Angiotensin II Type 1 Receptor-Dependent Oxidative Stress Mediates Endothelial Dysfunction in Type 2 Diabetic Mice

Aim. To investigate the combination effects and mechanisms of valsartan (angiotensin II type 1 receptor blocker) and LAF237 (DPP-IV inhibitor) on prevention against oxidative stress and inflammation injury in db/db mice aorta.Methods. Db/db mice (n=40) were randomized to receive valsartan, LAF237, valsartan plus LAF237, or saline. Oxidative stress and inflammatory reaction in diabetic mice aorta were examined.Results. Valsartan or LAF237 pretreatment significantly increased plasma GLP-1 expression, reduced apoptosis of endothelial cells isolated from diabetic mice aorta. The expression of NAD(P)H oxidase subunits also significantly decreased resulting in decreased superoxide production and ICAM-1 (fold change: valsartan : 7.5 ± 0.7,P<0.05; LAF237: 10.2 ± 1.7,P<0.05), VCAM-1 (fold change: valsartan : 5.2 ± 1.2,P<0.05; LAF237: 4.8 ± 0.6,P<0.05), and MCP-1 (fold change: valsartan: 3.2 ± 0.6, LAF237: 4.7 ± 0.8;P<0.05) expression. Moreover, the combination treatment with valsartan and LAF237 resulted in a more significant increase of GLP-1 expression. The decrease of the vascular oxidative stress and inflammation reaction was also higher than monotherapy with valsartan or LAF237.Conclusion. These data indicated that combination treatment with LAF237 and valsartan acts in a synergistic manner on vascular oxidative stress and inflammation in type 2 diabetic mice.

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Endothelial dysfunction and oxidative stress in type 1 and type 2 diabetic patients without clinical macrovascular complications

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2007.09.005 ◽

2008 ◽

Vol 79 (2) ◽

pp. 337-342 ◽

Cited By ~ 32

Author(s):

Giancarlo De Mattia ◽

Maria Cristina Bravi ◽

Oriana Laurenti ◽

Arianna Moretti ◽

Rosalba Cipriani ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Macrovascular Complications ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

And Oxidative Stress ◽

Type 2 Diabetic

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Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

Hypertension ◽

10.1161/hypertensionaha.112.192401 ◽

2012 ◽

Vol 59 (5) ◽

pp. 1079-1088 ◽

Cited By ~ 67

Author(s):

Li-Juan Min ◽

Masaki Mogi ◽

Masachika Shudou ◽

Fei Jing ◽

Kana Tsukuda ◽

...

Keyword(s):

Angiotensin Ii ◽

Cognitive Decline ◽

Blood Brain Barrier ◽

Peroxisome Proliferator ◽

Receptor Blockade ◽

Diabetic Mice ◽

Peroxisome Proliferator Activated Receptor ◽

Type 2 Diabetic

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Angiotensin II Type 1 Receptor Antagonism Mediates Uncoupling Protein 2-Driven Oxidative Stress and Ameliorates Pancreatic Islet β-Cell Function in Young Type 2 Diabetic Mice

Antioxidants and Redox Signaling ◽

10.1089/ars.2007.1590 ◽

2007 ◽

Vol 9 (7) ◽

pp. 869-878 ◽

Cited By ~ 61

Author(s):

Kwan Yi Chu ◽

Po Sing Leung

Keyword(s):

Oxidative Stress ◽

Cell Function ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Diabetic Mice ◽

Β Cell ◽

Β Cell Function ◽

Type 2 Diabetic

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Fibroblast growth factor 21 Ameliorates diabetes-induced endothelial dysfunction in mouse aorta via activation of the CaMKK2/AMPKα signaling pathway

Cell Death and Disease ◽

10.1038/s41419-019-1893-6 ◽

2019 ◽

Vol 10 (9) ◽

Cited By ~ 7

Author(s):

Lei Ying ◽

Na Li ◽

Zhengyue He ◽

Xueqin Zeng ◽

Yan Nan ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Signaling Pathway ◽

Oxidative Capacity ◽

Fibroblast Growth Factor 21 ◽

Diabetic Mice

Abstract Endothelial dysfunction initiates and exacerbates hypertension, atherosclerosis and other cardiovascular complications in diabetic mellitus. FGF21 is a hormone that mediates a number of beneficial effects relevant to metabolic disorders and their associated complications. Nevertheless, it remains unclear as to whether FGF21 ameliorates endothelial dysfunction. Therefore, we investigated the effect of FGF21 on endothelial function in both type 1 and type 2 diabetes. We found that FGF21 reduced hyperglycemia and ameliorated insulin resistance in type 2 diabetic mice, an effect that was totally lost in type 1 diabetic mice. However, FGF21 activated AMPKα, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of aorta in both types, suggesting a mechanism that is independent of its glucose-lowering and insulin-sensitizing effects. In vitro, we identified a direct action of FGF21 on endothelial cells of the aorta, in which it bounds to FGF receptors to alleviate impaired endothelial function challenged with high glucose. Furthermore, the CaMKK2-AMPKα signaling pathway was activated to suppress oxidative stress. Apart from its anti-oxidative capacity, FGF21 activated eNOS to dilate the aorta via CaMKK2/AMPKα activation. Our data suggest expanded potential uses of FGF21 for the treatment of vascular diseases in diabetes.

