessed the interplay between hepatocytes and hepatic stellate cells under normal and steatotic conditions. We hypothesized that hepatocyte-derived extracellular vesicles (EVs) modify the phenotype of stellate cells. By high speed centrifugation, EVs were isolated from conditioned media of the hepatocellular carcinoma cell line HepG2 under baseline conditions (C-EVs) or after induction of steatosis by linoleic and oleic acids for 24 h (FA-EVs). Migration of the human stellate cell line TWNT4 and of primary human stellate cells towards the respective EVs and sera of MAFLD patients were investigated using Boyden chambers. Phenotype alterations after incubation with EVs were determined by qRT-PCR, Western blotting and immunofluorescence staining. HepG2 cells released more EVs after treatment with fatty acids. Chemotactic migration of TWNT4 and primary hepatic stellate cells was increased, specifically towards FA-EVs. Prolonged incubation of TWNT4 cells with FA-EVs induced expression of proliferation markers and a myofibroblast-like phenotype. Though the expression of the collagen type 1

α

1 gene did not change after FA-EV treatment, expression of the myofibroblast markers, e.g.,

α

-smooth-muscle-cell actin and TIMP1, was significantly increased. We conclude that EVs from steatotic hepatocytes can influence the behavior, phenotypes and expression levels of remodeling markers of stellate cells and guides their directed migration. These findings imply EVs as operational, intercellular communicators in the pathophysiology of steatosis-associated liver fibrosis and might represent a novel diagnostic parameter and therapeutic target. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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Review

Jump to: Editorial, Research

13 pages, 851 KiB

Open AccessReview

Factors and Mechanisms of Thyroid Hormone Activity in the Brain: Possible Role in Recovery and Protection

by Laura Sabatino, Dominga Lapi and Cristina Del Seppia

Biomolecules 2024, 14(2), 198; https://doi.org/10.3390/biom14020198 - 7 Feb 2024

Cited by 5 | Viewed by 2584

Abstract

Thyroid hormones (THs) are essential in normal brain development, and cognitive and emotional functions. THs act through a cascade of events including uptake by the target cells by specific cell membrane transporters, activation or inactivation by deiodinase enzymes, and interaction with nuclear thyroid [...] Read more.

Thyroid hormones (THs) are essential in normal brain development, and cognitive and emotional functions. THs act through a cascade of events including uptake by the target cells by specific cell membrane transporters, activation or inactivation by deiodinase enzymes, and interaction with nuclear thyroid hormone receptors. Several thyroid responsive genes have been described in the developing and in the adult brain and many studies have demonstrated a systemic or local reduction in TH availability in neurologic disease and after brain injury. In this review, the main factors and mechanisms associated with the THs in the normal and damaged brain will be evaluated in different regions and cellular contexts. Furthermore, the most common animal models used to study the role of THs in brain damage and cognitive impairment will be described and the use of THs as a potential recovery strategy from neuropathological conditions will be evaluated. Finally, particular attention will be given to the link observed between TH alterations and increased risk of Alzheimer’s Disease (AD), the most prevalent neurodegenerative and dementing condition worldwide. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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16 pages, 2376 KiB

Open AccessReview

The Role of Inflammation in The Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease

by Oluwabukola T. Gbotosho, Jahnavi Gollamudi and Hyacinth I. Hyacinth

Biomolecules 2023, 13(2), 381; https://doi.org/10.3390/biom13020381 - 17 Feb 2023

Cited by 6 | Viewed by 3430

Abstract

Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in the lifespan of patients with sickle cell disease (SCD). Inflammation has been identified as a major risk modifier in the pathogenesis of SCD-associated cardiopulmonary complications in recent mechanistic and [...] Read more.

Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in the lifespan of patients with sickle cell disease (SCD). Inflammation has been identified as a major risk modifier in the pathogenesis of SCD-associated cardiopulmonary complications in recent mechanistic and observational studies. In this review, we discuss recent cellular and molecular mechanisms of cardiopulmonary complications in SCD and summarize the most recent evidence from clinical and laboratory studies. We emphasize the role of inflammation in the onset and progression of these complications to better understand the underlying pathobiological processes. We also discuss future basic and translational research in addressing questions about the complex role of inflammation in the development of SCD cardiopulmonary complications, which may lead to promising therapies and reduce morbidity and mortality in this vulnerable population. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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28 pages, 893 KiB

Open AccessReview

Cardiovascular Disease as a Consequence or a Cause of Cancer: Potential Role of Extracellular Vesicles

by Elisabeta Badila, Cristina Japie, Ana-Maria Vrabie, Adrian Badila and Adriana Georgescu

Biomolecules 2023, 13(2), 321; https://doi.org/10.3390/biom13020321 - 8 Feb 2023

Cited by 4 | Viewed by 3463

Abstract

Both cardiovascular disease and cancer continue to be causes of morbidity and mortality all over the world. Preventing and treating heart disease in patients undergoing cancer treatment remain an important and ongoing challenge for improving the lives of cancer patients, but also for [...] Read more.

Both cardiovascular disease and cancer continue to be causes of morbidity and mortality all over the world. Preventing and treating heart disease in patients undergoing cancer treatment remain an important and ongoing challenge for improving the lives of cancer patients, but also for their survival. Despite ongoing efforts to improve patient survival, minimal advances have been made in the early detection of cardiovascular disease in patients suffering from cancer. Understanding the communication between cancer and cardiovascular disease can be based on a deeper knowledge of the molecular mechanisms that define the profile of the bilateral network and establish disease-specific biomarkers and therapeutic targets. The role of exosomes, microvesicles, and apoptotic bodies, together defined as extracellular vesicles (EVs), in cross talk between cardiovascular disease and cancer is in an incipient form of research. Here, we will discuss the preclinical evidence on the bilateral connection between cancer and cardiovascular disease (especially early cardiac changes) through some specific mediators such as EVs. Investigating EV-based biomarkers and therapies may uncover the responsible mechanisms, detect the early stages of cardiovascular damage and elucidate novel therapeutic approaches. The ultimate goal is to reduce the burden of cardiovascular diseases by improving the standard of care in oncological patients treated with anticancer drugs or radiotherapy. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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15 pages, 1887 KiB

Open AccessReview

Myocarditis-like Episodes in Patients with Arrhythmogenic Cardiomyopathy: A Systematic Review on the So-Called Hot-Phase of the Disease

by Riccardo Bariani, Ilaria Rigato, Alberto Cipriani, Maria Bueno Marinas, Rudy Celeghin, Cristina Basso, Domenico Corrado, Kalliopi Pilichou and Barbara Bauce

Biomolecules 2022, 12(9), 1324; https://doi.org/10.3390/biom12091324 - 19 Sep 2022

