Topic Editors

Department of Clinical Therapeutics, Medical School of the National and Kapodistrian, University of Athens, P.O. Box 11528, 80 Vas. Sofias Str, Athens, Greece
Dr. Georgios Georgiopoulos
1. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, 11527 Athens, Greece
2. School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
3. Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
Department of Clinical Therapeutics, Faculty of Medicine, National and Kapodistrian University of Athens, Alexandra Hospital, 11528 Athens, Greece

Angiology and Endothelial Pathophysiology in Human Diseases

Abstract submission deadline
closed (31 December 2022)
Manuscript submission deadline
closed (31 March 2023)
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Topic Information

Dear Colleagues,

With growing awareness and the evolution of new therapies targeting atherosclerosis, there is a need to expand and disseminate knowledge on the emerging interplay between impaired vascular function and cardiac disease, novel treatment approaches, pathophysiology, and associated outcomes. This themed topic collection aims to summarize the growing body of literature regarding the interplay of vascular function and cardiac diseases and highlight new original findings across a wide spectrum of cardiovascular disease phenotypes. Topics spanning this theme will be considered, including the role of imaging and biomarkers in vascular disease, clinical management, emerging therapies, and other relevant issues. Authors are encouraged to submit original research articles, reviews, and meta-analyses.

Dr. Kimon Stamatelopoulos
Dr. Georgios Georgiopoulos
Dr. Alexandros Briasoulis
Topic Editors

Keywords

  • endothelial dysfunction
  • arterial stiffening
  • atherosclerosis
  • vascular aging
  • vascular inflammation
  • ventricular–arterial coupling
  • vascular function
  • cardiovascular disease prevention
  • biomarkers in cardiovascular disease

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomedicines
biomedicines
3.9 5.2 2013 15.3 Days CHF 2600
Diagnostics
diagnostics
3.0 4.7 2011 20.5 Days CHF 2600
Hearts
hearts
- - 2020 18.5 Days CHF 1000
International Journal of Molecular Sciences
ijms
4.9 8.1 2000 18.1 Days CHF 2900
Journal of Clinical Medicine
jcm
3.0 5.7 2012 17.3 Days CHF 2600

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Published Papers (18 papers)

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14 pages, 574 KiB  
Article
Involvement of APOE in Incidence of Revascularization in Patients Affected by Peripheral Arterial Disease: A Prospective Study from Southern Italy
by Giuseppe Di Stolfo, Michele Antonio Pacilli, Davide Seripa, Giovanni De Luca, Maria Urbano, Carlo Coli, Carolina Gravina, Antonio Greco, Domenico Rosario Potenza, Mauro Pellegrino Salvatori, Gerit-Holger Schernthaner, Pavel Poredos, Mariella Catalano and Sandra Mastroianno
J. Clin. Med. 2023, 12(16), 5178; https://doi.org/10.3390/jcm12165178 - 9 Aug 2023
Viewed by 805
Abstract
Introduction. Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from [...] Read more.
Introduction. Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from its polymorphism are derived three alleles (ε2, ε3 and ε4), which induce different phenotypes, while its impact on carotid and femoral atherosclerosis is still controversial. Objectives. The aim of the study is to investigate the relationship between APOE genotypes and peripheral revascularization in a cohort of patients affected by advanced peripheral arterial disease (PAD) at a prolonged follow-up. Materials and methods. Some 332 patients (259 males and 73 females; mean age 70.86 ± 7.95 years) with severe PAD were enrolled in a longitudinal study, with a 90.75 ± 32.25 month follow-up, assessing major adverse cardiovascular events (MACE). Results. As compared with ε3/ε3, in ε4 patients we observed a significant higher incidence of carotid (13.2% vs. 5.6%; HR = 2.485, 95% CI 1.062–5.814; p = 0.036) and lower limb (11.8% vs. 4.3%; HR = 2.765, 95% CI 1.091–7.008; p = 0.032) revascularizations and, accordingly, a higher incidence of total peripheral revascularizations (13.5% vs. 9.5%; HR = 2.705, 95% CI 1.420–5.151; p = 0.002). HR remained statistically significant even when adjusted for classic cardiovascular risk factors. Conclusions. In our observational study, we confirm that the ε4 allele is associated with higher total peripheral revascularization in patients with advanced atherosclerotic vascular disease at prolonged follow-up. Full article
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17 pages, 7028 KiB  
Article
Vascular Stem Cells and the Role of B-Raf Kinase in Survival, Proliferation, and Apoptosis
by Dipali Goyal, Sean W. Limesand and Ravi Goyal
Int. J. Mol. Sci. 2023, 24(8), 7483; https://doi.org/10.3390/ijms24087483 - 19 Apr 2023
Viewed by 1129
Abstract
Neovascularization is an essential process in organismal development and aging. With aging, from fetal to adult life, there is a significant reduction in neovascularization potential. However, the pathways which play a role in increased neovascularization potential during fetal life are unknown. Although several [...] Read more.