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Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01306.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. H306-H314 ◽

Cited By ~ 48

Author(s):

Sewon Lee ◽

Yoonjung Park ◽

Kevin C. Dellsperger ◽

Cuihua Zhang

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Exercise Training ◽

Endothelial Function ◽

Protein Expression ◽

Diabetic Mice ◽

Ifn Γ ◽

And Oxidative Stress ◽

Type 2 Diabetic

Type 2 diabetes (T2D) is a leading risk factor for a variety of cardiovascular diseases including coronary heart disease and atherosclerosis. Exercise training (ET) has a beneficial effect on these disorders, but the basis for this effect is not fully understood. This study was designed to investigate whether the ET abates endothelial dysfunction in the aorta in T2D. Heterozygous controls (m Lepr db) and type 2 diabetic mice ( db/db; Lepr db) were either exercise entrained by forced treadmill exercise or remained sedentary for 10 wk. Ex vivo functional assessment of aortic rings showed that ET restored acetylcholine-induced endothelial-dependent vasodilation of diabetic mice. Although the protein expression of endothelial nitric oxide synthase did not increase, ET reduced both IFN-γ and superoxide production by inhibiting gp91phox protein levels. In addition, ET increased the expression of adiponectin (APN) and the antioxidant enzyme, SOD-1. To investigate whether these beneficial effects of ET are APN dependent, we used adiponectin knockout (APNKO) mice. Indeed, impaired endothelial-dependent vasodilation occurred in APNKO mice, suggesting that APN plays a central role in prevention of endothelial dysfunction. APNKO mice also showed increased protein expression of IFN-γ, gp91phox, and nitrotyrosine but protein expression of SOD-1 and -3 were comparable between wild-type and APNKO. These findings in the aorta imply that APN suppresses inflammation and oxidative stress in the aorta, but not SOD-1 and -3. Thus ET improves endothelial function in the aorta in T2D via both APN-dependent and independent pathways. This improvement is due to the effects of ET in inhibiting inflammation and oxidative stress (APN-dependent) as well as in improving antioxidant enzyme (APN-independent) performance in T2D.

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Rap1a Overlaps the AGE/RAGE Signaling Cascade to Alter Expression of α-SMA, p-NF-κB, and p-PKC-ζ in Cardiac Fibroblasts Isolated from Type 2 Diabetic Mice

Cells ◽

10.3390/cells10030557 ◽

2021 ◽

Vol 10 (3) ◽

pp. 557

Author(s):

Stephanie D. Burr ◽

James A. Stewart

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Hydrogen Peroxide ◽

Cardiac Fibroblasts ◽

The Body ◽

Signaling Cascade ◽

Diabetic Mice ◽

Pkc Ζ ◽

Type 2 Diabetic

Cardiovascular disease, specifically heart failure, is a common complication for individuals with type 2 diabetes mellitus. Heart failure can arise with stiffening of the left ventricle, which can be caused by “active” cardiac fibroblasts (i.e., myofibroblasts) remodeling the extracellular matrix (ECM). Differentiation of fibroblasts to myofibroblasts has been demonstrated to be an outcome of AGE/RAGE signaling. Hyperglycemia causes advanced glycated end products (AGEs) to accumulate within the body, and this process is greatly accelerated under chronic diabetic conditions. AGEs can bind and activate their receptor (RAGE) to trigger multiple downstream outcomes, such as altering ECM remodeling, inflammation, and oxidative stress. Previously, our lab has identified a small GTPase, Rap1a, that possibly overlaps the AGE/RAGE signaling cascade to affect the downstream outcomes. Rap1a acts as a molecular switch connecting extracellular signals to intracellular responses. Therefore, we hypothesized that Rap1a crosses the AGE/RAGE cascade to alter the expression of AGE/RAGE associated signaling proteins in cardiac fibroblasts in type 2 diabetic mice. To delineate this cascade, we used genetically different cardiac fibroblasts from non-diabetic, diabetic, non-diabetic RAGE knockout, diabetic RAGE knockout, and Rap1a knockout mice and treated them with pharmacological modifiers (exogenous AGEs, EPAC, Rap1a siRNA, and pseudosubstrate PKC-ζ). We examined changes in expression of proteins implicated as markers for myofibroblasts (α-SMA) and inflammation/oxidative stress (NF-κB and SOD-1). In addition, oxidative stress was also assessed by measuring hydrogen peroxide concentration. Our results indicated that Rap1a connects to the AGE/RAGE cascade to promote and maintain α-SMA expression in cardiac fibroblasts. Moreover, Rap1a, in conjunction with activation of the AGE/RAGE cascade, increased NF-κB expression as well as hydrogen peroxide concentration, indicating a possible oxidative stress response. Additionally, knocking down Rap1a expression resulted in an increase in SOD-1 expression suggesting that Rap1a can affect oxidative stress markers independently of the AGE/RAGE signaling cascade. These results demonstrated that Rap1a contributes to the myofibroblast population within the heart via AGE/RAGE signaling as well as promotes possible oxidative stress. This study offers a new potential therapeutic target that could possibly reduce the risk for developing diabetic cardiovascular complications attributed to AGE/RAGE signaling.

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