816 research outputs found
Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms
Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes
Serotonin signaling through the 5-HT1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension
Objective: Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesise that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 anti-oxidant systems, promoting vascular injury.
Approach and Results: HPASMCs from controls and PAH patients, and PASMCs from Nox1-/- mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT1B receptor and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing (SERT+) female mice, a model of pulmonary hypertension (PH).
We confirmed serotonin increased superoxide and H2O2 production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and peroxiredoxin-SO3H and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated, and dependent on c-Src, 5-HT1B receptor and the serotonin transporter in PAH-hPASMCs. Proliferation and extracellular matrix remodeling were exaggerated in PAH-hPASMCs and dependent on 5-HT1B receptor signaling and Nox1, confirmed in PASMCs from Nox1-/- mice. In SERT+ mice, SB216641, a 5-HT1B receptor antagonist, prevented development of PH in a ROS-dependent manner.
Conclusions: Serotonin can induce c-Src-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins, activation of redox-sensitive signaling pathways in hPASMCs; associated with mitogenic responses. 5-HT1B receptors contribute to experimental PH by inducing lung ROS production. Our results suggest 5-HT1B receptor-dependent c-Src-Nox1-pathways contribute to vascular remodeling in PAH
Antiāatherosclerotic effect of the angiotensin 1ā7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
Background and Purpose:
Inflammation plays a key role in atherosclerosis. A protective role of angiotensin-(1-7) in vascular pathologies opened a possibility for therapeutic use of small molecule non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms of these vaso-protective effects of a Mas receptor agonist, AVE0991, remain unclear.
Experimental approach:
We investigated the effects of AVE0991 on the spontaneous atherosclerosis in ApoE-/- mice, in the context of vascular inflammation and plaque stability.
Key Results:
AVE0991 has significant anti-atherosclerotic properties in ApoE-/- mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using descending aorta of chow fed ApoE-/- mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (pVAT) and adventitial infiltration with macrophages and T cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability as a measure of endothelial function. AVE0991 inhibited perivascular inflammation, through the reduction of chemokine expression in pVAT, as well as through direct actions on monocytes/macrophages inhibiting their activation, characterized by IL-1Ī², TNF-Ī±, MCP-1 and CXCL10 and differentiation to M1 phenotype. Pre-treatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in pVAT and in THP-1 cells in vitro and anti-inflammatory effects of AVE0991 were partially Mas dependent.
Conclusions & implications:
Selective Mas receptor agonist AVE0991 possesses anti-atherosclerotic and anti-inflammatory properties, affecting monocyte/macrophage differentiation and recruitment to perivascular space at early stages of atherosclerosis in ApoE-/- mice
The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1 pulmonary circulation
Pulmonary arterial hypertension (PAH) is a devastating vasculopathy that predominates in women and has been associated with
dysregulated estrogen and serotonin signaling. Overexpression of the serotonin transporter (SERT+) in mice results in an estrogen-dependent
development of pulmonary hypertension (PH). Estrogen metabolism by cytochrome P450 1B1 (CYP1B1) contributes to the pathogenesis of
PAH, and serotonin can increase CYP1B1 expression in human pulmonary arterial smooth muscle cells (hPASMCs). We hypothesized that
an increase in intracellular serotonin via increased SERT expression may dysregulate estrogen metabolism via CYP1B1 to facilitate PAH.
Consistent with this hypothesis, we found elevated lung CYP1B1 protein expression in female SERT+ mice accompanied by PH, which was
attenuated by the CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS). Lungs from female SERT+ mice demonstrated an increase in oxidative
stress that was marked by the expression of 8-hydroxyguanosine; however, this was unaffected by CYP1B1 inhibition. SERT expression
was increased in monocrotaline-induced PH in female rats; however, TMS did not reverse PH in monocrotaline-treated rats but prolonged
survival. Stimulation of hPASMCs with the CYP1B1 metabolite 16Ī±-hydroxyestrone increased cellular proliferation, which was attenuated by
an inhibitor (MPP) of estrogen receptor alpha (ERĪ±) and a specific ERĪ± antibody. Thus, increased intracellular serotonin caused by increased
SERT expression may contribute to PAH pathobiology by dysregulation of estrogen metabolic pathways via increased CYP1B1 activity. This
promotes PASMC proliferation by the formation of pathogenic metabolites of estrogen that mediate their effects via ERĪ±. Our studies indicate
that targeting this pathway in PAH may provide a promising antiproliferative therapeutic strategy
Report of the International Society of Hypertension (ISH) Hypertension Teaching Seminar organized by the ISH Africa Regional Advisory Group: Maputo, Mozambique, 2016
The International Society of Hypertension (ISH), in fulfilment of its mission of promoting hypertension control and prevention and also of advancing knowledge globally, organizes hypertension teaching seminars or āsummer schoolsā worldwide through the ISH Regional Advisory Groups. In Africa, seven of such seminars have been organized. This is a report of the eighth seminar held in Maputo, Mozambique, April, 2016. The seminar was attended by over 65 participants from 11 African countries. The Faculty consisted of 11 international hypertension experts. The eighth African hypertension seminar was a great success as confirmed by a pre- and post-test questionnaire
Is it time to reappraise blood pressure thresholds and targets? Statement from the international society of hypertension - a global perspective
