International Journal of Molecular Sciences

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16 pages, 3340 KiB

Open AccessArticle

The Protein Kinase A Inhibitor KT5720 Prevents Endothelial Dysfunctions Induced by High-Dose Irradiation

by François-Xavier Boittin, Nathalie Guitard, Maeliss Toth, Diane Riccobono, Hélène Théry and Régis Bobe

Int. J. Mol. Sci. 2024, 25(4), 2269; https://doi.org/10.3390/ijms25042269 - 14 Feb 2024

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Abstract

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation [...] Read more.

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed. Here we report the beneficial effects of the PKA inhibitor KT5720 on a panel of irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). High-dose X-irradiation (15 Gy) triggered the late apoptosis of HPMECs independent of the ceramide/P38 MAP kinase pathway or p53. In contrast, the treatment of HPMECs with KT5720 completely prevented irradiation-induced apoptosis, whether applied before or after cell irradiation. Immunostainings of irradiated monolayers revealed that KT5720 treatment preserved the overall integrity of endothelial monolayers and adherens junctions linking endothelial cells. Real-time impedance measurements performed in HPMEC monolayers confirmed the overall protective role of KT5720 against irradiation. Treatment with KT5720 before or after irradiation also reduced irradiation-induced ICAM-1 overexpression. Finally, the possible role for PKA in the development of endothelial dysfunctions is discussed, but the potency of KT5720 to inhibit the development of a panel of irradiation-induced endothelial dysfunctions, whether applied before or after irradiation, suggests that this compound could be of great interest for both the prevention and treatment of vascular damages in the event of exposure to a high dose of radiation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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15 pages, 1692 KiB

Open AccessArticle

HTK vs. HTK-N for Coronary Endothelial Protection during Hypothermic, Oxygenated Perfusion of Hearts Donated after Circulatory Death

by Lars Saemann, Kristin Wächter, Nitin Gharpure, Sabine Pohl, Fabio Hoorn, Sevil Korkmaz-Icöz, Matthias Karck, Gábor Veres, Andreas Simm and Gábor Szabó

Int. J. Mol. Sci. 2024, 25(4), 2262; https://doi.org/10.3390/ijms25042262 - 13 Feb 2024

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Abstract

Protection of the coronary arteries during donor heart maintenance is pivotal to improve results and prevent the development of coronary allograft vasculopathy. The effect of hypothermic, oxygenated perfusion (HOP) with the traditional HTK and the novel HTK-N solution on the coronary microvasculature of [...] Read more.

Protection of the coronary arteries during donor heart maintenance is pivotal to improve results and prevent the development of coronary allograft vasculopathy. The effect of hypothermic, oxygenated perfusion (HOP) with the traditional HTK and the novel HTK-N solution on the coronary microvasculature of donation-after-circulatory-death (DCD) hearts is known. However, the effect on the coronary macrovasculature is unknown. Thus, we maintained porcine DCD hearts by HOP with HTK or HTK-N for 4 h, followed by transplantation-equivalent reperfusion with blood for 2 h. Then, we removed the left anterior descending coronary artery (LAD) and compared the endothelial-dependent and -independent vasomotor function of both groups using bradykinin and sodium-nitroprusside (SNP). We also determined the transcriptome of LAD samples using microarrays. The endothelial-dependent relaxation was significantly better after HOP with HTK-N. The endothelial-independent relaxation was comparable between both groups. In total, 257 genes were expressed higher, and 668 genes were expressed lower in the HTK-N group. Upregulated genes/pathways were involved in endothelial and vascular smooth muscle cell preservation and heart development. Downregulated genes were related to ischemia/reperfusion injury, oxidative stress, mitochondrion organization, and immune reaction. The novel HTK-N solution preserves the endothelial function of DCD heart coronary arteries more effectively than traditional HTK. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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15 pages, 2032 KiB

Open AccessArticle

Diabetic Endothelial Cell Glycogen Synthase Kinase 3β Activation Induces VCAM1 Ectodomain Shedding

by Masuma Akter Brishti, Somasundaram Raghavan, Kennedy Lamar, Udai P. Singh, Daniel M. Collier and M. Dennis Leo

Int. J. Mol. Sci. 2023, 24(18), 14105; https://doi.org/10.3390/ijms241814105 - 14 Sep 2023

Cited by 1 | Viewed by 820

Abstract

Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been found to be associated with poor cardiovascular [...] Read more.

Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been found to be associated with poor cardiovascular disease (CVD) outcomes, supporting VCAM1’s role as a potential diagnostic marker and therapeutic target. Inhibiting sVCAM1’s release or its interaction with immune cells could offer cardioprotection in conditions such as diabetes. Membrane-bound surface adhesion molecules are widely expressed in a wide variety of cell types with higher expression in endothelial cells (ECs). Still, the source of sCAMs in the circulation is not clear. Hypothesizing that endothelial cells (ECs) could be a potential source of sCAMs, this study investigated whether dysfunctional EC signaling mechanisms during diabetes cause VCAM1 ectodomain shedding. Our results from samples from an inducible diabetic mouse model revealed increased sVCAM1 plasma levels in diabetes. Protein analysis indicated upregulated VCAM1 expression and metalloproteases ADAM10 and ADAM17 in diabetic ECs. ADAMs are known for proteolytic cleavage of adhesion molecules, contributing to inflammation. GSK3β, implicated in EC VCAM1 expression, was found to be activated in diabetic ECs. GSK3β activation in control ECs increased ADAM10/17 and VCAM1. A GSK3β inhibitor reduced active GSK3β and VCAM1 ectodomain shedding. These findings suggest diabetic ECs with elevated GSK3β activity led to VCAM1 upregulation and ADAM10/17-mediated sVCAM1 shedding. This mechanism underscores the potential therapeutic role of GSK3β inhibition in reducing the levels of circulating sVCAM1. The complex roles of sCAMs extend well beyond CVD. Thus, unraveling the intricate involvement of sCAMs in the initiation and progression of vascular disease, particularly in diabetes, holds significant therapeutic potential. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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Review

Jump to: Research

14 pages, 1375 KiB

Open AccessReview

New Insights into Endothelial Dysfunction in Cardiometabolic Diseases: Potential Mechanisms and Clinical Implications

by Giovanna Gallo and Carmine Savoia

Int. J. Mol. Sci. 2024, 25(5), 2973; https://doi.org/10.3390/ijms25052973 - 04 Mar 2024

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Abstract

The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal [...] Read more.

The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal imbalance, different biological pathways are activated leading to oxidative stress, endothelial dysfunction, increased secretion of adipokines, cytokines, endothelin-1, and fibroblast growth factor, and reduced nitric oxide production, leading eventually to a loss of integrity. Endothelial dysfunction has emerged as a hallmark of dysmetabolic vascular impairment and contributes to detrimental effects on cardiac metabolism and diastolic dysfunction, and to the development of cardiovascular diseases including heart failure. Different biomarkers of endothelial dysfunction have been proposed to predict cardiovascular diseases in order to identify microvascular and macrovascular damage and the development of atherosclerosis, particularly in metabolic disorders. Endothelial dysfunction also plays an important role in the development of severe COVID-19 and cardiovascular complications in dysmetabolic patients after SARS-CoV-2 infection. In this review, we will discuss the biological mechanisms involved in endothelial dysregulation in the context of cardiometabolic diseases as well as the available and promising biomarkers of endothelial dysfunction in clinical practice. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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14 pages, 1190 KiB

Open AccessReview

Sex, Endothelial Cell Functions, and Peripheral Artery Disease

by Siân P. Cartland, Christopher P. Stanley, Christina Bursill, Freda Passam, Gemma A. Figtree, Sanjay Patel, Jacky Loa, Jonathan Golledge, David A. Robinson, Sarah J. Aitken and Mary M. Kavurma

Int. J. Mol. Sci. 2023, 24(24), 17439; https://doi.org/10.3390/ijms242417439 - 13 Dec 2023

Cited by 2 | Viewed by 1477

Abstract

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, [...] Read more.

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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16 pages, 708 KiB

Open AccessReview

Endothelial Dysfunction in Systemic Sclerosis

by Eshaan Patnaik, Matthew Lyons, Kimberly Tran and Debendra Pattanaik

Int. J. Mol. Sci. 2023, 24(18), 14385; https://doi.org/10.3390/ijms241814385 - 21 Sep 2023

Cited by 4 | Viewed by 2913

Abstract

Systemic sclerosis, commonly known as scleroderma, is an autoimmune disorder characterized by vascular abnormalities, autoimmunity, and multiorgan fibrosis. The exact etiology is not known but believed to be triggered by environmental agents in a genetically susceptible host. Vascular symptoms such as the Raynaud [...] Read more.