Cited by 25 | Viewed by 3107

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease, characterized by myocytes necrosis with fibrofatty substitution and ventricular arrhythmias that can even lead to sudden cardiac death. The presence of inflammatory cell infiltrates in endomyocardial biopsies or in autoptic specimens of ACM patients [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease, characterized by myocytes necrosis with fibrofatty substitution and ventricular arrhythmias that can even lead to sudden cardiac death. The presence of inflammatory cell infiltrates in endomyocardial biopsies or in autoptic specimens of ACM patients has been reported, suggesting a possible role of inflammation in the pathophysiology of the disease. Furthermore, chest pain episodes accompanied by electrocardiographic changes and troponin release have been observed and defined as the “hot-phase” phenomenon. The aim of this critical systematic review was to assess the clinical features of ACM patients presenting with “hot-phase” episodes. According to PRISMA guidelines, a search was run in the PubMed, Scopus and Web of Science electronic databases using the following keywords: “arrhythmogenic cardiomyopathy”; “myocarditis” or “arrhythmogenic cardiomyopathy”; “troponin” or “arrhythmogenic cardiomyopathy”; and “hot-phase”. A total of 1433 titles were retrieved, of which 65 studies were potentially relevant to the topic. Through the application of inclusion and exclusion criteria, 9 papers reporting 103 ACM patients who had experienced hot-phase episodes were selected for this review. Age at time of episodes was available in 76% of cases, with the mean age reported being 26 years ± 14 years (min 2–max 71 years). Overall, 86% of patients showed left ventricular epicardial LGE. At the time of hot-phase episodes, 49% received a diagnosis of ACM (Arrhythmogenic left ventricular cardiomyopathy in the majority of cases), 19% of dilated cardiomyopathy and 26% of acute myocarditis. At the genetic study, Desmoplakin (DSP) was the more represented disease-gene (69%), followed by Plakophillin-2 (9%) and Desmoglein-2 (6%). In conclusion, ACM patients showing hot-phase episodes are usually young, and DSP is the most common disease gene, accounting for 69% of cases. Currently, the role of “hot-phase” episodes in disease progression and arrhythmic risk stratification remains to be clarified. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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22 pages, 3630 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Understanding How Heart Metabolic Derangement Shows Differential Stage Specificity for Heart Failure with Preserved and Reduced Ejection Fraction

by Federico Ferro, Renza Spelat, Camilla Valente and Paolo Contessotto

Biomolecules 2022, 12(7), 969; https://doi.org/10.3390/biom12070969 - 11 Jul 2022

Cited by 11 | Viewed by 3736

Abstract

Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting [...] Read more.

Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting in delays in recognizing patients until heart dysfunction is manifested, thus increasing the chance of poor prognosis. Given the recent advances in metabolomics, in this review we dissect the main alterations occurring in the metabolic pathways behind the decrease in cardiac function caused by HF. Indeed, relevant preclinical and clinical research has been conducted on the metabolite connections and differences between HFpEF and HFrEF. Despite these promising results, it is crucial to note that, in addition to identifying single markers and reliable threshold levels within the healthy population, the introduction of composite panels would strongly help in the identification of those individuals with an increased HF risk. That said, additional research in the field is required to overcome the current drawbacks and shed light on the pathophysiological changes that lead to HF. Finally, greater collaborative data sharing, as well as standardization of procedures and approaches, would enhance this research field to fulfil its potential. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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22 pages, 3607 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Evidence of Failed Resolution Mechanisms in Arrhythmogenic Inflammation, Fibrosis and Right Heart Disease

by Rim Younes, Charles-Alexandre LeBlanc and Roddy Hiram

Biomolecules 2022, 12(5), 720; https://doi.org/10.3390/biom12050720 - 19 May 2022

Cited by 8 | Viewed by 5637

Abstract

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can [...] Read more.

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can lead to chronic inflammatory disorders due to aggravation of structural damages, development of a fibrous area, and loss of function. Various human conditions show a typical unresolved inflammatory profile. Inflammatory diseases include cancer, neurodegenerative disease, asthma, right heart disease, atherosclerosis, myocardial infarction, or atrial fibrillation. New evidence has started to emerge on the role, including pro-resolution involvement of chemical mediators in the acute phase of inflammation. Although flourishing knowledge is available about the role of specialized pro-resolving mediators in neurodegenerative diseases, atherosclerosis, obesity, or hepatic fibrosis, little is known about their efficacy to combat inflammation-associated arrhythmogenic cardiac disorders. It has been shown that resolvins, including RvD1, RvE1, or Mar1, are bioactive mediators of resolution. Resolvins can stop neutrophil activation and infiltration, stimulate monocytes polarization into anti-inflammatory-M2-macrophages, and activate macrophage phagocytosis of inflammation-debris and neutrophils to promote efferocytosis and clearance. This review aims to discuss the paradigm of failed-resolution mechanisms (FRM) potentially promoting arrhythmogenicity in right heart disease-induced inflammatory status. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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