Neovascularization is an essential process in organismal development and aging. With aging, from fetal to adult life, there is a significant reduction in neovascularization potential. However, the pathways which play a role in increased neovascularization potential during fetal life are unknown. Although several studies proposed the idea of vascular stem cells (VSCs), the identification and essential survival mechanism are still not clear. In the present study, we isolated fetal VSCs from the ovine carotid artery and identified the pathways involved in their survival. We tested the hypothesis that fetal vessels contain a population of VSCs, and that B-Raf kinase is required for their survival. We conducted viability, apoptotic, and cell cycle stage assays on fetal and adult carotid arteries and isolated cells. To determine molecular mechanisms, we conducted RNAseq, PCR, and western blot experiments to characterize them and identify pathways essential for their survival. Results: A stem cell-like population was isolated from fetal carotid arteries grown in serum-free media. The isolated fetal VSCs contained markers for endothelial, smooth muscle, and adventitial cells, and formed a de novo blood vessel ex vivo. A transcriptomic analysis that compared fetal and adult arteries identified pathway enrichment for several kinases, including B-Raf kinase in fetal arteries. Furthermore, we demonstrated that B-Raf- Signal Transducer and Activator of Transcription 3 (STAT3)-Bcl2 is critical for the survival of these cells. Fetal arteries, but not adult arteries, contain VSCs, and B-Raf-STAT3-Bcl2 plays an important role in their survival and proliferation. Full article
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7 pages, 2416 KiB  
Case Report
Is COVID-19 All That Glitters?
by Salvatore Spampinato, Maurizio Di Marco, Luciano Mammolito, Alessia Scarfia, Maurizio Valastro, Stefania Di Mauro, Giosiana Bosco, Francesco Purrello and Salvatore Piro
J. Clin. Med. 2023, 12(7), 2552; https://doi.org/10.3390/jcm12072552 - 28 Mar 2023
Cited by 1 | Viewed by 1105
Abstract
Over the last three years, the Coronavirus-19 disease has been a global health emergency, playing a primary role in the international scientific community. Clinical activity and scientific research have concentrated their efforts on facing the pandemic, allowing the description of novel pathologies correlated [...] Read more.
Over the last three years, the Coronavirus-19 disease has been a global health emergency, playing a primary role in the international scientific community. Clinical activity and scientific research have concentrated their efforts on facing the pandemic, allowing the description of novel pathologies correlated to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), such as the Multisystemic Inflammatory Syndrome in Children and Adults (MIS-C, MIS-A). Conversely, this shift of attention to COVID-19 disease and its complications could, in some cases, have delayed and underestimated the diagnosis of diseases not associated with SARS-CoV-2, including rare diseases. Here we describe the diagnostic process that led to the definition of a rare vasculitis in a young woman with a recent clinical history of SARS-CoV-2. Full article
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13 pages, 1985 KiB  
Article
Pregnancy-Specific Glycoprotein 9 Enhances Store-Operated Calcium Entry and Nitric Oxide Release in Human Umbilical Vein Endothelial Cells
by Ying Qin, Qinggang Meng, Qunhua Wang, Mingzhu Wu, Yan Fang, Chengcheng Tu, Xinyang Hu, Bing Shen, Hongbo Chen and Xiaohong Xu
Diagnostics 2023, 13(6), 1134; https://doi.org/10.3390/diagnostics13061134 - 16 Mar 2023
Viewed by 1382
Abstract
We explored changes in pregnancy-specific glycoprotein 9 (PSG9) levels in the serum of patients with preeclampsia and the effects and underlying mechanisms of PSG9 effects on calcium (Ca2+) homeostasis and nitric oxide (NO) release in human umbilical vein endothelial cells (HUVECs). [...] Read more.
We explored changes in pregnancy-specific glycoprotein 9 (PSG9) levels in the serum of patients with preeclampsia and the effects and underlying mechanisms of PSG9 effects on calcium (Ca2+) homeostasis and nitric oxide (NO) release in human umbilical vein endothelial cells (HUVECs). Western blotting was used to detect protein expression levels, and an NO fluorescence probe was used to examine NO production. Intracellular Ca2+ concentrations were measured using a Ca2+-sensitive fluorescent dye under a fluorescence microscope. Compared with those in healthy pregnant women, serum PSG9 levels were significantly decreased in patients with preeclampsia. PSG9 (0.1 μg/mL) treatment of HUVECs significantly enhanced the expression levels of store-operated calcium entry (SOCE) channel proteins Orai1 and Orai2, but not Orai3, and of endothelial nitric oxide synthase (eNOS) and NO production. Pretreatment with an inhibitor of SOCE (BTP2) abolished PSG9-enhanced Orai1, Orai2, and eNOS expression levels and NO production in HUVECs. The mechanisms underlying SOCE that were PSG9 enhanced in HUVECs appear to involve the Ca2+/eNOS/NO signaling pathway. These findings suggest that serum PSG9 levels may be a potential biomarker for monitoring the occurrence or development of preeclampsia in pregnancy and that PSG9 may be a potential therapeutic target for the treatment of preeclampsia. Full article
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20 pages, 1150 KiB  
Review
Vascular Function in Continuous Flow LVADs: Implications for Clinical Practice
by Fouad Khalil, Rabea Asleh, Radha Kanneganti Perue, Jean-Marc Weinstein, Adam Solomon, Batya Betesh-Abay, Alexandros Briasoulis and Hilmi Alnsasra
Biomedicines 2023, 11(3), 757; https://doi.org/10.3390/biomedicines11030757 - 2 Mar 2023
Cited by 4 | Viewed by 2621
Abstract
Left ventricular assist devices (LVADs) have been increasingly used in patients with advanced heart failure, either as a destination therapy or as a bridge to heart transplant. Continuous flow (CF) LVADs have revolutionized advanced heart failure treatment. However, significant vascular pathology and complications [...] Read more.
