Augmentation of Vascular Remodeling by Uncoupled Endothelial Nitric Oxide Synthase in a Mouse Model of Diabetes Mellitus

Sasaki, Naoto; Yamashita, Tomoya; Takaya, Tomofumi; Shinohara, Masakazu; Shiraki, Rio; Takeda, Masafumi; Emoto, Noriaki; Fukatsu, Atsushi; Hayashi, Toshio; Ikemoto, Kazuhisa; Nomura, T.; Yokoyama, Mitsuhiro; Hirata, Ken‐ichi; Kawashima, Seinosuke

doi:10.1161/atvbaha.107.160754

Cited by 50 publications

(32 citation statements)

References 51 publications

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“…24 Diabetic mice are shown to develop greater neointima formation than nondiabetic mice, mirroring an earlier report. 34 In that study, oxidative stress, which we here show to posttranscriptionally regulate PAR-4, was found to contribute to the augmented neointima formation. Diabetic mice deficient in PAR-4 showed no such augmented remodeling response; in fact, the neointimal area was smaller even than in nondiabetic wild-type mice.…”

Section: Discussionmentioning

confidence: 48%

Thrombin Receptor Protease-Activated Receptor 4 Is a Key Regulator of Exaggerated Intimal Thickening in Diabetes Mellitus

et al. 2014

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Background— Diabetes mellitus predisposes to thrombotic and proliferative vascular remodeling, to which thrombin contributes via activation of protease-activated receptor (PAR) 1. However, the use of PAR-1 inhibitors to suppress remodeling may be limited by severe bleeding. We recently reported upregulation of an additional thrombin receptor, PAR-4, in human vascular smooth muscle cells exposed to high glucose and have now examined PAR-4 as a novel mediator linking hyperglycemia, hypercoagulation, and vascular remodeling in diabetes mellitus. Methods and Results— PAR-4 expression was increased in carotid atherectomies and saphenous vein specimens from diabetic versus nondiabetic patients and in aorta and carotid arteries from streptozotocin-diabetic versus nondiabetic C57BL/6 mice. Vascular PAR-1 mRNA was not increased in diabetic mice. Ligated carotid arteries from diabetic mice developed more extensive neointimal hyperplasia and showed greater proliferation than arteries from nondiabetic mice. The augmented remodeling response was absent in diabetic mice deficient in PAR-4. At the cellular level, PAR-4 expression was controlled via the mRNA stabilizing actions of human antigen R, which accounted for the stimulatory actions of high glucose, angiotensin II, and H 2 O 2 on PAR-4 expression, whereas cicaprost via protein kinase A activation counteracted this effect. Conclusions— PAR-4 appears to play a hitherto unsuspected role in diabetic vasculopathy. The development of PAR-4 inhibitors might serve to limit mainly proliferative processes in restenosis-prone diabetic patients, particularly those patients in whom severe bleeding attributed to selective PAR-1 blockade or complete thrombin inhibition must be avoided or those who do not require anticoagulation.

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Section: Discussionmentioning

confidence: 48%

Thrombin Receptor Protease-Activated Receptor 4 Is a Key Regulator of Exaggerated Intimal Thickening in Diabetes Mellitus

et al. 2014

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“…48 Additionally, ONOO − serves to uncouple eNOS from its critical co-factor tetrahydrobiopterin (BH 4 ), resulting in preferential formation of O 2 ·− in the place of NO and hence further exacerbation of the problem. 49 In the setting of insulin resistance, experimental evidence has implicated endogenous ONOO − as a down-regulator of the PI3-K/Akt pathway. 50,51 Aside from uncoupled eNOS, significant sources of O 2 ·− include xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria.…”

Section: Oxidative Stressmentioning

confidence: 99%

Cellular and molecular mechanisms of endothelial dysfunction in diabetes

Roberts

Porter

2013

Diabetes and Vascular Disease Research

191

126

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In healthy individuals, the vascular endothelium regulates an intricate balance of factors that maintain vascular homeostasis and normal arterial function. Functional disruption of the endothelium is known to be an early event that underlies the development of subsequent cardiovascular disease (CVD) including atherosclerosis and coronary heart disease. In addition, the rising global epidemic of type 2 diabetes is a significant problem conferring a significantly higher risk of CVD to individuals in whom endothelial dysfunction is also notable. This review first summarises the role of endothelium in health and explores and evaluates the impact of diabetes on endothelial function. The characteristic features of insulin resistance and other metabolic disturbances that may underlie long-term changes in vascular endothelial function (metabolic memory) are described along with proposed cellular, molecular and epigenetic mechanisms. Through understanding the underlying mechanisms, novel targets for future therapies to restore endothelial homeostasis and 'drive' a reparative cellular phenotype are explored.

