Exercise during pregnancy mitigates the adverse effects of maternal obesity on adult male offspring vascular function and alters one-carbon metabolism.

Maternal obesity during pregnancy can adversely affect adult offspring vascular endothelial function. This study examined whether maternal exercise during pregnancy and lactation mitigates the adverse effects of maternal obesity on offspring vascular endothelial function. Female (C57BL/6N) mice were fed from weaning a control diet (10% kcal fat) or western diet (45% kcal fat) to induce excess adiposity (maternal obesity). After 13 weeks, the female mice were bred and maintained on the diets, with and without access to a running wheel (exercise), throughout breeding, pregnancy, and lactation. Offspring were weaned onto the control or western diet and fed for 13 weeks; male offspring were studied. Maternal exercise prevented the adverse effects of maternal obesity on offspring vascular endothelial function. However, this was dependent on offspring diet and the positive effect of maternal exercise was only observed in offspring fed the western diet. This was accompanied by alterations in aorta and liver one-carbon metabolism, suggesting a role for these pathways in the improved endothelial function observed in the offspring. Obesity and exercise had no effect on endothelial function in the dams but did affect aorta and liver one-carbon metabolism, suggesting the phenotype observed in the offspring may be due to obesity and exercise-induced changes in one-carbon metabolism in the dams. Our findings demonstrate that maternal exercise prevented vascular dysfunction in male offspring from obese dams and is associated with alterations in one-carbon metabolism.

Smoking and Endothelial Dysfunction.

Cigarette smoking is one of the most important health concerns worldwide. Even though the rate of smoking is declining in developed countries, it is still experiencing growth in developing regions. Many studies have examined the relationship between smoking, as an established risk factor, and cardiovascular diseases. We provide an updated review of the underlying mechanisms of smokinginduced cardiovascular diseases, with a focus on the relationship between smoking and oxidative stress, particularly from the perspective of endothelial cell dysfunction. We review smoking-induced oxidative stress as a trigger for a generalized vascular inflammation associated with cytokine release, adhesion of inflammatory cells and, ultimately, disruption of endothelial integrity as a protective barrier layer. We also briefly discuss the harms related to the vaping of electronic cigarettes, which many erroneously consider as a safe alternative to smoking. We conclude that even though e-cigarette could be a helpful device during the transition period of cigarette quitting, it is by no means a safe substitute.

Alpha Lipoic Acid Improves Endothelial Function and Oxidative Stress in Mice Exposed to Chronic Intermittent Hypoxia.

OBJECTIVE: Obstructive sleep apnea (OSA) is characterized by recurrent airway collapse that causes chronic intermittent hypoxia (CIH). OSA is associated with systemic inflammation and oxidative stress resulting in endothelial dysfunction and cardiovascular disease (CVD). Alpha lipoic acid (ALA) is a potent antioxidant with anti-inflammatory properties. We hypothesized that dietary ALA can improve endothelial function of mice exposed to CIH. METHODS: Mice were exposed to either CIH or intermittent air (IA) and treated with dietary ALA (0.2% w/w) or a regular chow diet for 8 weeks. Endothelial function, endothelial nitric oxide (eNOS) uncoupling, systemic oxidative stress, systemic inflammation, aortic expression of inflammatory cytokines, and antioxidant enzymes were measured after 8 weeks. RESULTS: Mice exposed to CIH exhibited endothelial dysfunction accompanied by systemic oxidative stress and inflammation as well as increased aortic expression of inflammatory cytokines. Furthermore, CIH led to eNOS uncoupling. Treatment with dietary ALA reversed endothelial dysfunction in mice exposed to CIH, lowered systemic oxidative stress and inflammation, prevented the increases of inflammatory cytokine gene expression, increased the expression of antioxidant enzymes, and preserved eNOS in a coupled state. CONCLUSION: ALA attenuates endothelial dysfunction by preventing oxidative stress and inflammation and restoring nitric oxide bioavailability in mice exposed to CIH. Our data suggests the potential beneficial use of ALA as adjunctive therapy in OSA.

Oxidative Stress: A Unifying Mechanism for Cell Damage Induced by Noise, (Water-Pipe) Smoking, and Emotional Stress-Therapeutic Strategies Targeting Redox Imbalance.

