NADPH Oxidase as a Mechanistic Link Between Erectile Dysfunction, Peripheral, and Coronary Endothelial Dysfunction in Obesity

Cardiovascular complications involving both microvascular and macrovascular tissues are the major cause of morbidity and mortality in obese patients. Clinical and epidemiological studies suggest that erectile dysfunction and peripheral endothelial dysfunction may predict cardiovascular risk. The purpose of these studies was to investigate NADPH oxidase, a major source of vascular derived oxidative stress, as a common mechanism between erectile dysfunction and coronary artery endothelial dysfunction in rats fed a Western diet (WD), and peripheral endothelial dysfunction in an obese group of human subjects. Male Sprague-Dawley rats were fed a control diet (CD) or WD for 4, 8, or 12 weeks. Erectile function was evaluated by measuring intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of (ACh) applied to pre-constricted segments of the left anterior descending coronary artery. Erectile function was significantly attenuated following 8-weeks (P < 0.05) and 12-weeks (P < 0.05) of the WD, whereas CAEF was significantly attenuated following 12-weeks of the WD (P < 0.01). Larger groups of rats were then fed the CD or WD for 12 weeks, and erectile function and CAEF were evaluated following intracavernosal injection or vessel incubation with apocynin, an NADPH oxidase inhibitor. Apocynin improved erectile function (P < 0.01) and CAEF (P < 0.05) in WD, and had no effect on CD rats. Sedentary, young adults were recruited across a body mass index (BMI) range of 18-40, and split into BMI tertiles. Microdialysis probes were inserted into the vastus lateralis, and in vivo reactive oxygen species (ROS) production was measured, and microvascular endothelial function was assessed via local ACh-stimulated blood flow. ROS production (P < 0.05) was elevated and ACh-stimulated blood flow (P < 0.05) was attenuated in the highest BMI tertile compared to both other tertiles. Apocynin had a greater effect of attenuating ROS production (P < 0.05) and augmenting ACh-stimulated blood flow (P < 0.05) in the highest compared to lowest BMI tertile. These studies suggest that NADPH oxidase contributes to obesity associated erectile dysfunction, peripheral endothelial dysfunction, and coronary artery disease development.Ph.D

Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase Influence of Exercise Training

Objective—The objectives of this study were to determine the impact of in vivo reactive oxygen species (ROS) on microvascular endothelial function in obese human subjects and the efficacy of an aerobic exercise intervention on alleviating obesity-associated dysfunctionality. Approach and Results—Young, sedentary men and women were divided into lean (body mass index 18–25; n=14), intermediate (body mass index 28–32.5; n=13), and obese (body mass index 33–40; n=15) groups. A novel microdialysis technique was utilized to detect elevated interstitial hydrogen peroxide (H2 O2 ) and superoxide levels in the vastus lateralis of obese compared with both lean and intermediate subjects. Nutritive blood flow was monitored in the vastus lateralis via the microdialysis-ethanol technique. A decrement in acetylcholine-stimulated blood flow revealed impaired microvascular endothelial function in the obese subjects. Perfusion of apocynin, an NADPH oxidase inhibitor, lowered (normalized) H2 O2 and superoxide levels, and reversed microvascular endothelial dysfunction in obese subjects. After 8 weeks of exercise, H2 O2 levels were decreased in the obese subjects and microvascular endothelial function in these subjects was restored to levels similar to lean subjects. Skeletal muscle protein expression of the NADPH oxidase subunits p22phox, p47phox, and p67phox was increased in obese relative to lean subjects, where p22phox and p67phox expression was attenuated by exercise training in obese subjects. Conclusions—This study implicates NADPH oxidase as a source of excessive ROS production in skeletal muscle of obese individuals and links excessive NADPH oxidase–derived ROS to microvascular endothelial dysfunction in obesity. Furthermore, aerobic exercise training proved to be an effective strategy for alleviating these malad

Novel role for thioredoxin reductase-2 in mitochondrial redox adaptations to obesogenic diet and exercise in heart and skeletal muscle

