THE IMPACT OF ENDOTHELIAL DYSFUNCTION IN THE DEVELOPMENT OF DIABETIC RETINOPATHY: ROLE OF INFLAMMATION

The endothelium is the single-cell monolayer that lines the entire vasculature. The endothelium has a barrier function to separate blood from organs and tissues but also has an increasingly appreciated role in anti-coagulation, vascular senescence, endocrine secretion, suppression of inflammation and beyond. In modern times, endothelial cells have been identified as the source of major endocrine and vaso-regulatory factors principally the dissolved lipophilic vosodilating gas, nitric oxide and the potent vascular constricting G protein receptor agonists, the peptide endothelin. The role of the endothelium can be conveniently conceptualized. Continued investigations of the mechanism of endothelial dysfunction will lead to novel therapies for cardiovascular disease. In this review, we discuss the impact of endothelial dysfunction on cardiovascular disease and assess the clinical relevance of endothelial dysfunction.

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Abstract 610: Context-Dependent Effects of Suppressor of Cytokine Signaling 3 (SOCS3) in Angiotensin II-Induced Vascular Dysfunction: Mechanisms and Role of Bone Marrow-Derived Cells

Hypertension ◽

10.1161/hyp.64.suppl_1.610 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Ying Li ◽

Dale Kinzenbaw ◽

Mary Modrick ◽

Lecia Epping ◽

John T Harty ◽

...

Keyword(s):

Bone Marrow ◽

Angiotensin Ii ◽

Endothelial Dysfunction ◽

Vascular Disease ◽

Vascular Dysfunction ◽

Pressor Response ◽

Ang Ii ◽

Bone Marrow Derived Cells ◽

The Impact

Angiotensin II (Ang II) promotes vascular disease and hypertension, in part, by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Although SOCS3 regulates this pathway in the immune system, its role in vascular disease and hypertension is unknown. In this study, we investigated the role of SOCS3 in a model of Ang II-induced vascular disease. To exam direct effects, carotid arteries from wild-type (WT) and SOCS3 haplodeficient (SOCS3 +/- ) mice were incubated with Ang II for 22 hrs, followed by examination of endothelial function using acetylcholine (Ach). Relaxation to Ach was similar in all arteries incubated with vehicle. A low concentration of Ang II (1 nmol/L) did not affect Ach-induced vasodilation in WT mice, but reduced that of SOCS3 +/- mice by ~50% (P<0.05). Ang II-induced impairment was prevented by inhibitors of STAT3, IL-6, NF-κB, or a scavenger of superoxide. Responses to nitroprusside were similar in all groups. We also tested the impact of SOCS3 in vivo by systemically infusing Ang II (1.4 mg/kg per day) for 14 days via osmotic mini-pumps. Ach-induced vasodilation in carotid and resistance arteries in brain from WT mice was reduced by ~60% (P<0.05). Surprisingly, deficiency in SOCS3 prevented the majority of Ang II-induced endothelial dysfunction without affecting the pressor response to Ang II. Lethally irradiated WT mice reconstituted with SOCS3 +/- bone marrow were protected from Ang II-induced endothelial dysfunction (P<0.05), while reconstitution of irradiated SOCS3 +/- mice with WT bone marrow exacerbated Ang II-induced vascular dysfunction (P<0.05). WT into WT and SOCS3 +/- into SOCS3 +/- bone marrow chimeras exhibited vascular function consistent with non-irradiated controls. The pressor response to Ang II was reduced by ~50% in WT mice reconstituted with bone marrow from SOCS3 +/- mice (P<0.05). These data suggest SOCS3 exerts divergent local versus systemic effects on Ang II-induced vascular dysfunction. In the face of SOCS3 deficiency, bone marrow-derived cells protect against Ang II-induced vascular dysfunction and hypertension.