Left ventricular assist devices (LVADs) have been increasingly used in patients with advanced heart failure, either as a destination therapy or as a bridge to heart transplant. Continuous flow (CF) LVADs have revolutionized advanced heart failure treatment. However, significant vascular pathology and complications have been linked to their use. While the newer CF-LVAD generations have led to a reduction in some vascular complications such as stroke, no major improvement was noticed in the rate of other vascular complications such as gastrointestinal bleeding. This review attempts to provide a comprehensive summary of the effects of CF-LVAD on vasculature, including pathophysiology, clinical implications, and future directions. Full article
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19 pages, 6929 KiB  
Article
Potassium Dehydroandrograpolide Succinate Targets NRP1 Mediated VEGFR2/VE-Cadherin Signaling Pathway to Promote Endothelial Barrier Repair
by Zheng Wang, Xiao Wu, Jiali Li, Qiru Guo, Zhong Jin, Hongfei Li, Bing Liang, Wangming Hu, Huan Xu, Liangqin Shi, Lan Yang and Yong Wang
Int. J. Mol. Sci. 2023, 24(4), 3096; https://doi.org/10.3390/ijms24043096 - 4 Feb 2023
Cited by 1 | Viewed by 1680
Abstract
Impairment of vascular endothelial integrity is associated with various vascular diseases. Our previous studies demonstrated that andrographolide is critical to maintaining gastric vascular homeostasis, as well as to regulating pathological vascular remodeling. Potassium dehydroandrograpolide succinate (PDA), a derivative of andrographolide, has been clinically [...] Read more.
Impairment of vascular endothelial integrity is associated with various vascular diseases. Our previous studies demonstrated that andrographolide is critical to maintaining gastric vascular homeostasis, as well as to regulating pathological vascular remodeling. Potassium dehydroandrograpolide succinate (PDA), a derivative of andrographolide, has been clinically used for the therapeutic treatment of inflammatory diseases. This study aimed to determine whether PDA promotes endothelial barrier repair in pathological vascular remodeling. Partial ligation of the carotid artery in ApoE−/− mice was used to evaluate whether PDA can regulate pathological vascular remodeling. A flow cytometry assay, BRDU incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay and Matrigel-based tube formation assay were performed to determine whether PDA can regulate the proliferation and motility of HUVEC. A molecular docking simulation and CO-immunoprecipitation assay were performed to observe protein interactions. We observed that PDA induced pathological vascular remodeling characterized by enhanced neointima formation. PDA treatment significantly enhanced the proliferation and migration of vascular endothelial cells. Investigating the potential mechanisms and signaling pathways, we observed that PDA induced endothelial NRP1 expression and activated the VEGF signaling pathway. Knockdown of NRP1 using siRNA transfection attenuated PDA-induced VEGFR2 expression. The interaction between NRP1 and VEGFR2 caused VE-Cad-dependent endothelial barrier impairment, which was characterized by enhanced vascular inflammation. Our study demonstrated that PDA plays a critical role in promoting endothelial barrier repair in pathological vascular remodeling. Full article
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13 pages, 1317 KiB  
Article
Rheopheresis Performed in Hemodialysis Patients Targets Endothelium and Has an Acute Anti-Inflammatory Effect
by Justine Solignac, Romaric Lacroix, Laurent Arnaud, Evelyne Abdili, Dammar Bouchouareb, Stéphane Burtey, Philippe Brunet, Françoise Dignat-George and Thomas Robert
J. Clin. Med. 2023, 12(1), 105; https://doi.org/10.3390/jcm12010105 - 23 Dec 2022
Viewed by 1830
Abstract
Background: Rheopheresis is a double-filtration plasmapheresis that removes a defined spectrum of high-molecular-weight proteins to lower plasma viscosity and improves microcirculation disorders. This technique can be performed in hemodialysis (HD) patients with severe microischemia. Interestingly, some studies showed that rheopheresis sessions improve endothelial [...] Read more.
