Sulodexide. Prophylactic and therapy response to endothelial dysfunction

Endothelial dysfunction plays the key role in the development of cardiovascular system disorders. Sulodexide, decreasing oxidative stress and stabilizing endothelial cells, has protective properties on endothelial dysfunction. The article describes the role of sulodexide both in prophylaxis and therapy of venous and arterial diseases, underlining its clinical efficacy as demonstrated in clinical trials. Besides, the article describes its role in the management of some other diseases, like diabetic nephropathy, diabetic foot, tinnitus, or hemorrhoids.

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SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

Frontiers in Physiology ◽

10.3389/fphys.2020.605908 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ryan Chang ◽

Abrar Mamun ◽

Abishai Dominic ◽

Nhat-Tu Le

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Endothelial Dysfunction ◽

Lung Injury ◽

Mitochondrial Dysfunction ◽

Redox Status ◽

Feedback Loops ◽

Chronic Oxidative Stress

Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial cells can promote chronic inflammation and disease processes like thrombosis, atherosclerosis, and lung injury. In endothelial cells, mitochondria regulate these inflammatory pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that can initiate and exacerbate senescence, a state that promotes inflammation and chronic endothelial dysfunction. Oxidative stress can also activate feedback loops that perpetuate mitochondrial dysfunction, mtROS overproduction, and inflammation. In this review, we provide an overview of phenotypes mediated by mtROS in endothelial cells – such as mitochondrial dysfunction, inflammation, and senescence – as well as how these chronic states may be initiated by SARS-CoV-2 infection of endothelial cells. We also propose that SARS-CoV-2 activates mtROS-mediated feedback loops that cause long-term changes in host redox status and endothelial function, promoting cardiovascular disease and lung injury after recovery from COVID-19. Finally, we discuss the implications of these proposed pathways on long-term vascular health and potential treatments to address these chronic conditions.

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Sex differences in control of blood pressure: role of oxidative stress in hypertension in females

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01232.2007 ◽

2008 ◽

Vol 295 (2) ◽

pp. H466-H474 ◽

Cited By ~ 55

Author(s):

Arnaldo Lopez-Ruiz ◽

Julio Sartori-Valinotti ◽

Licy L. Yanes ◽

Radu Iliescu ◽

Jane F. Reckelhoff

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Clinical Trials ◽

Sex Differences ◽

Endothelial Dysfunction ◽

Animal Studies ◽

Reduce Blood Pressure ◽

Male Rats ◽

Men And Women

In general, blood pressure is higher in normotensive men than in age-matched women, and the prevalence of hypertension in men is also higher until after menopause, when the prevalence of hypertension increases for women. It is likely then that the mechanisms by which blood pressure increases in men and women with aging may be different. Although clinical trials to reduce blood pressure with antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating hypertension. The exact mechanisms by which oxidative stress increases blood pressure have not been completely elucidated. There may be several reasons for the discrepancies between clinical and animal studies. In this review, the data obtained in selected clinical and animal studies are discussed, and the hypothesis is put forward that oxidative stress may not be as important in mediating hypertension in females as has been shown previously in male rats. Furthermore, it is likely that differences in genetics, age, length of time with hypertension, endothelial dysfunction, and sex are all factored in to modulate the responses to antioxidants in humans. As such, future clinical trials should be designed and powered to evaluate the effects of oxidative stress on blood pressure separately in men and women.

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P717Glucagon-like peptide 1 (GLP-1) improves endothelial dysfunction and vascular inflammation in polymicrobial sepsis induced by cecal ligation and puncture (CLP)

European Heart Journal ◽

10.1093/eurheartj/ehz747.0322 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Steven ◽

J Helmstaedter ◽

F Pawelke ◽

K Filippou ◽

K Frenies ◽

...

Keyword(s):

Oxidative Stress ◽

Clinical Trials ◽

Endothelial Dysfunction ◽

Knockout Mice ◽

Vascular Inflammation ◽

Cecal Ligation ◽

Cecal Ligation And Puncture ◽

Glucose Levels ◽

Dpp4 Inhibitor ◽

Cardioprotective Effects

Abstract Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.