Systemic sclerosis, commonly known as scleroderma, is an autoimmune disorder characterized by vascular abnormalities, autoimmunity, and multiorgan fibrosis. The exact etiology is not known but believed to be triggered by environmental agents in a genetically susceptible host. Vascular symptoms such as the Raynaud phenomenon often precede other fibrotic manifestations such as skin thickening indicating that vascular dysfunction is the primary event. Endothelial damage and activation occur early, possibly triggered by various infectious agents and autoantibodies. Endothelial dysfunction, along with defects in endothelial progenitor cells, leads to defective angiogenesis and vasculogenesis. Endothelial to mesenchymal cell transformation is another seminal event during pathogenesis that progresses to tissue fibrosis. The goal of the review is to discuss the molecular aspect of the endothelial dysfunction that leads to the development of systemic sclerosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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12 pages, 824 KiB

Open AccessReview

Endothelial Dysfunction in Cardiorenal Conditions: Implications of Endothelial Glucocorticoid Receptor-Wnt Signaling

by Mohammad Shohel Akhter and Julie Elizabeth Goodwin

Int. J. Mol. Sci. 2023, 24(18), 14261; https://doi.org/10.3390/ijms241814261 - 19 Sep 2023

Viewed by 1065

Abstract

The endothelium constitutes the innermost lining of the blood vessels and controls blood fluidity, vessel permeability, platelet aggregation, and vascular tone. Endothelial dysfunction plays a key role in initiating a vascular inflammatory cascade and is the pivotal cause of various devastating diseases in [...] Read more.

The endothelium constitutes the innermost lining of the blood vessels and controls blood fluidity, vessel permeability, platelet aggregation, and vascular tone. Endothelial dysfunction plays a key role in initiating a vascular inflammatory cascade and is the pivotal cause of various devastating diseases in multiple organs including the heart, lung, kidney, and brain. Glucocorticoids have traditionally been used to combat vascular inflammation. Endothelial cells express glucocorticoid receptors (GRs), and recent studies have demonstrated that endothelial GR negatively regulates vascular inflammation in different pathological conditions such as sepsis, diabetes, and atherosclerosis. Mechanistically, the anti-inflammatory effects of GR are mediated, in part, through the suppression of Wnt signaling. Moreover, GR modulates the fatty acid oxidation (FAO) pathway in endothelial cells and hence can influence FAO-mediated fibrosis in several organs including the kidneys. This review summarizes the relationship between GR and Wnt signaling in endothelial cells and the effects of the Wnt pathway in different cardiac and renal diseases. Available data suggest that GR plays a significant role in restoring endothelial integrity, and research on endothelial GR–Wnt interactions could facilitate the development of novel therapies for many cardiorenal conditions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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19 pages, 914 KiB

Open AccessReview

The Role of Aryl Hydrocarbon Receptor in the Endothelium: A Systematic Review

by Sol Guerra-Ojeda, Andrea Suarez, Alicia Valls, David Verdú, Javier Pereda, Elena Ortiz-Zapater, Julián Carretero, Maria D. Mauricio and Eva Serna

Int. J. Mol. Sci. 2023, 24(17), 13537; https://doi.org/10.3390/ijms241713537 - 31 Aug 2023

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Abstract

Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current [...] Read more.

Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current knowledge on the AhR role in the endothelium and its cardiovascular implications. We focus on endogenous AhR agonists, such as some uremic toxins and other agonists unrelated to environmental pollutants, as well as studies using AhR knockout models. We conclude that AhR activation leads to vascular oxidative stress and endothelial dysfunction and that blocking AhR signalling could provide a new target for the treatment of vascular disorders such as cardiovascular complications in patients with chronic kidney disease or pulmonary arterial hypertension. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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36 pages, 2232 KiB

Open AccessReview

A Scoping Review on Biomarkers of Endothelial Dysfunction in Small Vessel Disease: Molecular Insights from Human Studies

by Daniela Jaime Garcia, Audrey Chagnot, Joanna M. Wardlaw and Axel Montagne

Int. J. Mol. Sci. 2023, 24(17), 13114; https://doi.org/10.3390/ijms241713114 - 23 Aug 2023

Cited by 3 | Viewed by 1958

Abstract

Small vessel disease (SVD) is a highly prevalent disorder of the brain’s microvessels and a common cause of dementia as well as ischaemic and haemorrhagic strokes. Though much about the underlying pathophysiology of SVD remains poorly understood, a wealth of recently published evidence [...] Read more.

Small vessel disease (SVD) is a highly prevalent disorder of the brain’s microvessels and a common cause of dementia as well as ischaemic and haemorrhagic strokes. Though much about the underlying pathophysiology of SVD remains poorly understood, a wealth of recently published evidence strongly suggests a key role of microvessel endothelial dysfunction and a compromised blood–brain barrier (BBB) in the development and progression of the disease. Understanding the causes and downstream consequences associated with endothelial dysfunction in this pathological context could aid in the development of effective diagnostic and prognostic tools and provide promising avenues for potential therapeutic interventions. In this scoping review, we aim to summarise the findings from clinical studies examining the role of the molecular mechanisms underlying endothelial dysfunction in SVD, focussing on biochemical markers of endothelial dysfunction detectable in biofluids, including cell adhesion molecules, BBB transporters, cytokines/chemokines, inflammatory markers, coagulation factors, growth factors, and markers involved in the nitric oxide cascade. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)

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