Background: Rheopheresis is a double-filtration plasmapheresis that removes a defined spectrum of high-molecular-weight proteins to lower plasma viscosity and improves microcirculation disorders. This technique can be performed in hemodialysis (HD) patients with severe microischemia. Interestingly, some studies showed that rheopheresis sessions improve endothelial function. Methods: Our study evaluated the inflammatory and endothelial biomarker evolution in 23 HD patients treated or not with rheopheresis. A p value ≤ 0.001 was considered statistically significant. Results: Thirteen HD patients treated by rheopheresis either for a severe peripheral arterial disease (N = 8) or calciphylaxis (N = 5) were analyzed. Ten control HD patients were also included in order to avoid any misinterpretation of the rheopheresis effects in regard to the HD circuit. In the HD group without rheopheresis, the circulating endothelial adhesion molecules, cytokines, angiogenic factor concentrations, and circulating levels were not modified. In the HD group with rheopheresis, the circulating endothelial adhesion molecules (sVCAM-1, sP-selectin, and sE-selectin) experienced a significant reduction, except sICAM-1. Among the pro-inflammatory cytokines, TNF-α was significantly reduced by 32.6% [(−42.2)–(−22.5)] (p < 0.0001), while the anti-inflammatory cytokine IL-10 increased by 674% (306–1299) (p < 0.0001). Among the angiogenic factors, only sEndoglin experienced a significant reduction. The CEC level trended to increase from 13 (3–33) cells/mL to 43 (8–140) cells/mL (p = 0.002). We did not observe any difference on the pre-session values of the molecules of interest between the first rheopheresis session and the last rheopheresis session. Conclusion: Rheopheresis immediately modified the inflammation balance and the endothelial injury biomarkers. Further studies are needed to understand the mechanisms underlying these biological observations. Full article
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10 pages, 912 KiB  
Article
Plasma Endocan as a Biomarker of Thrombotic Events in COVID-19 Patients
by Camille Chenevier-Gobeaux, Morgane Ducastel, Jean-François Meritet, Yassine Ballaa, Nicolas Chapuis, Frédéric Pene, Nicolas Carlier, Nicolas Roche, Tali-Anne Szwebel, Benjamin Terrier and Didier Borderie
J. Clin. Med. 2022, 11(19), 5560; https://doi.org/10.3390/jcm11195560 - 22 Sep 2022
Cited by 6 | Viewed by 1664
Abstract
(1) Background: Endocan is a marker of endothelial dysfunction that may be associated with thrombotic events. The aim of the study was to investigate the performance of endocan as a marker of thrombotic events in COVID-19 patients. (2) Methods: We measured endocan in [...] Read more.
(1) Background: Endocan is a marker of endothelial dysfunction that may be associated with thrombotic events. The aim of the study was to investigate the performance of endocan as a marker of thrombotic events in COVID-19 patients. (2) Methods: We measured endocan in plasma from 79 documented COVID-19 patients classified according to disease severity (from mild to critical). Thrombotic events were recorded. (3) Results: Endocan concentrations at admission were significantly increased according to COVID-19 severity. Levels of endocan were significantly increased in patients experiencing thrombotic events in comparison with those without (16.2 (5.5–26.7) vs. 1.81 (0.71–10.5) ng/mL, p < 0.001). However, endocan concentrations were not different between pulmonary embolism and other thrombotic events. The Receiver Operating Characteristic (ROC) analysis for the identification of thrombotic events showed an area under the ROC curve (AUC) of 0.776 with an optimal threshold at 2.83 ng/mL (93.8% sensitivity and 54.7% specificity). When combining an endocan measurement with D-dimers, the AUC increased to 0.853. When considering both biomarkers, the Kaplan–Meier survival curves showed that the combination of endocan and D-dimers better discriminated patients with thrombotic events than those without. The combination of D-dimers and endocan was independently associated with thrombotic events. (4) Conclusions: Endocan might be a useful and informative biomarker to better identify thrombotic events in COVID-19 patients. Full article
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13 pages, 12282 KiB  
Article
Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells
by Xi Liu, Yi Li, Zhen Zhang, Juan Lu, Gang Pei and Shichao Huang
Int. J. Mol. Sci. 2022, 23(16), 9118; https://doi.org/10.3390/ijms23169118 - 14 Aug 2022
Cited by 4 | Viewed by 2568
Abstract
Structural and functional alterations of vasculature caused by age-related factors is critically involved in the pathogenesis of ischemic stroke. The longevity genes sirtuins (SIRTs) are extensively investigated in aging-associated pathologies, but their distinct roles in ischemic stroke still remain to be clarified. To [...] Read more.