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Regulation of miRNAs by Natural Antioxidants in Cardiovascular Diseases: Focus on SIRT1 and eNOS

Antioxidants ◽

10.3390/antiox10030377 ◽

2021 ◽

Vol 10 (3) ◽

pp. 377

Author(s):

Yunna Lee ◽

Eunok Im

Keyword(s):

Oxidative Stress ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Natural Antioxidants ◽

Sirtuin 1 ◽

Potential Benefits ◽

New Perspective ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality worldwide. The potential benefits of natural antioxidants derived from supplemental nutrients against CVDs are well known. Remarkably, natural antioxidants exert cardioprotective effects by reducing oxidative stress, increasing vasodilation, and normalizing endothelial dysfunction. Recently, considerable evidence has highlighted an important role played by the synergistic interaction between endothelial nitric oxide synthase (eNOS) and sirtuin 1 (SIRT1) in the maintenance of endothelial function. To provide a new perspective on the role of natural antioxidants against CVDs, we focused on microRNAs (miRNAs), which are important posttranscriptional modulators in human diseases. Several miRNAs are regulated via the consumption of natural antioxidants and are related to the regulation of oxidative stress by targeting eNOS and/or SIRT1. In this review, we have discussed the specific molecular regulation of eNOS/SIRT1-related endothelial dysfunction and its contribution to CVD pathologies; furthermore, we selected nine different miRNAs that target the expression of eNOS and SIRT1 in CVDs. Additionally, we have summarized the alteration of miRNA expression and regulation of activities of miRNA through natural antioxidant consumption.

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Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Scientific Reports ◽

10.1038/s41598-021-95511-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samir Sissaoui ◽

Stuart Egginton ◽

Ling Ting ◽

Asif Ahmed ◽

Peter W. Hewett

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Akt Activation ◽

Forkhead Box ◽

Pi3k Activity ◽

Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

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Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

Experimental Diabetes Research ◽

10.1155/2012/481840 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 56

Author(s):

Basma Basha ◽

Samson Mathews Samuel ◽

Chris R. Triggle ◽

Hong Ding

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Clinical Trials ◽

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Cardiovascular Complications ◽

Therapeutic Agents ◽

Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

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High stretch induces endothelial dysfunction accompanied by oxidative stress and actin remodeling in human saphenous vein endothelial cells

Scientific Reports ◽

10.1038/s41598-021-93081-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

T. Girão-Silva ◽

M. H. Fonseca-Alaniz ◽

J. C. Ribeiro-Silva ◽

J. Lee ◽

N. P. Patil ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Endothelial Cell ◽

Endothelial Dysfunction ◽

Saphenous Vein ◽

Saphenous Vein Graft ◽

Artery Bypass ◽

Bypass Graft ◽

Human Saphenous Vein ◽

Actin Remodeling

AbstractThe rate of the remodeling of the arterialized saphenous vein conduit limits the outcomes of coronary artery bypass graft surgery (CABG), which may be influenced by endothelial dysfunction. We tested the hypothesis that high stretch (HS) induces human saphenous vein endothelial cell (hSVEC) dysfunction and examined candidate underlying mechanisms. Our results showed that in vitro HS reduces NO bioavailability, increases inflammatory adhesion molecule expression (E-selectin and VCAM1) and THP-1 cell adhesion. HS decreases F-actin in hSVECs, but not in human arterial endothelial cells, and is accompanied by G-actin and cofilin’s nuclear shuttling and increased reactive oxidative species (ROS). Pre-treatment with the broad-acting antioxidant N-acetylcysteine (NAC) supported this observation and diminished stretch-induced actin remodeling and inflammatory adhesive molecule expression. Altogether, we provide evidence that increased oxidative stress and actin cytoskeleton remodeling play a role in HS-induced saphenous vein endothelial cell dysfunction, which may contribute to predisposing saphenous vein graft to failure.

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Interactive role of oxidative stress and inflammation in the development of diabetic foot

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2021.08.144 ◽

2021 ◽

Vol 177 ◽

pp. S100-S101

Author(s):

Sanja Vujčić ◽

Jelena Kotur-Stevuljević ◽

Iva Perović-Blagojević ◽

Tatjana Stefanović ◽

Sanja Ilić-Mijailović ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Foot

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Abstract MP30: Circulating Sars-cov-2 Spike Protein 1 Causes Microarteriolar Oxidative Stress, Endothelial Dysfunction And Enhanced Thromboxane And Endothelin Contractility That Are Prevented By Spironolactone.

