Background-Arginase competes with endothelial nitric oxide synthase (eNOS) for the substrate L-arginine and decreases NO production. This study investigated regulatory mechanisms of arginase activity in endothelial cells and its role in atherosclerosis. Methods and Results-In human endothelial cells isolated from umbilical veins, thrombin concentration-and timedependently stimulated arginase enzymatic activity, reaching a 1.9-fold increase (PϽ0.001) at 1 U/mL for 24 hours. The effect of thrombin was prevented by C3 exoenzyme or the HMG-CoA reductase inhibitor fluvastatin, which inhibit RhoA, or by the ROCK inhibitors Y-27632 and HA-1077. Adenoviral expression of constitutively active RhoA or ROCK mutants enhanced arginase activity (Ϸ3-fold, PϽ0.001), and the effect of active RhoA mutant was inhibited by the ROCK inhibitors. Neither thrombin nor the active RhoA/ROCK mutants affected arginase II protein level, the only isozyme detectable in the cells. Moreover, a significantly higher arginase II activity (1.5-fold, not the protein level) and RhoA protein level (4-fold) were observed in atherosclerotic aortas of apoE Ϫ/Ϫ compared with wild-type mice. Interestingly, L-arginine (1 mmol/L), despite a significantly higher eNOS expression in aortas of apoE Ϫ/Ϫ mice, evoked a more pronounced contraction, which was reverted to a greater vasodilation by the arginase inhibitor L-norvaline (20 mmol/L) compared with the wild-type animals (nϭ5, PϽ0.001). Conclusions-Thrombin
BackgroundMacrophage‐mediated chronic inflammation is mechanistically linked to insulin resistance and atherosclerosis. Although arginase I is considered antiinflammatory, the role of arginase II (Arg‐II) in macrophage function remains elusive. This study characterizes the role of Arg‐II in macrophage inflammatory responses and its impact on obesity‐linked type II diabetes mellitus and atherosclerosis.Methods and ResultsIn human monocytes, silencing Arg‐II decreases the monocytes’ adhesion to endothelial cells and their production of proinflammatory mediators stimulated by oxidized low‐density lipoprotein or lipopolysaccharides, as evaluated by real‐time quantitative reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay. Macrophages differentiated from bone marrow cells of Arg‐II–deficient (Arg‐II−/−) mice express lower levels of lipopolysaccharide‐induced proinflammatory mediators than do macrophages of wild‐type mice. Importantly, reintroducing Arg‐II cDNA into Arg‐II−/− macrophages restores the inflammatory responses, with concomitant enhancement of mitochondrial reactive oxygen species. Scavenging of reactive oxygen species by N‐acetylcysteine prevents the Arg‐II–mediated inflammatory responses. Moreover, high‐fat diet–induced infiltration of macrophages in various organs and expression of proinflammatory cytokines in adipose tissue are blunted in Arg‐II−/− mice. Accordingly, Arg‐II−/− mice reveal lower fasting blood glucose and improved glucose tolerance and insulin sensitivity. Furthermore, apolipoprotein E (ApoE)–deficient mice with Arg‐II deficiency (ApoE−/−Arg‐II−/−) display reduced lesion size with characteristics of stable plaques, such as decreased macrophage inflammation and necrotic core. In vivo adoptive transfer experiments reveal that fewer donor ApoE−/−Arg‐II−/− than ApoE−/−Arg‐II+/+ monocytes infiltrate into the plaque of ApoE−/−Arg‐II+/+ mice. Conversely, recipient ApoE−/−Arg‐II−/− mice accumulate fewer donor monocytes than do recipient ApoE−/−Arg‐II+/+ animals.ConclusionsArg‐II promotes macrophage proinflammatory responses through mitochondrial reactive oxygen species, contributing to insulin resistance and atherogenesis. Targeting Arg‐II represents a potential therapeutic strategy in type II diabetes mellitus and atherosclerosis. (J Am Heart Assoc. 2012;1:e000992 doi: 10.1161/JAHA.112.000992.)