Structural and functional alterations of vasculature caused by age-related factors is critically involved in the pathogenesis of ischemic stroke. The longevity genes sirtuins (SIRTs) are extensively investigated in aging-associated pathologies, but their distinct roles in ischemic stroke still remain to be clarified. To address this question, we applied oxygen and glucose deprived/reperfusion (OGD/R) to induce ischemic injury in human endothelial cells (ECs), which are the main component of vasculature in the brain. The results showed that OGD/R led to various damages to ECs, including compromised cell viability, increased LDH release, overproduced ROS, enhanced apoptosis and caspase activity. Meanwhile, the expression of mitochondrial SIRT3 was robustly decreased in ECs after OGD/R treatment. Consistently, rescue of SIRT3 by ectopic expression, but not nuclear SIRT1, in ECs reversed the OGD/R-induced cell damage. Interestingly, some front-line drugs for ischemic stroke, including clopidogrel, aspirin and dl-3-n-butylphthalide (NBP), also rescued SIRT3 and reduced OGD/R-induced endothelial injury, suggesting that the recovery of SIRT3 expression was critical for the protection of these drugs. Moreover, our results demonstrated that 10-hydroxy-NBP (OHNBP), a major metabolite of NBP, showed better blood-brain barrier crossing capability than NBP, but still retained the effects on SIRT3 by NBP. Together, our results suggested that SIRT3 may serve as a potential novel target for treatment of ischemic stroke. Full article
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10 pages, 701 KiB  
Article
Tooth Loss and Carotid Intima-Media Thickness in Relation to Functional Atherosclerosis: A Cross-Sectional Study
by Yuji Shimizu, Hirotomo Yamanashi, Masayasu Kitamura, Jun Miyata, Fumiaki Nonaka, Seiko Nakamichi, Toshiyuki Saito, Yasuhiro Nagata and Takahiro Maeda
J. Clin. Med. 2022, 11(14), 3993; https://doi.org/10.3390/jcm11143993 - 10 Jul 2022
Cited by 3 | Viewed by 1799
Abstract
Structural arterial stiffness can be evaluated with carotid intima-media thickness (CIMT). Functional arterial stiffness can be evaluated with cardio-ankle vascular index (CAVI). A positive association between CIMT and tooth loss has been reported, but no studies have evaluated the association between CIMT and [...] Read more.
Structural arterial stiffness can be evaluated with carotid intima-media thickness (CIMT). Functional arterial stiffness can be evaluated with cardio-ankle vascular index (CAVI). A positive association between CIMT and tooth loss has been reported, but no studies have evaluated the association between CIMT and tooth loss in relation to functional arterial stiffness (functional atherosclerosis). A cross-sectional study of 1235 Japanese individuals aged 40–89 years was conducted. Tooth loss was defined as being in the lowest tertile for the number of remaining teeth (≤20 in men and ≤19 in women). Functional atherosclerosis was defined as CAVI ≥ 9.0. Independent of known confounding factors, CIMT was positively associated with tooth loss only in participants without functional atherosclerosis. Adjusted odds ratios for tooth loss and a 1 standard deviation increment in CIMT were 1.27 (1.04–1.55) for participants without functional atherosclerosis and 0.99 (0.77–1.26) for participants with functional atherosclerosis. CIMT and functional atherosclerosis had a significant effect on tooth loss; the fully adjusted p-value for the interaction on tooth loss was 0.019. Independent of known confounding factors, CIMT is positively associated with tooth loss only in participants without functional atherosclerosis. This finding helps clarify the influence of the progression of arterial stiffness on tooth loss because the progression of structural atherosclerosis might have a beneficial influence on the maintenance of the microcirculation. Full article
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14 pages, 1209 KiB  
Article
Elevated Intrarenal Resistive Index Predicted Faster Renal Function Decline and Long-Term Mortality in Non-Proteinuric Chronic Kidney Disease
by Giulio Romano, Roberto Mioni, Nicola Danieli, Martina Bertoni, Elisa Croatto, Lucia Merla, Lucia Alcaro, Antonio Pedduzza, Xenia Metcalf, Alessandra Rigamonti, Cristiana Catena, Leonardo A. Sechi and GianLuca Colussi
J. Clin. Med. 2022, 11(11), 2995; https://doi.org/10.3390/jcm11112995 - 25 May 2022
Cited by 9 | Viewed by 2346
Abstract
Background. Intrarenal resistive index (RI) ≥ 0.80 predicts renal outcomes in proteinuric chronic kidney disease (CKD). However, this evidence in non-proteinuric patients with CKD of unknown etiology is lacking. In this study, we assessed the effect of intrarenal RI on renal function and [...] Read more.
Background. Intrarenal resistive index (RI) ≥ 0.80 predicts renal outcomes in proteinuric chronic kidney disease (CKD). However, this evidence in non-proteinuric patients with CKD of unknown etiology is lacking. In this study, we assessed the effect of intrarenal RI on renal function and all-cause mortality in non-proteinuric patients with CKD of unknown etiology despite an extensive diagnostic work-up. Methods. Non-proteinuric CKD patients were evaluated in a retrospective longitudinal study. Progression of renal disease was investigated by checking serum creatinine levels at 1, 3, and 5 years and defined by a creatinine level increase of at least 0.5 mg/dL. The discrimination performance of intrarenal RI in predicting the 5-year progression of renal disease was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Results. One-hundred-thirty-one patients (76 ± 9 years, 56% males) were included. The median follow-up was 7.5 years (interquartile range 4.3–10.5) with a cumulative mortality of 53%, and 5-year renal disease progression occurred in 25%. Patients with intrarenal RI ≥ 0.80 had a faster increase of serum creatinine levels compared to those with RI < 0.80 (+0.06 mg/dL each year, 95% CI 0.02–0.10, p < 0.010). Each 0.1-unit increment of intrarenal RI was an independent determinant of 5-year renal disease progression (odds ratio 4.13, 95% CI 1.45–12.9, p = 0.010) and predictor of mortality (hazards ratio 1.80, 95% CI 1.05–3.09, p = 0.034). AUROCs of intrarenal RI for predicting 5-year renal disease progression and mortality were 0.66 (95% CI 0.57–0.76) and 0.67 (95% CI 0.58–0.74), respectively. Conclusions. In non-proteinuric patients with CKD of unknown etiology, increased intrarenal RI predicted both a faster decline in renal function and higher long-term mortality, but as a single marker, it showed poor discrimination performance. Full article
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18 pages, 6132 KiB  
Article
MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis
by Yi Zeng, Ji Cao, Chun-Xia Li, Chun-Yan Wang, Ruo-Man Wu and Xiao-Le Xu
Int. J. Mol. Sci. 2022, 23(10), 5766; https://doi.org/10.3390/ijms23105766 - 21 May 2022
Cited by 9 | Viewed by 2359
Abstract
A novel function of retinoid X receptor beta (RXRβ) in endothelial cells has been reported by us during the formation of atherosclerosis. Here, we extended the study to explore the cellular mechanisms of RXRβ protein stability regulation. In this study, we discovered that [...] Read more.