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The Adenosinergic System in Diabetic Retinopathy

Journal of Diabetes Research ◽

10.1155/2016/4270301 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

J. Vindeirinho ◽

A. R. Santiago ◽

C. Cavadas ◽

A. F. Ambrósio ◽

P. F. Santos

Keyword(s):

Diabetic Retinopathy ◽

Inflammatory Response ◽

Adenosine Receptors ◽

Therapeutic Targets ◽

Experimental Results ◽

Early Stages ◽

The Impact

The neurodegenerative and inflammatory environment that is prevalent in the diabetic eye is a key player in the development and progression of diabetic retinopathy. The adenosinergic system is widely regarded as a significant modulator of neurotransmission and the inflammatory response, through the actions of the four types of adenosine receptors (A1R, A2AR, A2BR, and A3R), and thus could be revealed as a potential player in the events unfolding in the early stages of diabetic retinopathy. Herein, we review the studies that explore the impact of diabetic conditions on the retinal adenosinergic system, as well as the role of the said system in ameliorating or exacerbating those conditions. The experimental results described suggest that this system is heavily affected by diabetic conditions and that the modulation of its components could reveal potential therapeutic targets for the treatment of diabetic retinopathy, particularly in the early stages of the disease.

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Role of Endothelial Dysfunction and Arterial Stiffness in the Development of Diabetic Retinopathy: Figure 1

Diabetes Care ◽

10.2337/dc14-1741 ◽

2014 ◽

Vol 38 (1) ◽

pp. e9-e10 ◽

Cited By ~ 24

Author(s):

Gerasimos Siasos ◽

Nikolaos Gouliopoulos ◽

Marilita M. Moschos ◽

Evangelos Oikonomou ◽

Christina Kollia ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Endothelial Dysfunction ◽

Arterial Stiffness

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Abstract 183: Oxidized LDL Cholesterol Induces Endothelial Dysfunction in the Aorta and Lox-1 Expression in Macrophages

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a183 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Anja Leuner ◽

David M Poitz ◽

Robert Augustin ◽

Heike Neubauer ◽

Coy Brunssen ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

High Fat Diet ◽

Ldl Cholesterol ◽

Oxidized Ldl ◽

High Fat ◽

Human Macrophages ◽

Atherosclerotic Lesions ◽

The Impact

Elevated plasma cholesterol is one of the major risk factors in the development of atherosclerotic lesions. Oxidation of native LDL cholesterol (nLDL) by reactive oxygen species leads to the formation of oxidized LDL (oxLDL). An important receptor for the cellular uptake of oxLDL is the lectin-like oxidized low-density lipoprotein receptor-1 (Lox-1). Lox-1 is highly expressed on macrophages, but also present on arterial endothelial and vascular smooth muscle cells. Especially the uptake by macrophages leads to the formation of foam cells in atherosclerotic lesions. Aim of the present study was to analyze the impact of oxLDL on endothelial function in murine aortas and on Lox-1 expression in human macrophages. In addition, we analyzed the effect of a high-fat diet on vascular function in mice with an endothelial Lox-1 overexpression. First, we incubated aortic rings of wild-type mice for 2 h with 100 μg/mL oxLDL and analyzed the endothelial function using a Mulvany myograph. Compared to basal conditions, oxLDL significantly impaired endothelium-dependent vasodilation. Next, we fed mice with an endothelial overexpression of Lox-1 for 20 weeks a high-fat diet and analyzed the endothelial function in the thoracic aorta. Interestingly, these mice had no impaired endothelium-dependent relaxation after high-fat diet feeding. To get further insight into Lox-1 regulation by oxLDL, we analyzed the impact of oxLDL on Lox-1 expression in human macrophages. Monocytic THP-1 cells were differentiated with phorbol myristate acetate into macrophages and stimulated for 24 h with nLDL or oxLDL. We found a significant induction of Lox-1 mRNA expression after oxLDL incubation, whereas nLDL had no effect. Our data suggest an increased oxLDL uptake in oxLDL-treated macrophages by increased Lox-1 receptor expression. In conclusion, our data support an important role of oxLDL as a proatherosclerotic risk factor by its ability to induce endothelial dysfunction and Lox-1 expression in macrophages. Both processes may be involved in the development of atherosclerotic lesions but the physiological significance and functional role of Lox-1 in contributing to the human disease warrants further investigations.