SIGNIFICANCE: Modern technologies have eased our lives but these conveniences can impact our lifestyles in destructive ways. Noise pollution, mental stresses, and smoking (as a stress-relieving solution) are some environmental hazards that affect our well-being and healthcare budgets. Scrutinizing their pathophysiology could lead to solutions to reduce their harmful effects. Recent Advances: Oxidative stress plays an important role in initiating local and systemic inflammation after noise pollution, mental stress, and smoking. Lipid peroxidation and release of lysolipid by-products, disturbance in activation and function of nuclear factor erythroid 2-related factor 2 (Nrf2), induction of stress hormones and their secondary effects on intracellular kinases, and dysregulation of intracellular Ca2+ can all potentially trigger other vicious cycles. Recent clinical data suggest that boosting the antioxidant system through nonpharmacological measures, for example, lifestyle changes that include exercise have benefits that cannot easily be achieved with pharmacological interventions alone. CRITICAL ISSUES: Indiscriminate manipulation of the cellular redox network could lead to a new series of ailments. An ideal approach requires meticulous scrutiny of redox balance mechanisms for individual pathologies so as to create new treatment strategies that target key pathways while minimizing side effects. FUTURE DIRECTIONS: Extrapolating our understanding of redox balance to other debilitating conditions such as diabetes and the metabolic syndrome could potentially lead to devising a unifying therapeutic strategy. Antioxid. Redox Signal. 28, 741-759.

Health Benefits of Fasting and Caloric Restriction.

PURPOSE OF REVIEW: Obesity and obesity-related diseases, largely resulting from urbanization and behavioral changes, are now of global importance. Energy restriction, though, is associated with health improvements and increased longevity. We review some important mechanisms related to calorie limitation aimed at controlling of metabolic diseases, particularly diabetes. RECENT FINDINGS: Calorie restriction triggers a complex series of intricate events, including activation of cellular stress response elements, improved autophagy, modification of apoptosis, and alteration in hormonal balance. Intermittent fasting is not only more acceptable to patients, but it also prevents some of the adverse effects of chronic calorie restriction, especially malnutrition. There are many somatic and potentially psychologic benefits of fasting or intermittent calorie restriction. However, some behavioral modifications related to abstinence of binge eating following a fasting period are crucial in maintaining the desired favorable outcomes.

Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia.

Objective. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is often present in diabetic (DB) patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7m +/+ Leprdb /J) (db/db) mice (10 weeks old) and their heterozygote littermates were subjected to CIH or intermittent air (IA) for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic), IH (intermittent hypoxia nondiabetic), IADB (intermittent air diabetic), and IHDB (intermittent hypoxia diabetic) groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO) were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6), and asymmetric dimethylarginine (ADMA) were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE) staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

Nitric Oxide Bioavailability in Obstructive Sleep Apnea: Interplay of Asymmetric Dimethylarginine and Free Radicals.

Obstructive sleep apnea (OSA) occurs in 2% of middle-aged women and 4% of middle-aged men and is considered an independent risk factor for cerebrovascular and cardiovascular diseases. Nitric oxide (NO) is an important endothelium derived vasodilating substance that plays a critical role in maintaining vascular homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in the human circulation. Elevated levels of ADMA inhibit NO synthesis while oxidative stress decreases its bioavailability, so impairing endothelial function and promoting atherosclerosis. Several clinical trials report increased oxidative stress and ADMA levels in patients with OSA. This review discusses the role of oxidative stress and increased ADMA levels in cardiovascular disease resulting from OSA.

Chronic stress impacts the cardiovascular system: animal models and clinical outcomes.

Psychological stresses are associated with cardiovascular diseases to the extent that cardiovascular diseases are among the most important group of psychosomatic diseases. The longstanding association between stress and cardiovascular disease exists despite a large ambiguity about the underlying mechanisms. An array of possibilities have been proposed including overactivity of the autonomic nervous system and humoral changes, which then converge on endothelial dysfunction that initiates unwanted cardiovascular consequences. We review some of the features of the two most important stress-activated systems, i.e., the humoral and nervous systems, and focus on alterations in endothelial function that could ensue as a result of these changes. Cardiac and hematologic consequences of stress are also addressed briefly. It is likely that activation of the inflammatory cascade in association with oxidative imbalance represents key pathophysiological components of stress-induced cardiovascular changes. We also review some of the commonly used animal models of stress and discuss the cardiovascular outcomes reported in these models of stress. The unique ability of animals for adaptation under stressful conditions lessens the extrapolation of laboratory findings to conditions of human stress. An animal model of unpredictable chronic stress, which applies various stress modules in a random fashion, might be a useful solution to this predicament. The use of stress markers as indicators of stress intensity is also discussed in various models of animal stress and in clinical studies.