Increased fatty acid availability and oxidative stress are physiological consequences of exercise (Ex) and a high-fat, high-sugar (HFHS) diet. Despite these similarities, the global effects of Ex are beneficial, whereas HFHS diets are largely deleterious to the cardiovascular system. The reasons for this disparity are multifactorial and incompletely understood. We hypothesized that differences in redox adaptations following HFHS diet in comparison to exercise may underlie this disparity, particularly in mitochondria. Our objective in this study was to determine mechanisms by which heart and skeletal muscle (red gastrocnemius, RG) mitochondria experience differential redox adaptations to 12 weeks of HFHS diet and/or exercise training (Ex) in rats. Surprisingly, both HFHS feeding and Ex led to contrasting effects in heart and RG, in that mitochondrial H2O2 decreased in heart but increased in RG following both HFHS diet and Ex, in comparison to sedentary animals fed a control diet. These differences were determined to be due largely to increased antioxidant/anti-inflammatory enzymes in the heart following the HFHS diet, which did not occur in RG. Specifically, upregulation of mitochondrial thioredoxin reductase-2 occurred with both HFHS and Ex in the heart, but only with Ex in RG, and systematic evaluation of this enzyme revealed that it is critical for suppressing mitochondrial H2O2 during fatty acid oxidation. These findings are novel and important in that they illustrate the unique ability of the heart to adapt to oxidative stress imposed by HFHS diet, in part through upregulation of thioredoxin reductase-2. Furthermore, upregulation of thioredoxin reductase-2 plays a critical role in preserving the mitochondrial redox status in the heart and skeletal muscle with exercise.Funding from the National Institutes of Health, United State

NADPH Oxidase as a Mechanistic Link Between Erectile Dysfunction Peripheral and Coronary Endothelial Dysfunction in Obesity

Cardiovascular complications involving both microvascular and macrovascular tissues are the major cause of morbidity and mortality in obese patients. Clinical and epidemiological studies suggest that erectile dysfunction and peripheral endothelial dysfunction may predict cardiovascular risk. The purpose of these studies was to investigate NADPH oxidase a major source of vascular derived oxidative stress as a common mechanism between erectile dysfunction and coronary artery endothelial dysfunction in rats fed a Western diet (WD) and peripheral endothelial dysfunction in an obese group of human subjects. Male Sprague-Dawley rats were fed a control diet (CD) or WD for 4 8 or 12 weeks. Erectile function was evaluated by measuring intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of (ACh) applied to pre-constricted segments of the left anterior descending coronary artery. Erectile function was significantly attenuated following 8-weeks (P &lt; 0.05) and 12-weeks (P &lt; 0.05) of the WD whereas CAEF was significantly attenuated following 12-weeks of the WD (P &lt; 0.01). Larger groups of rats were then fed the CD or WD for 12 weeks and erectile function and CAEF were evaluated following intracavernosal injection or vessel incubation with apocynin an NADPH oxidase inhibitor. Apocynin improved erectile function (P &lt; 0.01) and CAEF (P &lt; 0.05) in WD and had no effect on CD rats. Sedentary young adults were recruited across a body mass index (BMI) range of 18-40 and split into BMI tertiles. Microdialysis probes were inserted into the vastus lateralis and in vivo reactive oxygen species (ROS) production was measured and microvascular endothelial function was assessed via local ACh-stimulated blood flow. ROS production (P &lt; 0.05) was elevated and ACh-stimulated blood flow (P &lt; 0.05) was attenuated in the highest BMI tertile compared to both other tertiles. Apocynin had a greater effect of attenuating ROS production (P &lt; 0.05) and augmenting ACh-stimulated blood flow (P &lt; 0.05) in the highest compared to lowest BMI tertile. These studies suggest that NADPH oxidase contributes to obesity associated erectile dysfunction peripheral endothelial dysfunction and coronary artery disease development

NADPH Oxidase as a Mechanistic Link Between Erectile Dysfunction, Peripheral, and Coronary Endothelial Dysfunction in Obesity

