Endothelial Dysfunction in Diabetes

Diabetes is a worldwide health issue closely associated with cardiovascular events. Given the pandemic of obesity, the identification of the basic underpinnings of vascular disease is strongly needed. Emerging evidence has suggested that endothelial dysfunction is a critical step in the progression of atherosclerosis. However, how diabetes affects the endothelium is poorly understood. Experimental and clinical studies have illuminated the tight link between insulin resistance and endothelial dysfunction. In addition, macrophage polarization from M2 towards M1 contributes to the process of endothelial damage. The possibility that novel classes of anti-hyperglycemic agents exert beneficial effects on the endothelial function and macrophage polarization has been raised. In this review, we discuss the current status of knowledge regarding the pathological significance of insulin signaling in endothelium. Finally, we summarize recent therapeutic strategies against endothelial dysfunction with an emphasis on macrophage polarity.

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Cardiac Rehabilitation and Endothelial Function

Journal of Clinical Medicine ◽

10.3390/jcm9082487 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2487 ◽

Cited By ~ 1

Author(s):

Gaetano Antonio Lanza ◽

Michele Golino ◽

Angelo Villano ◽

Oreste Lanza ◽

Priscilla Lamendola ◽

...

Keyword(s):

Cardiovascular Disease ◽

Endothelial Dysfunction ◽

Clinical Outcome ◽

Endothelial Function ◽

Cardiac Rehabilitation ◽

Cardiac Disease ◽

Cardiovascular Events ◽

Beneficial Effects

Endothelial dysfunction is an early abnormality in the process of atherosclerosis and cardiovascular disease and has been associated with worse clinical outcome. Cardiac rehabilitation (CR) has been reported to be helpful to reduce cardiovascular events in various types of cardiac disease, but the mechanisms of its beneficial effects remain only partially known. In this article, we review the studies that assessed the effect of CR on endothelial function in patients with various cardiac conditions. Available data show that CR significantly improves impaired endothelial function in these patients, which may contribute to the beneficial effects of CR on clinical outcome.

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Therapeutic Approaches to Limit Hemolysis-Driven Endothelial Dysfunction: Scavenging Free Heme to Preserve Vasculature Homeostasis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/396527 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 24

Author(s):

Francesca Vinchi ◽

Emanuela Tolosano

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Vascular Function ◽

Bacterial Infections ◽

Thrombus Formation ◽

Endothelial Activation ◽

Endothelial Damage ◽

Heme Iron ◽

Therapeutic Approaches ◽

Beneficial Effects

Hemolysis results in the release of hemoglobin and heme into the bloodstream and is associated with the development of several pathologic conditions of different etiology, including hemoglobinopathies, hemolytic anemias, bacterial infections, malaria, and trauma. In addition, hemolysis is associated with surgical procedures, hemodialysis, blood transfusion, and other conditions in which mechanical forces can lead to red blood cell rupture. Free plasma hemoglobin and heme are toxic for the vascular endothelium since heme iron promotes oxidative stress that causes endothelial activation responsible for vasoocclusive events and thrombus formation. Moreover, free hemoglobin scavenges nitric oxide, reducing its bioavailability, and heme favours ROS production, thus causing oxidative nitric oxide consumption. This results in the dysregulation of the endothelium vasodilator:vasoconstrictor balance, leading to severe vasoconstriction and hypertension. Thus, endothelial dysfunction and impairment of cardiovascular function represent a common feature of pathologic conditions associated with hemolysis. In this review, we discuss how hemoglobin/heme released following hemolysis may affect vascular function and summarise the therapeutic approaches available to limit hemolysis-driven endothelial dysfunction. Particular emphasis is put on recent data showing the beneficial effects obtained through the use of the plasma heme scavenger hemopexin in counteracting heme-mediated endothelial damage in mouse models of hemolytic diseases.