Chronic intermittent hypoxia causes endothelial dysfunction in a mouse model of diet-induced obesity.

BACKGROUND: Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). OSA is prevalent in obese subjects and is associated with endothelial dysfunction and cardiovascular disorders. We tested the hypothesis that the deleterious effects of IH could be further modulated by diet-induced obesity. DESIGN: Thirty adult (8-10 weeks) male C57BL/6J mice were divided into four groups. Mice were subjected to CIH or intermittent air (IA) for 12h a day and fed either a high fat (HF) or a low fat control diet (CD) for 6weeks. We analyzed endothelial function using a wire myograph, and measured markers of oxidative stress (plasma malondialdehyde (MDA) and total antioxidant capacity (TAC)) using colorimetrical assays. We also measured C-reactive protein (CRP) using ELISA and endothelial nitric oxide (eNOS) gene expression using real time PCR. RESULTS: Stimulated endothelial dependent dilation was significantly impaired only in the group fed high fat diet and subjected to CIH (Emax: HFIH 78±2%, p<0.0001) when compared to the other groups (Emax: HFIA 95±0.7%, CDIH 94±2%, CDIA 97±1%). Also basal endothelial dependant dilation was attenuated in the HFIH group compared to the HFIA group (Emax: HFIH: 179±10% vs. HFIA: 149±11% in the presence of L-NAME). Levels of MDA were elevated in the CDIH group when compared to CDIA (0.68±0.04 vs. 0.41±0.03 µM, p<0.05) but were greatest in the HFIH group (0.83±0.08 µM, p<0.05). However, there was no significant increase in MDA levels in the HFIA group (0.45±0.03 µM, p=NS) when compared to all other groups. Similar effects were observed with CRP levels; CRP levels were significantly higher in the CDIH group compared with intermittent air (10.39±0.38 vs. 8.70±0.21 µg/ml, p<0.05) but the HFIH had the greatest levels of CRP (11.87±0.31 µg/ml, p<0.05). In the HFIA group, CRP levels were not elevated (9.96±0.37 µg/ml, p=NS). Nevertheless, total antioxidant capacity and eNOS gene expression were not significantly different in the groups. CONCLUSION: CIH caused endothelial dysfunction in mice fed an obesogenic diet. Inflammation and oxidative stress were increased in CIH and an obesogenic diet exacerbated these effects.

Exercise induced adipokine changes and the metabolic syndrome.

The lack of adequate physical activity and obesity created a worldwide pandemic. Obesity is characterized by the deposition of adipose tissue in various parts of the body; it is now evident that adipose tissue also acts as an endocrine organ capable of secreting many cytokines that are though to be involved in the pathophysiology of obesity, insulin resistance, and metabolic syndrome. Adipokines, or adipose tissue-derived proteins, play a pivotal role in this scenario. Increased secretion of proinflammatory adipokines leads to a chronic inflammatory state that is accompanied by insulin resistance and glucose intolerance. Lifestyle change in terms of increased physical activity and exercise is the best nonpharmacological treatment for obesity since these can reduce insulin resistance, counteract the inflammatory state, and improve the lipid profile. There is growing evidence that exercise exerts its beneficial effects partly through alterations in the adipokine profile; that is, exercise increases secretion of anti-inflammatory adipokines and reduces proinflammatory cytokines. In this paper we briefly describe the pathophysiologic role of four important adipokines (adiponectin, leptin, TNF-α, and IL-6) in the metabolic syndrome and review some of the clinical trials that monitored these adipokines as a clinical outcome before and after exercise.

Exercise and the aging endothelium.

The endothelium plays a critical role in the maintenance of cardiovascular health by producing nitric oxide and other vasoactive materials. Aging is associated with a gradual decline in this functional aspect of endothelial regulation of cardiovascular homeostasis. Indeed, age is an independent risk factor for cardiovascular diseases and is in part an important factor in the increased exponential mortality rates from vascular disease such as myocardial infarction and stroke that occurs in the ageing population. There are a number of mechanisms suggested to explain age-related endothelial dysfunction. However, recent scientific studies have advanced the notion of oxidative stress and inflammation as the two major risk factors underlying aging and age-related diseases. Regular physical activity, known to have a favorable effect on cardiovascular health, can also improve the function of the ageing endothelium by modulating oxidative stress and inflammatory processes, as we discuss in this paper.