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Characterization of CD38 in the major cell types of the heart: endothelial cells highly express CD38 with activation by hypoxia-reoxygenation triggering NAD(P)H depletion

AJP Cell Physiology ◽

10.1152/ajpcell.00139.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. C297-C309 ◽

Cited By ~ 13

Author(s):

James Boslett ◽

Craig Hemann ◽

Fedias L. Christofi ◽

Jay L. Zweier

Keyword(s):

Endothelial Cells ◽

Endothelial Dysfunction ◽

Cardiac Myocytes ◽

Cell Types ◽

No Production ◽

Imaging Method ◽

Enos Uncoupling ◽

The Impact ◽

Hypoxia Reoxygenation

The NAD(P)+-hydrolyzing enzyme CD38 is activated in the heart during the process of ischemia and reperfusion, triggering NAD(P)(H) depletion. However, the presence and role of CD38 in the major cell types of the heart are unknown. Therefore, we characterize the presence and function of CD38 in cardiac myocytes, endothelial cells, and fibroblasts. To comprehensively evaluate CD38 in these cells, we measured gene transcription via mRNA, as well as protein expression and enzymatic activity. Endothelial cells strongly expressed CD38, while only low expression was present in cardiac myocytes with intermediate levels in fibroblasts. In view of this high level expression in endothelial cells and the proposed role of CD38 in the pathogenesis of endothelial dysfunction, endothelial cells were subjected to hypoxia-reoxygenation to characterize the effect of this stress on CD38 expression and activity. An activity-based CD38 imaging method and CD38 activity assays were used to characterize CD38 activity in normoxic and hypoxic-reoxygenated endothelial cells, with marked CD38 activation seen following hypoxia-reoxygenation. To test the impact of hypoxia-reoxygenation-induced CD38 activation on endothelial cells, NAD(P)(H) levels and endothelial nitric oxide synthase (eNOS)-derived NO production were measured. Marked NADP(H) depletion with loss of NO and increase in superoxide production occurred following hypoxia-reoxygenation that was prevented by CD38 inhibition or knockdown. Thus, endothelial cells have high expression of CD38 which is activated by hypoxia-reoxygenation triggering CD38-mediated NADP(H) depletion with loss of eNOS-mediated NO generation and increased eNOS uncoupling. This demonstrates the importance of CD38 in the endothelium and explains the basis by which CD38 triggers post-ischemic endothelial dysfunction.

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The predictive role of markers of Inflammation and endothelial dysfunction on the course of diabetic retinopathy in type 1 diabetes

Journal of Diabetes and its Complications ◽

10.1016/j.jdiacomp.2014.08.004 ◽

2015 ◽

Vol 29 (1) ◽

pp. 108-114 ◽

Cited By ~ 14

Author(s):

Hussein A. Rajab ◽

Nathaniel L. Baker ◽

Kelly J. Hunt ◽

Richard Klein ◽

Patricia A. Cleary ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Retinopathy ◽

Endothelial Dysfunction ◽

Markers Of Inflammation ◽

Predictive Role

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The role of oxidative stress in postprandial endothelial dysfunction

Nutrition Research Reviews ◽

10.1017/s0954422412000182 ◽

2012 ◽

Vol 25 (2) ◽

pp. 288-301 ◽

Cited By ~ 32

Author(s):

Sébastien Lacroix ◽

Christine Des Rosiers ◽

Jean-Claude Tardif ◽

Anil Nigam

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Potential Role ◽

Present Review ◽

High Fat ◽

High Carbohydrate ◽

Transient Impairment ◽

The Impact

Endothelial dysfunction is a turning point in the initiation and development of atherosclerosis and its complications and is predictive of future cardiovascular events. Ingestion of high-carbohydrate or high-fat meals often results in postprandial hyperglycaemia and/or hypertriacylglycerolaemia that may lead to a transient impairment in endothelial function. The present review will discuss human studies evaluating the impact of high-carbohydrate and high-fat challenges on postprandial endothelial function as well as the potential role of oxidative stress in such postprandial metabolic alterations. Moreover, the present review will differentiate the postprandial endothelial and oxidative impact of meals rich in varying fatty acid types.

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