A novel function of retinoid X receptor beta (RXRβ) in endothelial cells has been reported by us during the formation of atherosclerosis. Here, we extended the study to explore the cellular mechanisms of RXRβ protein stability regulation. In this study, we discovered that murine double minute-2 (MDM2) acts as an E3 ubiquitin ligase to target RXRβ for degradation. The result showed that MDM2 directly interacted with and regulated RXRβ protein stability. MDM2 promoted RXRβ poly-ubiquitination and degradation by proteasomes. Moreover, mutated MDM2 RING domain (C464A) or treatment with an MDM2 inhibitor targeting the RING domain of MDM2 lost the ability of MDM2 to regulate RXRβ protein expression and ubiquitination. Furthermore, treatment with MDM2 inhibitor alleviated oxidized low-density lipoprotein-induced mitochondrial damage, activation of TLR9/NF-κB and NLRP3/caspase-1 pathway and production of pro-inflammatory cytokines in endothelial cells. However, all these beneficial effects were reduced by the transfection of RXRβ siRNA. Moreover, pharmacological inhibition of MDM2 attenuated the development of atherosclerosis and reversed mitochondrial damage and related inflammation in the atherosclerotic process in LDLr-/- mice, along with the increased RXRβ protein expression in the aorta. Therefore, our study uncovers a previously unknown ubiquitination pathway and suggests MDM2-mediated RXRβ ubiquitination as a new therapeutic target in atherosclerosis. Full article
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22 pages, 1951 KiB  
Review
Endothelial Dysfunction Induced by Extracellular Neutrophil Traps Plays Important Role in the Occurrence and Treatment of Extracellular Neutrophil Traps-Related Disease
by Shuyang Yu, Jingyu Liu and Nianlong Yan
Int. J. Mol. Sci. 2022, 23(10), 5626; https://doi.org/10.3390/ijms23105626 - 17 May 2022
Cited by 16 | Viewed by 5149
Abstract
Many articles have demonstrated that extracellular neutrophil traps (NETs) are often described as part of the antibacterial function. However, since the components of NETs are non-specific, excessive NETs usually cause inflammation and tissue damage. Endothelial dysfunction (ED) caused by NETs is the major [...] Read more.
Many articles have demonstrated that extracellular neutrophil traps (NETs) are often described as part of the antibacterial function. However, since the components of NETs are non-specific, excessive NETs usually cause inflammation and tissue damage. Endothelial dysfunction (ED) caused by NETs is the major focus of tissue damage, which is highly related to many inflammatory diseases. Therefore, this review summarizes the latest advances in the primary and secondary mechanisms between NETs and ED regarding inflammation as a mediator. Moreover, the detailed molecular mechanisms with emphasis on the disadvantages from NETs are elaborated: NETs can use its own enzymes, release particles as damage-associated molecular patterns (DAMPs) and activate the complement system to interact with endothelial cells (ECs), drive ECs damage and eventually aggravate inflammation. In view of the role of NETs-induced ED in different diseases, we also discussed possible molecular mechanisms and the treatments of NETs-related diseases. Full article
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15 pages, 3063 KiB  
Article
Is Infantile Hemangioma a Neuroendocrine Tumor?
by Priscilla Kaulanjan-Checkmodine, Sandra Oucherif, Sorilla Prey, Etienne Gontier, Sabrina Lacomme, Maya Loot, Marijana Miljkovic-Licina, Muriel Cario, Christine Léauté-Labrèze, Alain Taieb, François Moisan and Hamid Reza Rezvani
Int. J. Mol. Sci. 2022, 23(9), 5140; https://doi.org/10.3390/ijms23095140 - 5 May 2022
Cited by 4 | Viewed by 2071
Abstract
Infantile hemangioma (IH) is the most common infantile tumor, affecting 5–10% of newborns. Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is currently the first-line treatment for severe IH; however, both its mechanism of action and its main cellular target remain poorly understood. Since [...] Read more.