Potential mechanisms of exercise in gestational diabetes.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during pregnancy. This condition shares same array of underlying abnormalities as occurs in diabetes outside of pregnancy, for example, genetic and environmental causes. However, the role of a sedentary lifestyle and/or excess energy intake is more prominent in GDM. Physically active women are less likely to develop GDM and other pregnancy-related diseases. Weight gain in pregnancy causes increased release of adipokines from adipose tissue; many adipokines increase oxidative stress and insulin resistance. Increased intramyocellular lipids also increase cellular oxidative stress with subsequent generation of reactive oxygen species. A well-planned program of exercise is an important component of a healthy lifestyle and, in spite of old myths, is also recommended during pregnancy. This paper briefly reviews the role of adipokines in gestational diabetes and attempts to shed some light on the mechanisms by which exercise can be beneficial as an adjuvant therapy in GDM. In this regard, we discuss the mechanisms by which exercise increases insulin sensitivity, changes adipokine profile levels, and boosts antioxidant mechanisms.

Notch-dependent regulation of the ischemic vasodilatory response--brief report.

OBJECTIVE: We have recently described that Notch activates nitric oxide (NO) signaling in the embryonic endocardium. Both Notch signaling and NO signaling have been shown to be important during adult arteriogenesis. Notch has been shown to be required for remodeling of the collateral vessels, whereas NO is required for the initial vasodilatory response to ischemia. Whether Notch also has an impact on the vasodilatory phase of arteriogenesis after ischemia is not known. We tested the hypothesis that endothelial cell-Notch function is required for NO induction and vasodilation, in response to ischemia in the adult vasculature. METHODS AND RESULTS: We observed a significant decrease in NO levels in the dorsal aorta using a mouse model where Notch was inhibited in endothelial cell in a Tet-inducible fashion. In a femoral artery ligation model, inhibition of endothelial cell-Notch reduced reperfusion and NO generation, as quantified by laser Doppler perfusion imaging and by phosphoendothelial NO synthase, nitrotyrosine, and phosphovasodilator-stimulated phosphoprotein staining, respectively. CONCLUSIONS: Endothelial Notch activation is required for NO production and reactive vasodilation in a femoral artery ligation model.

Exercise in the metabolic syndrome.

The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension that is occurring in increasing frequency across the global population. Although there is some controversy about its diagnostic criteria, oxidative stress, which is defined as imbalance between the production and inactivation of reactive oxygen species, has a major pathophysiological role in all the components of this disease. Oxidative stress and consequent inflammation induce insulin resistance, which likely links the various components of this disease. We briefly review the role of oxidative stress as a major component of the metabolic syndrome and then discuss the impact of exercise on these pathophysiological pathways. Included in this paper is the effect of exercise in reducing fat-induced inflammation, blood pressure, and improving muscular metabolism.

Exercise and the cardiovascular system.

There are alarming increases in the incidence of obesity, insulin resistance, type II diabetes, and cardiovascular disease. The risk of these diseases is significantly reduced by appropriate lifestyle modifications such as increased physical activity. However, the exact mechanisms by which exercise influences the development and progression of cardiovascular disease are unclear. In this paper we review some important exercise-induced changes in cardiac, vascular, and blood tissues and discuss recent clinical trials related to the benefits of exercise. We also discuss the roles of boosting antioxidant levels, consequences of epicardial fat reduction, increases in expression of heat shock proteins and endoplasmic reticulum stress proteins, mitochondrial adaptation, and the role of sarcolemmal and mitochondrial potassium channels in the contributing to the cardioprotection offered by exercise. In terms of vascular benefits, the main effects discussed are changes in exercise-induced vascular remodeling and endothelial function. Exercise-induced fibrinolytic and rheological changes also underlie the hematological benefits of exercise.

Antioxidant and anti-inflammatory effects of exercise in diabetic patients.