Overconsumption of fructose, particularly in the form of soft drinks, is increasingly recognized as a public health concern. The acute cardiovascular responses to ingesting fructose have not, however, been well-studied in humans. In this randomized crossover study, we compared cardiovascular autonomic regulation after ingesting water and drinks containing either glucose or fructose in 15 healthy volunteers (aged 21-33 yr). The total volume of each drink was 500 ml, and the sugar content 60 g. For 30 min before and 2 h after each drink, we recorded beat-to-beat heart rate, arterial blood pressure, and cardiac output. Energy expenditure was determined on a minute-by-minute basis. Ingesting the fructose drink significantly increased blood pressure, heart rate, and cardiac output but not total peripheral resistance. Glucose ingestion resulted in a significantly greater increase in cardiac output than fructose but no change in blood pressure and a concomitant decrease in total peripheral resistance. Ingesting glucose and fructose, but not water, significantly increased blood pressure variability and decreased cardiovagal baroreflex sensitivity. Energy expenditure increased by a similar amount after glucose and fructose ingestion, but fructose elicited a significantly greater increase in respiratory quotient. These results show that ingestion of glucose and fructose drinks is characterized by specific hemodynamic responses. In particular, fructose ingestion elicits an increase in blood pressure that is probably mediated by an increase in cardiac output without compensatory peripheral vasodilatation.
In humans and most animal models, the development of obesity leads not only to increased fat depots in classical adipose tissue locations but also to significant lipid deposits within and around other tissues and organs, a phenomenon known as ectopic fat storage. The purpose of this review is to explore the possible locations of ectopic fat in key target-organs of cardiovascular control (heart, blood vessels and kidneys) and to propose how ectopic fat storage can play a role in the pathogenesis of cardiovascular diseases associated with obesity. In animals fed a high-fat diet, cardiac fat depots within and around the heart impair both systolic and diastolic functions, and may in the long-term promote heart failure. Accumulation of fat around blood vessels (perivascular fat) may affect vascular function in a paracrine manner, as perivascular fat cells secrete vascular relaxing factors, proatherogenic cytokines and smooth muscle cell growth factors. Furthermore, high amounts of perivascular fat could mechanically contribute to the increased vascular stiffness seen in obesity. Finally, accumulation of fat in the renal sinus may limit the outflow of blood and lymph from the kidney, which would alter intrarenal physical forces and promote sodium reabsorption and arterial hypertension. Taken together, ectopic fat storage in key target-organs of cardiovascular control may impair their functions, contributing to the increased prevalence of cardiovascular diseases in obese subjects.
Dynamic changes in body weight have long been recognized as important indicators of risk for debilitating diseases. While weight loss or impaired growth can lead to muscle wastage, as well as to susceptibility to infections and organ dysfunctions, the development of excess fat predisposes to type 2 diabetes and cardiovascular diseases, with insulin resistance as a central feature of the disease entities of the metabolic syndrome. Although widely used as the phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI), that is, weight/height 2 (H 2 ), which was developed as an operational definition for classifying both obesity and malnutrition, has considerable limitations in delineating fat mass (FM) from fat-free mass (FFM), in particular at the individual level. After an examination of these limitations within the constraints of the BMI-FM% relationship, this paper reviews recent advances in concepts about health risks related to body composition phenotypes, which center upon (i) the partitioning of BMI into an FM index (FM/H 2 ) and an FFM index (FFM/H 2 ), (ii) the partitioning of FFM into organ mass and skeletal muscle mass, (iii) the anatomical partitioning of FM into hazardous fat and protective fat and (iv) the interplay between adipose tissue expandability and ectopic fat deposition within or around organs/tissues that constitute the lean body mass. These concepts about body composition phenotypes and health risks are reviewed in the light of race/ethnic variability in metabolic susceptibility to obesity and the metabolic syndrome.