Infantile hemangioma (IH) is the most common infantile tumor, affecting 5–10% of newborns. Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is currently the first-line treatment for severe IH; however, both its mechanism of action and its main cellular target remain poorly understood. Since betablockers can antagonize the effect of natural ADRB agonists, we postulated that the catecholamine produced in situ in IH may have a role in the propranolol response. By quantifying catecholamines in the IH tissues, we found a higher amount of noradrenaline (NA) in untreated proliferative IHs than in involuted IHs or propranolol-treated IHs. We further found that the first three enzymes of the catecholamine biosynthesis pathway are expressed by IH cells and that their levels are reduced in propranolol-treated tumors. To study the role of NA in the pathophysiology of IH and its response to propranolol, we performed an in vitro angiogenesis assay in which IH-derived endothelial cells, pericytes and/or telocytes were incorporated. The results showed that the total tube formation is sensitive to propranolol only when exogenous NA is added in the three-cell model. We conclude that the IH’s sensitivity to propranolol depends on crosstalk between the endothelial cells, pericytes and telocytes in the context of a high local amount of local NA. Full article
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13 pages, 1563 KiB  
Brief Report
Endothelial Cells Activated by Extracellular Histones Promote Foxp3+ Suppressive Treg Cells In Vitro
by Marine Arnaud, Jordane Demonchy, Eden Arrii, Marta Luperto, Julien Lion, Sofiane Fodil, Stéphanie Pons, Nuala Mooney and Lara Zafrani
Int. J. Mol. Sci. 2022, 23(9), 4527; https://doi.org/10.3390/ijms23094527 - 20 Apr 2022
Cited by 2 | Viewed by 2216
Abstract
Histones are widely recognized as pro-inflammatory mediators upon their release from the nucleus into the extracellular space. However, their impact on endothelial cell immunogenicity is unknown. Endothelial cells, Human Microvascular Endothelial cells 1 (HMEC1), have been exposed to recombinant histones in order to [...] Read more.
Histones are widely recognized as pro-inflammatory mediators upon their release from the nucleus into the extracellular space. However, their impact on endothelial cell immunogenicity is unknown. Endothelial cells, Human Microvascular Endothelial cells 1 (HMEC1), have been exposed to recombinant histones in order to study their effect on the endothelial phenotype. We then studied the differentiation of CD4+-T lymphocytes subpopulations after three days of interaction with endothelial cells in vitro and observed that histone-treated endothelial cells differentiate a suppressive FoxP3+ T regulator subpopulation that expressed Human Leucocyte Antigen DR (HLA-DR) and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA4). Toll-Like Receptor 4 (TLR4) inhibition significantly decreased the expansion of these Treg cells. Moreover, blockade of Interleukin (IL)-6 and Intercellular Adhesion Molecule (ICAM)-1 in cocultures significantly decreased the expansion of Tregs, suggesting an IL-6 and ICAM-1 dependent pathway. Thus, beyond their inflammatory effects, extracellular histones may induce an increase of immunosuppressive Treg population via their action on endothelial cells. Further studies are needed to evaluate the impact on immunosuppression of an increase of peripheral suppressive Treg via endothelial cell activation by histones in vivo. Full article
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13 pages, 879 KiB  
Article
Accentuated Peripheral Blood NK Cytotoxicity Forms an Unfavorable Background for Embryo Implantation and Gestation
by Boris Dons’koi, Oksana Onyshchuk, Iryna Kononenko, Vira Sirenko, Natalia Bodnar, Andrii Serbyn, Anzhela Kozachok, Yulia Brovarska, Dariia Osypchuk, Yaroslava Anochko and Viktor Chernychov
Diagnostics 2022, 12(4), 908; https://doi.org/10.3390/diagnostics12040908 - 6 Apr 2022
Cited by 7 | Viewed by 2188
Abstract
Problem Many studies have demonstrated the negative impact of high rates of NK cytotoxicity (NKc) on reproductive processes, but there is no agreement as to the appropriateness and feasibility of using the NKc for routine diagnostic in IVF patients. This study conducted a [...] Read more.
Problem Many studies have demonstrated the negative impact of high rates of NK cytotoxicity (NKc) on reproductive processes, but there is no agreement as to the appropriateness and feasibility of using the NKc for routine diagnostic in IVF patients. This study conducted a retrospective analysis of embryo transfer (ET) success rates and live birth rates (LBR) in patients with different NKc values. Method of study 1854 cycles of ET were selected and divided into three groups according to NKc levels, and randomized by anamnesis and age: normal (nNKc, n = 871), elevated (eNKc, n = 759), and reduced NKc (rNKc, n = 123). ET with donors’ embryos (n = 101) were analyzed separately. NKc-to-K562 was measured in PBMC (peripheral blood mononuclear cells) by flow cytometry before ET. The patients did not obtain any additional treatments. Results Patients with eNKc, in addition to having reduced clinical pregnancy rates (OR1.59, p < 0.0001), had increased levels of subsequent pregnancy failures (OR2.545, p < 0.0001) when compared to nNKc patients. As a result, patients with eNKc had almost half the LBR than patients with nNKc (OR2.2, p < 0.0001). In patients with rNKc, LBR was also lowered. eNKc was equally unfavorable for implantation and delivery in cryo- or fresh cycles. Markedly, eNKc was much more unfavorable for reproduction than slightly elevated NKc. The donor’s embryos were implanted irrespective of the recipient’s NKc levels, but the later stages of pregnancy were worse in patients with eNKc. Conclusions Our findings highlighted the negative impact of high levels of NK cytotoxicity on pregnancy outcomes. Full article
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9 pages, 724 KiB  
Article
Mid-Term Clinical Outcomes Following Drug-Coated Balloons in Coronary Artery Disease
by Gal Sella, Gera Gandelman, Nicholay Teodorovich, Ortal Tuvali, Omar Ayyad, Haitham Abu Khadija, Dan Haberman, Lion Poles, Michael Jonas, Igor Volodarsky, Jacob George and Alex Blatt
J. Clin. Med. 2022, 11(7), 1859; https://doi.org/10.3390/jcm11071859 - 27 Mar 2022
Cited by 3 | Viewed by 2284
Abstract
Objective: The aim of this study was to evaluate the mid-term efficacy of drug-coated balloons (DCB) in percutaneous coronary intervention (PCI) in two different pathophysiologic scenarios. Background: There are different underlying pathological processes in coronary artery disease. Mid-term safety and efficacy of DCB [...] Read more.