Diabetes is a chronic metabolic disease which is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action. The key roles of oxidative stress and inflammation in the progression of vascular complications of this disease are well recognized. Accumulating epidemiologic evidence confirms that physical inactivity is an independent risk factor for insulin resistance and type II diabetes. This paper briefly reviews the pathophysiological pathways associated with oxidative stress and inflammation in diabetes mellitus and then discusses the impact of exercise on these systems. In this regard, we discuss exercise induced activation of cellular antioxidant systems through "nuclear factor erythroid 2-related factor." We also discuss anti-inflammatory myokines, which are produced and released by contracting muscle fibers. Antiapoptotic, anti-inflammatory and chaperon effects of exercise-induced heat shock proteins are also reviewed.

Cardiovascular consequences of sleep apnea.

Sleep apnea is a common health concern that is characterized by repetitive episodes of asphyxia. This condition has been linked to serious long-term adverse effects such as hypertension, metabolic dysregulation, and cardiovascular disease. Although the mechanism for the initiation and aggravation of cardiovascular disease has not been fully elucidated, oxidative stress and subsequent endothelial dysfunction play major roles. Animal models, which have the advantage of being free of comorbidities and/or behavioral variables (that commonly occur in humans), allow invasive measurements under well-controlled experimental conditions, and as such are useful tools in the study of the pathophysiological mechanisms of sleep apnea. This review summarizes currently available information on the cardiovascular consequences of sleep apnea and briefly describes common experimental approaches useful to sleep apnea in different animal models.

Diabetes and alpha lipoic Acid.

Diabetes mellitus is a multi-faceted metabolic disorder where there is increased oxidative stress that contributes to the pathogenesis of this debilitating disease. This has prompted several investigations into the use of antioxidants as a complementary therapeutic approach. Alpha lipoic acid, a naturally occurring dithiol compound which plays an essential role in mitochondrial bioenergetic reactions, has gained considerable attention as an antioxidant for use in managing diabetic complications. Lipoic acid quenches reactive oxygen species, chelates metal ions, and reduces the oxidized forms of other antioxidants such as vitamin C, vitamin E, and glutathione. It also boosts antioxidant defense system through Nrf-2-mediated antioxidant gene expression and by modulation of peroxisome proliferator activated receptors-regulated genes. ALA inhibits nuclear factor kappa B and activates AMPK in skeletal muscles, which in turn have a plethora of metabolic consequences. These diverse actions suggest that lipoic acid acts by multiple mechanisms, many of which have only been uncovered recently. In this review we briefly summarize the known biochemical properties of lipoic acid and then discussed the oxidative mechanisms implicated in diabetic complications and the mechanisms by which lipoic acid may ameliorate these reactions. The findings of some of the clinical trials in which lipoic acid administration has been tested in diabetic patients during the last 10 years are summarized. It appears that the clearest benefit of lipoic acid supplementation is in patients with diabetic neuropathy.

Weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice.

The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress play in the progression of diabetes vascular complications are well recognized; however, the relative contribution and importance of these individual factors remain uncertain. At 6, 10, or 14 weeks old, blood samples and thoracic aortae were collected from db/db mice and their non-diabetic controls. Plasma samples were analyzed for glucose, 8-isoprostane, CRP, triglycerides, LDL, and HDL as markers of glycemic status, oxidative stress, inflammation, and dyslipidemia, respectively. The responses of the aortic rings to high KCl, phenylephrine (PE), acetylcholine (ACh), and sodium nitroprusside were examined. Statistical methods were used to estimate the strength of the association between plasma variables and vascular functions. Systemic inflammation occurred in db/db mice at an earlier age than did hyperglycemia or oxidative stress. Aortae of db/db showed augmented contractions to PE which were positively correlated with weight, plasma glucose, 8-isoprostane, and CRP. Also, db/db mice showed impaired endothelium-dependent ACh vasorelaxation which was negatively correlated with weight, plasma glucose, and 8-isoprostane. Multivariate analysis and stepwise modeling show that CRP is the major determinant of the contractile responses, while weight and HDL are the major determinants of ACh-induced relaxation. Among the traditional risk factors of obesity, hyperglycemia, oxidative stress, inflammation, and dyslipidemia, our study reveals that weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice. Our findings partially resolve the complexity of diabetes vasculopathies and suggest targeting weight loss and inflammation for effective therapeutic approaches.

Molecular mechanisms in exercise-induced cardioprotection.

Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. However, most investigations focus on sarcolemmal KATP channels, NO production, and mitochondrial changes although it is very likely that other mechanisms may also exist. This paper discusses current information about these aforementioned topics and does not consider potentially important adaptations within blood or the autonomic nervous system. A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.