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Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches

International Journal of Molecular Sciences ◽

10.3390/ijms22083850 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3850

Author(s):

Diana Jhoseline Medina-Leyte ◽

Oscar Zepeda-García ◽

Mayra Domínguez-Pérez ◽

Antonia González-Garrido ◽

Teresa Villarreal-Molina ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Endothelial Dysfunction ◽

Preventive Treatment ◽

Therapeutic Strategies ◽

Endothelial Damage ◽

Liquid Biopsies ◽

Cellular Markers ◽

Artery Disease ◽

Potential Biomarkers

Coronary artery disease (CAD) and its complications are the leading cause of death worldwide. Inflammatory activation and dysfunction of the endothelium are key events in the development and pathophysiology of atherosclerosis and are associated with an elevated risk of cardiovascular events. There is great interest to further understand the pathophysiologic mechanisms underlying endothelial dysfunction and atherosclerosis progression, and to identify novel biomarkers and therapeutic strategies to prevent endothelial dysfunction, atherosclerosis and to reduce the risk of developing CAD and its complications. The use of liquid biopsies and new molecular biology techniques have allowed the identification of a growing list of molecular and cellular markers of endothelial dysfunction, which have provided insight on the molecular basis of atherosclerosis and are potential biomarkers and therapeutic targets for the prevention and or treatment of atherosclerosis and CAD. This review describes recent information on normal vascular endothelium function, as well as traditional and novel potential biomarkers of endothelial dysfunction and inflammation, and pharmacological and non-pharmacological therapeutic strategies aimed to protect the endothelium or reverse endothelial damage, as a preventive treatment for CAD and related complications.

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Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18084049 ◽

2021 ◽

Vol 18 (8) ◽

pp. 4049

Author(s):

Jukka Hintikka ◽

Sanna Lensu ◽

Elina Mäkinen ◽

Sira Karvinen ◽

Marjaana Honkanen ◽

...

Keyword(s):

Amino Acids ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

Insulin Signaling ◽

Aromatic Amino Acids ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Beneficial Effects ◽

Male Wistar Rats ◽

Branched Chain

We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms associated with these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12 weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.

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Comparison of biomarkers of endothelial dysfunction and microvascular endothelial function in patients with primary aldosteronism and essential hypertension

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320321999491 ◽

2021 ◽

Vol 22 (1) ◽

pp. 147032032199949

Author(s):

Miaomiao Sang ◽

Yu Fu ◽

Chenmin Wei ◽

Jing Yang ◽

Xueting Qiu ◽

...

Keyword(s):

Essential Hypertension ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Primary Aldosteronism ◽

Cardiovascular Events ◽

Statistical Significance ◽

Enzyme Linked Immunosorbent Assay ◽

Microvascular Endothelial ◽

Pai 1 ◽

Microvascular Endothelial Function

Introduction: Studies have shown that primary aldosteronism (PA) has a higher risk of cardiovascular events than essential hypertension (EH). Endothelial dysfunction is an independent predictor of cardiovascular events. Whether PA and EH differ in the endothelial dysfunction is uncertain. Our study was designed to investigate the levels of biomarkers of endothelial dysfunction (Asymmetric dimethylarginine, ADMA; E-selectin, and Plasminogen activator inhibitor-1, PAI-1) and assess the microvascular endothelial function in patients with PA and EH, respectively. Methods: The biomarkers of endothelial dysfunction were measured by enzyme-linked immunosorbent assay (ELISA). Microvascular endothelial function was evaluated by Pulse amplitude tonometry (PAT). Results: Thirty-one subjects with EH and 36 subjects with PA including 22 with aldosterone-producing adenoma (APA) and 14 with idiopathic hyperaldosteronism (IHA) were enrolled in our study. The ADMA levels among the three groups were different (APA 47.83 (27.50, 87.74) ng/ml vs EH 25.08 (22.44, 39.79) ng/ml vs IHA 26.00 (22.23, 33.75) ng/ml; p = 0.04), however, when the APA group was compared with EH and IHA group, there was no statistical significance (47.83 (27.50, 87.74) ng/ml vs 25.08 (22.44, 39.79) ng/ml for EH, p = 0.11; 47.83 (27.50, 87.74) ng/ml vs IHA 26.00 (33.75) ng/ml, p = 0.07). The results of ADMA levels are presented as Median (p25, p75). Whereas, levels of PAI-1 and E-selectin, microvascular endothelial function were not significantly different between PA and EH subjects. Conclusions: Our study shows no significant differences between PA and EH in terms of biomarkers of endothelial dysfunction and microvascular endothelial function. The microvascular endothelial function of PA and EH patients is comparable.

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New-Onset Diabetes, Endothelial Dysfunction, and Cardiovascular Outcomes in Hypertensive Patients: An Illness-Event Model Analysis

Biomedicines ◽

10.3390/biomedicines9070721 ◽

2021 ◽

Vol 9 (7) ◽

pp. 721

Author(s):

Raffaele Maio ◽

Edoardo Suraci ◽

Benedetto Caroleo ◽

Cristina Politi ◽

Simona Gigliotti ◽

...