Cardiovascular complications involving both microvascular and macrovascular tissues are the major cause of morbidity and mortality in obese patients. Clinical and epidemiological studies suggest that erectile dysfunction and peripheral endothelial dysfunction may predict cardiovascular risk. The purpose of these studies was to investigate NADPH oxidase, a major source of vascular derived oxidative stress, as a common mechanism between erectile dysfunction and coronary artery endothelial dysfunction in rats fed a Western diet (WD), and peripheral endothelial dysfunction in an obese group of human subjects. Male Sprague-Dawley rats were fed a control diet (CD) or WD for 4, 8, or 12 weeks. Erectile function was evaluated by measuring intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of (ACh) applied to pre-constricted segments of the left anterior descending coronary artery. Erectile function was significantly attenuated following 8-weeks (P &lt; 0.05) and 12-weeks (P &lt; 0.05) of the WD, whereas CAEF was significantly attenuated following 12-weeks of the WD (P &lt; 0.01). Larger groups of rats were then fed the CD or WD for 12 weeks, and erectile function and CAEF were evaluated following intracavernosal injection or vessel incubation with apocynin, an NADPH oxidase inhibitor. Apocynin improved erectile function (P &lt; 0.01) and CAEF (P &lt; 0.05) in WD, and had no effect on CD rats. Sedentary, young adults were recruited across a body mass index (BMI) range of 18-40, and split into BMI tertiles. Microdialysis probes were inserted into the vastus lateralis, and in vivo reactive oxygen species (ROS) production was measured, and microvascular endothelial function was assessed via local ACh-stimulated blood flow. ROS production (P &lt; 0.05) was elevated and ACh-stimulated blood flow (P &lt; 0.05) was attenuated in the highest BMI tertile compared to both other tertiles. Apocynin had a greater effect of attenuating ROS production (P &lt; 0.05) and augmenting ACh-stimulated blood flow (P &lt; 0.05) in the highest compared to lowest BMI tertile. These studies suggest that NADPH oxidase contributes to obesity associated erectile dysfunction, peripheral endothelial dysfunction, and coronary artery disease development

Rapamycin Suppresses Penile NADPH Oxidase Activity to Preserve Erectile Function in Mice Fed a Western Diet

The mechanistic target of rapamycin (mTOR) is a nutrient-sensitive cellular signaling kinase that has been implicated in the excess production of reactive oxygen species (ROS). NADPH oxidase-derived ROS have been implicated in erectile dysfunction pathogenesis. The objective of this study was to determine if mTOR is an activator of NADPH oxidase in the penis and to determine the functional relevance of this pathway in a translationally relevant model of diet-induced erectile dysfunction. Male mice were fed a control diet or a high-fat, high-sucrose Western style diet (WD) for 12 weeks and treated with vehicle or rapamycin for the final 4 weeks of the dietary intervention. Following the intervention, erectile function was assessed by cavernous nerve-stimulated intracavernous pressure measurement, in vivo ROS production was measured in the penis using a microdialysis approach, and relative protein contents from the corpus cavernosum were determined by Western blot. Erectile function was impaired in vehicle treated WD-mice and was preserved in rapamycin treated WD-mice. Penile NADPH oxidase-mediated ROS were elevated in WD-mice and suppressed by rapamycin treatment. Western blot analysis suggests mTOR activation with WD by increased active site phosphorylation of mTOR and p70S6K, and increased expression of NADPH oxidase subunits, all of which were suppressed by rapamycin. These data suggest that mTOR is an upstream mediator of NADPH oxidase in the corpus cavernosum in response to a chronic Western diet, which has an adverse effect on erectile function

Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase Influence of Exercise Training

Objective-”The objectives of this study were to determine the impact of in vivo reactive oxygen species (ROS) onmicrovascular endothelial function in obese human subjects and the efficacy of an aerobic exercise intervention onalleviating obesity-associated dysfunctionality.Approach and Results-”Young, sedentary men and women were divided into lean (body mass index 18--25; n=14),intermediate (body mass index 28--32.5; n=13), and obese (body mass index 33--40; n=15) groups. A novel microdialysistechnique was utilized to detect elevated interstitial hydrogen peroxide (H2O2) and superoxide levels in the vastus lateralisof obese compared with both lean and intermediate subjects. Nutritive blood flow was monitored in the vastus lateralis viathe microdialysis-ethanol technique. A decrement in acetylcholine-stimulated blood flow revealed impaired microvascularendothelial function in the obese subjects. Perfusion of apocynin, an NADPH oxidase inhibitor, lowered (normalized)H2O2 and superoxide levels, and reversed microvascular endothelial dysfunction in obese subjects. After 8 weeks ofexercise, H2O2 levels were decreased in the obese subjects and microvascular endothelial function in these subjects wasrestored to levels similar to lean subjects. Skeletal muscle protein expression of the NADPH oxidase subunits p22phox,p47phox, and p67phox was increased in obese relative to lean subjects, where p22phox and p67phox expression was attenuatedby exercise training in obese subjects.Conclusions-”This study implicates NADPH oxidase as a source of excessive ROS production in skeletal muscleof obese individuals and links excessive NADPH oxidase--derived ROS to microvascular endothelial dysfunction inobesity. Furthermore, aerobic exercise training proved to be an effective strategy for alleviating these malad