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“…The poor vasorelaxation responses to CCh and the enhanced L-NAMEinhibitable superoxide generation in these mice could be attributed to decreased BH4 levels and BH4/BH2 ratio. 31 Due to limited availability of aortic tissue and number of mice, BH4 levels were not determined. It is compelling to speculate that enhanced vasorelaxation could be achieved in TgeNOS-GFP-Ins2…”

mentioning

confidence: 99%

Enhancing eNOS activity with simultaneous inhibition of IKKβ restores vascular function in Ins2Akita+/− type-1 diabetic mice

Krishnan

Janardhanan

Roman

et al. 2015

Laboratory Investigation

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The balance of nitric oxide (NO) versus superoxide generation has a major role in the initiation and progression of endothelial dysfunction. Under conditions of high glucose, endothelial nitric oxide synthase (eNOS) functions as a chief source of superoxide rather than NO. In order to improve NO bioavailability within the vessel wall in type-1 diabetes, we investigated treatment strategies that improve eNOS phosphorylation and NO-dependent vasorelaxation. We evaluated methods to increase the eNOS activity by (1) feeding Ins2Akita spontaneously diabetic (type-1) mice with L-arginine in the presence of sepiapterin, a precursor of tetrahydrobiopterin; (2) preventing eNOS/NO deregulation by the inclusion of inhibitor kappa B kinase beta (IKKβ) inhibitor, salsalate, in the diet regimen in combination with L-arginine and sepiapterin; and (3) independently increasing eNOS expression to improve eNOS activity and associated NO production through generating Ins2Akita diabetic mice that overexpress human eNOS predominantly in vascular endothelial cells. Our results clearly demonstrated that diet supplementation with L-arginine, sepiapterin along with salsalate improved phosphorylation of eNOS and enhanced vasorelaxation of thoracic/abdominal aorta in type-1 diabetic mice. More interestingly, despite the overexpression of eNOS, the in-house generated transgenic eNOS-GFP (TgeNOS-GFP)-Ins2 Akita cross mice showed an unanticipated effect of reduced eNOS phosphorylation and enhanced superoxide production. Our results demonstrate that enhancement of endogenous eNOS activity by nutritional modulation is more beneficial than increasing the endogenous expression of eNOS by gene therapy modalities. Endothelial nitric oxide synthase (eNOS) that utilizes L-arginine as a substrate to generate nitric oxide (NO) is a key regulator of vascular function. Even though endothelial cells, a predominant source of eNOS exhibit constitutive enzyme activity, several other regulators are necessary to induce eNOS activity based on local demand for NO. Reduced bioavailability of NO that causes endothelial dysfunction is a hallmark of diabetes. Several mechanisms have been implicated causing 'endothelial dysfunction' in diabetes. The reduced availability of the substrate L-arginine and the cofactor tetrahydrobiopterin (BH4) has been implicated due to increased arginase activity and enhanced superoxide generation. 1 Uncoupling of eNOS has been shown to be central to robust superoxide generation and the associated vascular dysfunction. 2 Increased levels of asymmetric NG, NG-dimethyl arginine (ADMA-a substrate analog of L-arginine) in circulation have also been shown in diabetic patients limiting the availability of L-arginine to eNOS. 3 In vitro studies from our laboratory and reports from other investigators have shown that the regulation of eNOS activity is mediated by heat shock protein-90 (Hsp-90). 4,5 The interaction of eNOS with Hsp-90 favors the phosphorylation of eNOS at Ser1177 by Akt kinase. This phosphorylation process is a key event which a...

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Augmentation of Vascular Remodeling by Uncoupled Endothelial Nitric Oxide Synthase in a Mouse Model of Diabetes Mellitus

Cited by 50 publications

References 51 publications

Thrombin Receptor Protease-Activated Receptor 4 Is a Key Regulator of Exaggerated Intimal Thickening in Diabetes Mellitus

Thrombin Receptor Protease-Activated Receptor 4 Is a Key Regulator of Exaggerated Intimal Thickening in Diabetes Mellitus

Cellular and molecular mechanisms of endothelial dysfunction in diabetes

Enhancing eNOS activity with simultaneous inhibition of IKKβ restores vascular function in Ins2Akita+/− type-1 diabetic mice

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