Keyword(s):

Blood Flow ◽

Endothelial Dysfunction ◽

Confidence Interval ◽

Cardiovascular Events ◽

Forearm Blood Flow ◽

Cardiovascular Outcomes ◽

Hazard Ratio ◽

Baseline Status ◽

Event Model ◽

New Onset

Background. Insulin resistance and endothelial dysfunction are common findings in hypertensives, both predisposing to a higher risk of diabetes and cardiovascular events. We designed this study to evaluate the role of endothelial dysfunction in three pathogenetic pathways: (1) from baseline to cardiovascular events, (2) from baseline to diabetes, and (3) from new-onset diabetes to cardiovascular events. Methods. We enrolled 653 Caucasian never-treated hypertensives. Endothelial dysfunction was investigated by strain-gauge plethysmography; incident diabetes and cardiovascular events were evaluated by an illness-event model analysis. Results. During the follow-up (median 113 months), we documented 191 new cardiovascular events and 92 new cases of diabetes. In a multiple Cox regression analysis, acetylcholine-stimulated forearm blood flow [100% decrease, hazard ratio: 2.42 (95% confidence interval = 1.72–3.40)] and serum high-sensitivity C-reactive protein [hazard ratio: 1.30 (95% confidence interval = 1.21–1.40)] had an independent association with cardiovascular outcomes. The incidence rate of cardiovascular outcomes in diabetes-developer patients was higher than in the diabetes-free ones (34.9 vs. 2.5 events per 100 persons-year). In an illness-event model, a 100% decrease in forearm blood flow was associated with a 55.5% hazard ratio increase (hazard ratio: 1.56, 95% confidence interval: 1.33–1.82) of transition 1 (from baseline status to cardiovascular events) and to an almost doubled increase (hazard ratio: 2.54, 95% CI: 2.00–3.25) of the risk of transition 2 (from baseline status to diabetes). No such effects were found in transition 3 (from diabetes to cardiovascular events). Conclusions. Endothelial dysfunction plays a primary role in the pathways leading to diabetes and cardiovascular events in hypertensives. When diabetes is overt, endothelial dysfunction has no predictive value for subsequent cardiovascular events.

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Major adverse cardiovascular events in the Psoriasis Longitudinal Assessment and Registry Study (PSOLAR): Current status of observations

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2015.02.963 ◽

2015 ◽

Vol 72 (5) ◽

pp. AB240

Keyword(s):

Cardiovascular Events ◽

Current Status ◽

Major Adverse Cardiovascular Events ◽

Registry Study ◽

Longitudinal Assessment

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Nonsteroid anti-inflammatory drugs (NSAID) and risk of cardiovascular events. Literature review and clinical implications

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2014.58 ◽

2015 ◽

Vol 82 (3) ◽

Cited By ~ 1

Author(s):

Pier Luigi Temporelli ◽

Giovanni Battista Zito ◽

Roberto Franco Pedretti ◽

Francesco Iachini Belisarii ◽

Giuseppe Putortì ◽

...

Keyword(s):

Chronic Pain ◽

Cardiovascular Events ◽

Large Body ◽

Cyclooxygenase Inhibitors ◽

Current Status ◽

Analgesic Drugs ◽

Drug Agency ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Artery Disease

Non steroid anti-inflammatory drugs (NSAIDs) are largely used for treatment of acute and chronic pain, even for long periods of time (months or years). While it is known that their use is frequently associated with gastrointestinal damage, including major bleedings from peptic ulcer, the risk of cardiovascular events related to NSAID has received much less attention. However, there is a large body of evidence showing that NSAIDs (both “traditional”, such as diclofenac or indobufen, and selective cyclooxygenase inhibitors, COX-2) are associated with a significant increase of risk of cardiovascular events, both fatal and nonfatal. Consequently, several options have been proposed for the treatment of pain, including the use of analgesic drugs with different mechanisms of action, such as the opiates. Of interest, the Italian Drug Agency (AIFA) published a few years ago a warning (Nota 66) on the careful prescription of NSAIDs in patients with overt heart disease, such as coronary artery disease and heart failure. Aim of this paper is to present the current status of knowledge on the proper use of NSAIDs and other analgesic drugs in the management of acute and chronic pain.

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