Objective: The aim of this study was to evaluate the mid-term efficacy of drug-coated balloons (DCB) in percutaneous coronary intervention (PCI) in two different pathophysiologic scenarios. Background: There are different underlying pathological processes in coronary artery disease. Mid-term safety and efficacy of DCB approach is still limited. Methods: Medical records of all consecutive patients undergoing DCB were evaluated. The primary endpoint was the rate of clinically driven target lesion revascularization (TLR) after 24 months. Results: Between January 2011 and December 2017, 442 patients were included, representing 4.4% of all PCIs in our institution. A total of 460 DCB lesions were treated, of which 328 (71.3%) were de novo and 132 (28.7%) were combined bare metal or drug-eluting stents with in-stent restenosis (ISR). The patients’ mean age was 66.2 ± 11.7 years with a diabetes prevalence of 45.3%. The TLR rate was lower in the de novo group (5.3%) compared to the ISR group (9.4%) (p = 0.04). No differences were observed in major adverse cardiovascular events (MACE) between the de novo group (38.9%) and ISR group (42.5%) (p = 0.47). No significant differences were detected in the TLR occurrence in the subgroup analysis. Conclusion: Our extended experience demonstrates that the mid-term DCB approach in these two pathophysiologic settings represent a reasonable option, with low TLR rate. Full article
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13 pages, 2020 KiB  
Article
Impaired Endothelial Function in Convalescent Phase of COVID-19: A 3 Month Follow Up Observational Prospective Study
by Luca Santoro, Lorenzo Falsetti, Vincenzo Zaccone, Antonio Nesci, Matteo Tosato, Bianca Giupponi, Maria Cristina Savastano, Gianluca Moroncini, Antonio Gasbarrini, Francesco Landi, Angelo Santoliquido and on behalf of Gemelli against COVID-19 Post-Acute Care Study Group
J. Clin. Med. 2022, 11(7), 1774; https://doi.org/10.3390/jcm11071774 - 23 Mar 2022
Cited by 18 | Viewed by 2356
Abstract
Background: Endothelial dysfunction has a role in acute COVID-19, contributing to systemic inflammatory syndrome, acute respiratory distress syndrome, and vascular events. Evidence regarding COVID-19 middle- and long-term consequences on endothelium are still lacking. Our study aimed to evaluate if COVID-19 severity could significantly [...] Read more.
Background: Endothelial dysfunction has a role in acute COVID-19, contributing to systemic inflammatory syndrome, acute respiratory distress syndrome, and vascular events. Evidence regarding COVID-19 middle- and long-term consequences on endothelium are still lacking. Our study aimed to evaluate if COVID-19 severity could significantly affect the endothelial function after three months from the acute phase. Methods: We assessed endothelial function in outpatients with previous COVID-19 three months after negative SARS-CoV-2 molecular test by measuring flow-mediated dilation (FMD) in patients categorized according to a four-variable COVID-19 severity scale (“home care”; “hospital, no oxygen”; “hospital, oxygen”; “hospital requiring high-flow nasal canula, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation”). FMD difference among COVID-19 severity categories was assessed with analysis of variance; we further clarified the relationship between FMD and previous COVID-19 severity with multivariate logistic models. Results: Among 658 consecutive COVID-19 subjects, we observed a significant linear trend of FMD reduction with the increase of the COVID-19 category (p < 0.0001). The presence of endothelial dysfunction was more frequent among hospitalized patients (78.3%) with respect to home-care patients (21.7%; p < 0.0001). COVID-19 severity was associated with increased endothelial dysfunction risk (OR: 1.354; 95% CI: 1.06–1.71; p = 0.011) at multivariate binary logistic analysis. FMD showed a significant direct correlation with PaO2 (p = 0.004), P/F ratio (p = 0.004), FEV1 (p = 0.008), and 6MWT (p = 0.0001). Conclusions: Hospitalized COVID-19 subjects showed an impaired endothelial function three months after the acute phase that correlated with pulmonary function impairment. Further studies are needed to evaluate if these subjects are at higher risk of developing pulmonary disease or future cardiovascular events. Full article
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