Hypercholesterolemia-Induced Erectile Dysfunction: Endothelial Nitric Oxide Synthase (eNOS) Uncoupling in the Mouse Penis by NAD(P)H Oxidase

Musicki, Biljana; Liu, Tongyun; Lagoda, Gwen A.; Strong, Travis D.; Sezen, Sena F.; Johnson, Justin M.; Burnett, Arthur L.

doi:10.1111/j.1743-6109.2010.01880.x

Cited by 95 publications

(116 citation statements)

References 59 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…17 In mice, uncoupling of eNOS can be caused by hypercholesterolemia. 18 The present study demonstrates that loss of function of TLR4 rescues diabetic obese mice from the impaired relaxations. The likely mechanism underlying this effect is a reduced superoxide anion production leading to prevention of eNOS uncoupling.…”

supporting

confidence: 56%

See 1 more Smart Citation

Toll-Like Receptor 4 Mutation Protects Obese Mice Against Endothelial Dysfunction by Decreasing NADPH Oxidase Isoforms 1 and 4

Liang

Liu

Wang

et al. 2013

ATVB

104

View full text Add to dashboard Cite

O besity and diabetes mellitus are associated with augmented circulating levels of free fatty acids, low-grade chronic inflammation, 1 and endothelial dysfunction attributable to impaired release of endothelium-derived relaxing and augmented production of endothelium-derived contracting (EDCF) factors.2 Thus, the bioavailability of NO is reduced by obesity and diabetes mellitus, 3 and relaxations attributable to endothelium-derived hyperpolarization (EDH) are impaired at the early stage of diabetes mellitus. 4 Finally, increased release of endothelium-derived vasoconstrictor prostanoids and reactive oxygen species (ROS) also contributes to endothelial dysfunction in obesity and diabetes mellitus. 5 Proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin 6 [IL-6], resistin, and lipocalin-2) link obesity to metabolic and vascular dysfunction.1 Bacterial endotoxin lipopolysaccharide (LPS) and saturated fatty acids share as pattern recognition target toll-like receptors 4 (TLR4), which activate inflammatory pathways, induce cytokine expression in the endothelium, 6,7 and augment the expression of NADPH oxidase in macrophages. 8 The absence of TLR4 protects mice against obesity-induced insulin resistance. 7NADPH oxidase is a major source of endothelial ROS. 9,10 ROS decrease the bioavailability of NO 11 and facilitate the production of EDCF. 12It is unknown whether or not TLR4 signaling contributes to the impaired NO-and EDHF-mediated relaxations and the amplified EDCF-mediated contractions seen in obesity and diabetes mellitus. Therefore, the present experiments tested the hypothesis that TLR4 signaling mediates, at least in part, the deleterious effects of diet-induced and genetic obesity leading to endothelial dysfunction. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results General CharacteristicsThere were no significant differences in food intake between wild-type (WT) and TLR4 −/− mice ( Figure Objective-To analyze the role of toll-like receptor 4 in modulating metabolism and endothelial function. Approach and Results-Type 2 diabetic mice with mutated toll-like receptor 4 (DWM) were protected from hyperglycemia and hypertension, despite an increased body weight. Isometric tension was measured in arterial rings with endothelium.Relaxations to acetylcholine were blunted in aortae and mesenteric arteries of Lepr db/db mice, but not in DWM mice; the endothelial NO synthase dimer/monomer ratio and endothelial NO synthase phosphorylation levels were higher in DWM preparations. These differences were abolished by apocynin. Contractions to acetylcholine (in the presence of L-NAME) were larger in carotid arteries from Lepr db/db mice than from DWM mice and were inhibited by indomethacin and SC560, demonstrating involvement of cyclooxygenase-1. The release of 6-ketoprostaglandin F 1α was lower in DWM mice arteries, implying lower cyclooxygenase-1 activity. Apocynin, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, catalase, and diethyldithiocarbamat...

show abstract

supporting

confidence: 56%

“…In the presence of L-NAME (10 −4 mol/L, to optimize endothelium-dependent contractions), 18 acetylcholine induced increases in tension in the quiescent carotid arteries of WT and TLR4 −/− mice ( Figure 1). These contractions were significantly attenuated in TLR4 −/− mice arteries.…”

Section: Mutation Of Tlr4mentioning

confidence: 99%

Toll-Like Receptor 4 Mutation Protects Obese Mice Against Endothelial Dysfunction by Decreasing NADPH Oxidase Isoforms 1 and 4

Liang

Liu

Wang

et al. 2013

ATVB

104

View full text Add to dashboard Cite

show abstract

“…This would in turn be a source of oxidative stress, which would result in NO synthase uncoupling and endothelial dysfunction. 39 Large prospective studies consistently show that a low level of high-density lipoprotein cholesterol (HDL-C) is a stronger risk factor for CHD than a high level of low-density lipoprotein cholesterol (LDL-C). 40,41 A study on 250 men aged 26 to 83 years without any preexisting ED concluded that high levels of total cholesterol and a low level of HDL-C were also risk factors for ED.…”