Hypertension ◽

10.1161/hyp.78.suppl_1.mp30 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Dan Wang ◽

Christopher S Wilcox

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Endothelial Dysfunction ◽

Fluorescence Microscopy ◽

Vascular Dysfunction ◽

Microvascular Complications ◽

Spike Protein ◽

Ros Generation ◽

Intravenous Injections ◽

Novel Model

Introduction and hypothesis: Following bodily entry, the SARS-CoV-2 virus undergoes pulmonary replication with release of circulating viral spike protein 1 (SP1) into the bloodstream. Uptake of SP1 by endothelial cells might provoke vascular dysfunction and thrombosis. We hypothesized that spironolactone could prevent microvascular complications from circulating SP1 in COVID-19. Methods: male C57Bl/6 mice received spironolactone (100 mg · kg -1 · d -1 PO x 3d) or vehicle and intravenous injections of recombinant full-length human SP1 (10 μg per mouse) or vehicle. They were euthanized after 3 days. Mesenteric resistant arterioles (n=4 per group) were dissected and mounted on isometric myographs. Acetylcholine-induced EDRF responses and L-NAME-inhibitable NO generation (DAF-FM fluorescence) were studied in pre-constricted vessels and contraction to endothelin 1 (ET1) or thromboxane (U-46, 619) and ET1-induced ROS (PEG-SOD inhibitable ethidium: dihydroethidium fluorescence) were studied by fluorescence microscopy in other vessels. Results: SP1 reduced acetylcholine-induced EDRF (17 ± 3 vs 27 ± 5 % mean ± sem; P < 0.05) and NO generation (0.21 ± 0.03 vs 0.36 ± 0.04, F 1 /F 0 ; P < 0.05) while increasing contraction to ET1 (10 -7 mol·l -1 : 124 ± 13 vs 89 ± 4 %; P < 0.05) and U-46, 619 (10 -6 mol·l -1 :114± 5 vs 87± 6 %; P < 0.05) and ET1-induced ROS generation(0.30± 0.08 vs 0.09± 0.03; P < 0.05). Spironolactone did not modify any of these responses in vessels from normal mice but prevented all the effects of SP1. Conclusion: these preliminary studies provide a novel model to study COVID-19 vasculopathy. They indicate that spironolactone can provide protection from microvascular oxidative stress, endothelial dysfunction and enhanced contractility and might thereby moderate COVID-19 complications.

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Peroxiredoxin 6 is required for blood vessel integrity in wounded skin

The Journal of Cell Biology ◽

10.1083/jcb.200706090 ◽

2007 ◽

Vol 179 (4) ◽

pp. 747-760 ◽

Cited By ~ 51

Author(s):

Angelika Kümin ◽

Matthias Schäfer ◽

Nikolas Epp ◽

Philippe Bugnon ◽

Christiane Born-Berclaz ◽

...

Keyword(s):

Oxidative Stress ◽

Wound Healing ◽

Endothelial Cells ◽

Ultrastructural Level ◽

Peroxiredoxin 6 ◽

Severe Hemorrhage ◽

Vessel Integrity ◽

Knockout Animals

Peroxiredoxin 6 (Prdx6) is a cytoprotective enzyme with largely unknown in vivo functions. Here, we use Prdx6 knockout mice to determine its role in UV protection and wound healing. UV-mediated keratinocyte apoptosis is enhanced in Prdx6-deficient mice. Upon skin injury, we observe a severe hemorrhage in the granulation tissue of knockout animals, which correlates with the extent of oxidative stress. At the ultrastructural level endothelial cells appear highly damaged, and their rate of apoptosis is enhanced. Knock-down of Prdx6 in cultured endothelial cells also increases their susceptibility to oxidative stress, thus confirming the sensitivity of this cell type to loss of Prdx6. Wound healing studies in bone marrow chimeric mice demonstrate that Prdx6-deficient inflammatory and endothelial cells contribute to the hemorrhage phenotype. These results provide insight into the cross-talk between hematopoietic and resident cells at the wound site and the role of reactive oxygen species in this interplay.

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