No abstract available
Notch3 signaling and vascular remodeling in pulmonary arterial hypertension
Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1ā4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH
Prevalence of DSM-5 diagnostic threshold eating disorders and features amongst Aboriginal and Torres Strait islander peoples (First Australians)
Background: There is a dearth of research into mental disorders amongst Aboriginal and Torres Strait Islander peoples (herein First Australians) and especially into eating disorders. In order to understand the healthcare needs of this population, accurate prevalence data is needed. This study aimed to estimate the prevalence of eating disorders amongst First Australians at the diagnostic threshold level and to compare clinical features and health related quality of life (HRQoL) in First and other Australians with and without an eating disorder. Methods: Data were sourced from the general population 2015 and 2016 Health Omnibus Surveys in South Australia. Trained interviewers conducted via face to face interviews with 6052 people over 15 years old. Eating disorder questions were based on the Eating Disorder Examination and Health Related Quality of Life (HRQoL) measured with the Short-Form 12 v1. The response and participation rates were over 50% and 68% respectively in both surveys. Body Mass Index (BMI) and First Australian status were derived from interview questions. Data were weighted to population norms and analysed using statistical methods for complex surveys. Results: Twenty-five of 92 (27%) First Australian survey respondents had an eating disorder (majority Other or Unspecified Feeding or Eating Disorder characterised by recurrent binge eating). This was significantly more than the prevalence of other Australians with an eating disorder group (p = .04). First Australians with an eating disorder had higher levels of weight/shape overvaluation than all other groups. They were also younger and had poorer Mental HRQoL (MHRQoL) than other Australians without an eating disorder. On logistic regression, First Australian status was not independently associated with having an eating disorder, however, age, Body Mass Index (BMI) and MHRQoL emerged as significant independent variables for the increased rate of eating disorders in First Australians. Conclusions: Eating disorders were very common in First Australians and were associated with high levels of overvaluation, binge eating frequency and poor MHRQoL. High levels of overvaluation were unexpected. The implications of these findings include an urgent need for further research, and the development of culturally appropriate assessment instruments and treatments for First Australians with eating disorders
Impulsivity and its relationship with lisdexamfetamine dimesylate treatment in binge eating disorder
High trait impulsivity is thought to contribute to the sense of loss of control over eating and impulses to binge eat experienced by those with binge eating disorder (BED). Lisdexamfetamine dimesylate (LDX), a drug approved for treatment of moderate to severe BED, has been shown to decrease impulsive features of BED. However, the relationship between LDX-related reductions of binge eating (BE) episodes and impulsivity has not yet been explored. Forty-one adults aged 18-40years with moderate to severe BED completed questionnaires and tasks assessing impulsivity at baseline and after 8weeks of 50-70mg of LDX. Twenty age-matched healthy controls were also assessed at two timepoints for normative comparison. Data were analysed using linear mixed models. BED participants exhibited increased self-reported motor, non-planning, cognitive and food-related impulsivity relative to controls but no differences in objective task-based measures of impulsivity. Food-related and non-planning impulsivity was significantly reduced by LDX, but not to normative levels. Individuals with higher baseline levels of motor and non-planning impulsivity, and loss of control over eating scores experienced the greatest reduction in BE frequency after 8weeks of LDX. Further, there were significant associations between the degree to which subjective loss of control over eating, non-planning impulsivity and BE frequency reduced after 8weeks of LDX. These data suggest that specific subjective measures of impulsivity may be able to predict who will have the greatest benefit from LDX treatment and that reductions in BE frequency may be moderated by concurrent reductions in non-planning impulsivity
Associations between parents' body weight/shape comments and disordered eating amongst adolescents over time : a longitudinal study
Parents are key influencers of adolescentsā attitudes on weight, shape, and eating, and make more positive than negative comments, with negative comments most impactful. This study examined prospective unique associations of parental positive and negative comments in a community sample of adolescents with paediatric psychosocial quality of life (PED-QoL), Eating Disorder Weight/Shape Cognitions (EDEQ-WS), BMI percentile, and Psychological Distress (K10) scales. Data were from 2056 adolescents from the EveryBODY study cohort. Multiple regressions were conducted for the impacts of parental positive and negative comments on four dependent variables at one year after controlling for their stage of adolescence (early, middle, late). Multiple imputation and bootstrapping were used for handling missing data and violations of normality. Results indicated that positive maternal comments on eating were associated with increased EDCs and better quality of life at one year. Paternal positive weight shape comments were associated with a decrease in psychological distress, but positive eating comments saw a decrease in quality of life. Findings highlight the nuances of parental comments and how these are perceived and interpreted, and could alert health care workers and family practitioners who have weight, shape, and eating conversations to be aware of the potential influence of their communication
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