Section: Cigarette Smokingmentioning

confidence: 99%

Erectile Dysfunction and Cardiovascular Disease

Menezes¹,

Artham²,

Lavie³

et al. 2011

Postgraduate Medicine

View full text Add to dashboard Cite

Cardiovascular disease (CVD) and erectile dysfunction (ED) are 2 closely intertwined disease processes. Over the past 2 decades, there have been many studies that have linked both conditions and established ED as a risk factor for CVD. In the United States and worldwide, a large population of adult men has ED and/or CVD. Worldwide, approximately 140 million men have ED, and the number is expected to double in the next 15 years. Because ED and CVD share many of the same risk factors, the relationship between CVD and ED is a very valid concern. Our goal is to examine the association and pathophysiological relationship between ED and CVD. We will also review common risk factors, current treatments, and management of the 2 conditions. Finally, we will discuss the risks of sexual activity in patients who have CVD.

show abstract

“…However, there are more mouse models of hyperlipidemia and atherosclerosis than in rats, including ApoEknockout mice, LDL receptor-knockout mice 89 and the db/db mouse that is prone to develop hypertriglyceridemia. 89 These mice, especially ApoE-knockout mice, develop more widely distributed centralized atherosclerosis than in rats, but still not approaching that seen in primates. Mice, while more cost effective than rats, are limited by being even smaller than rats and harder to instrument.…”

Section: Animal Modelsmentioning

confidence: 99%

Animal models of erectile dysfunction (ED): potential utility of non-human primates as a model of atherosclerosis-induced vascular ED

Christ

2011

Int J Impot Res

View full text Add to dashboard Cite

Erectile dysfunction (ED) is a prevalent medical condition affecting 18 million men and their sexual partners in the United States alone. In the majority of patients, ED is related to alterations in the flow of blood to or from the penis. Undeniably, significant progress has been made in understanding the multifactorial mechanisms that modulate erectile capacity and predispose one to ED, and this, in turn, has led to the availability of more effective treatment options. Nonetheless, all current therapies have untoward side effects, and moreover, there are still no satisfactory treatments for many patients with ED. Further enhancements in the treatment of ED would logically result from both early intervention and more detailed mechanistic insight into the characteristics of the disease process per se. This fact underscores the importance of improved understanding of the initiation, development and progression of ED. However, to do so requires longitudinal studies on animal models that more closely approximate the corresponding clinical features and time course of human disease. The goal of this report is twofold. First, to provide a brief general overview of the applicability of commonly used animal models for the study of ED. The second and primary goal is to highlight the scientific rationale for using non-human primates to evaluate the impact of atherosclerosis-induced vascular disease on the penile and systemic circulatory systems. This latter goal seems especially relevant in light of the recent literature documenting a link between ED and systemic vascular disease, a finding that has major implications in an aging US male population consuming a high fat diet. Keywords: animal models; atherosclerosis; non-human primates; vascular disease INTRODUCTION Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.1 --4 ED often has profound effects on intimate relationships, quality of life and overall self-esteem, causing serious distress and prompting men to seek medical attention. The economic impact of ED is multifaceted, with direct costs that include physician evaluation, pharmacotherapy and diagnostic testing, and indirect costs that include lost time at work, lost productivity and effects on the man's partner, family and coworkers. The Massachusetts Male Aging Study indicates that the prevalence of ED increases sharply with age. ED of some degree of severity is observed in 39% of men aged 40 years and in 67% of men aged 70 years.

show abstract

Hypercholesterolemia-Induced Erectile Dysfunction: Endothelial Nitric Oxide Synthase (eNOS) Uncoupling in the Mouse Penis by NAD(P)H Oxidase

Abstract: INTRODUCTION-Hypercholesterolemia induces erectile dysfunction (ED) mostly by increasing oxidative stress and impairing endothelial function in the penis, but the mechanisms regulating reactive oxygen species (ROS) production in the penis are not understood.

Cited by 95 publications

References 59 publications

Toll-Like Receptor 4 Mutation Protects Obese Mice Against Endothelial Dysfunction by Decreasing NADPH Oxidase Isoforms 1 and 4

Toll-Like Receptor 4 Mutation Protects Obese Mice Against Endothelial Dysfunction by Decreasing NADPH Oxidase Isoforms 1 and 4

Erectile Dysfunction and Cardiovascular Disease

Animal models of erectile dysfunction (ED): potential utility of non-human primates as a model of atherosclerosis-induced vascular ED

Contact Info

Product

Resources

About