SummaryAugmented activities of both arginase and S6K1 are involved in endothelial dysfunction in aging. This study was to investigate whether or not there is a crosstalk between arginase and S6K1 in endothelial inflammation and aging in senescent human umbilical vein endothelial cells and in aging mouse models. We show increased arginase-II (Arg-II) expression ⁄ activity in senescent endothelial cells. Silencing Arg-II in senescent cells suppresses eNOSuncoupling, several senescence markers such as senescence-associated-b-galactosidase activity, p53-S15, p21, and expression of vascular adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1). Conversely, overexpressing Arg-II in nonsenescent cells promotes eNOS-uncoupling, endothelial senescence, and enhances VCAM1 ⁄ ICAM1 levels and monocyte adhesion, which are inhibited by co-expressing superoxide dismutase-1. Moreover, overexpressing S6K1 in nonsenescent cells increases, whereas silencing S6K1 in senescent cells decreases Arg-II gene expression ⁄ activity through regulation of Arg-II mRNA stability. Furthermore, S6K1 overexpression exerts the same effects as Arg-II on endothelial senescence and inflammation responses, which are prevented by silencing Arg-II, demonstrating a role of Arg-II as the mediator of S6K1-induced endothelial aging. Interestingly, mice that are deficient in Arg-II gene (Arg-II ) ⁄ ) ) are not only protected from age-associated increase in Arg-II, VCAM1 ⁄ ICAM1, aging markers, and eNOS-uncoupling in the aortas but also reveal a decrease in S6K1 activity. Similarly, silencing Arg-II in senescent cells decreases S6K1 activity, demonstrating that Arg-II also stimulates S6K1 in aging. Our study reveals a novel mechanism of mutual positive regulation between S6K1 and Arg-II in endothelial inflammation and aging. Targeting S6K1 and ⁄ or Arg-II may decelerate vascular aging and age-associated cardiovascular disease development.
SummaryDespite the poor prognosis of dieting in obesity management, which often results in repeated attempts at weight loss and hence weight cycling, the prevalence of dieting has increased continuously in the past decades in parallel to the steadily increasing prevalence of obesity. However, dieting and weight cycling are not limited to those who are obese or overweight as substantial proportions of the various population groups with normal body weight also attempt to lose weight. These include young and older adults as well as children and adolescents who perceive themselves as too fat (due to media, parental and social pressures), athletes in weight-sensitive competitive sports (i.e. mandatory weight categories, gravitational and aesthetic sports) or among performers for whom a slim image is professionally an advantage. Of particular concern is the emergence of evidence that some of the potentially negative health consequences of repeated dieting and weight cycling are more readily seen in people of normal body weight rather than in those who are overweight or obese. In particular, several metabolic and cardiovascular risk factors associated with weight cycling in normal-weight individuals have been identified from cross-sectional and prospective studies as well as from studies of experimentally induced weight cycling. In addition, findings from studies of experimental weight cycling have reinforced the notion that fluctuations of cardiovascular risk variables (such as blood pressure, heart rate, sympathetic activity, blood glucose, lipids and insulin) with probable repeated overshoots above normal values during periods of weight regain put an additional stress on the cardiovascular system. As the prevalence of diet-induced weight cycling is increasing due to the opposing forces of an 'obesigenic' environment and the media pressure for a slim figure (that even targets children), dieting and weight cycling is likely to become an increasingly serious public health issue.
Abstract-The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2-to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (PϽ0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (PϽ0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (rϭ0.87; PϽ0.01). Intracerebroventricular leptin administration (5 to 100 g) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: Ϫ54%, paraventricular: Ϫ69%, and dorsomedial hypothalamus: Ϫ65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals. (Hypertension. 2010;55:862-868.)Key Words: obesity-related hypertension Ⅲ sympathetic nervous system Ⅲ hypothalamus Ⅲ leptin Ⅲ leptin resistance Ⅲ New Zealand white rabbit O besity is associated with an elevated risk of cardiovascular morbidity and mortality with both clinical and animal studies reporting a strong association between body weight and blood pressure. 1 Several candidate mechanisms are implicated in the development of obesity-related hypertension and include hemodynamic alterations, endothelial dysfunction, impaired renal-pressure natriuresis, and activation of the renin-angiotensin and sympathetic nervous systems (SNS). 2-4 Converging lines of evidence from animals 5,6 and humans 7,8 indicate that obesity is characterized by a marked sympathetic activation. In humans, norepinephrine spillover and sympathetic nerve recording have established a greater sympathetic outflow to the kidneys and skeletal muscle vasculature in obese subjects, whereas cardiac sympathetic nerve activity is reduced. 7-9 Despite these observations, convincing direct evidence for elevated renal sympathetic nerve activity (RSNA) in obesity-related hypertension is lacking, and it is unknown whether SNS activation occurs early in the process or secondary to long-standing obesity...
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