Background and Purpose
Metabolic and vascular dysfunction are common features of obesity. Aryl hydrocarbon receptor (AhR) regulates lipid metabolism and vascular homeostasis, but whether vascular AhR ...are activated in obesity or have a protective and/or harmful effects on vascular function in obesity are unknown. Our study addresses whether AhR activation contributes to obesity‐associated vascular dysfunction and the mechanisms involved in these AhR effects.
Experimental Approach
Male AhR KO (Ahr−/−) and WT mice were fed either control or a HF (high‐fat) diet for 10 weeks. Metabolic and inflammatory parameters were measured in serum and adipose tissue. Vascular reactivity (isometric force) was evaluated using a myography. Endothelial NOS (eNOS) and AhR protein expression was determined by western blot, Cyp1A1 and Nos3 gene expression by RT‐PCR and.NO production was quantified by DAF fluorescence.
Key Results
HF diet increased total serum HDL and LDL, as well as vascular AhR protein expression and proinflammatory cytokines in the adipose tissue. HF diet decreased endothelium‐dependent vasodilation. AhR deletion protected mice from HF diet‐induced dyslipidaemia, weight gain and inflammatory processes. HF diet‐induced endothelial dysfunction was attenuated in Ahr−/− mice. Vessels from Ahr−/− mice exhibited a greater NO reserve. In cultured endothelial cells, lysophosphatidylcholine (LPC) a major component of LDL and oxidized LDL oxLDL) reduced Nos3 gene expression and NO production. Antagonism of the AhR inhibited LPC effects on endothelial cells and induced decreased endothelium‐dependent vasodilation.
Conclusion and Implications
AhR deletion attenuates HF diet‐induced dyslipidaemia and vascular dysfunction by improving eNOS/NO signalling. Targeting AhRs may prevent obesity‐associated vascular dysfunction.
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Baroreceptor and chemoreceptor reflexes modulate inflammatory responses. However, whether these reflexes attenuate periodontal diseases has been poorly examined. Thus, the present study determined ...the effects of electrical activation of the carotid sinus nerve (CSN) in rats with periodontitis. We hypothesized that activation of the baro and chemoreflexes attenuates alveolar bone loss and the associated inflammatory processes. Electrodes were implanted around the CSN, and bilateral ligation of the first mandibular molar was performed to, respectively, stimulate the CNS and induce periodontitis. The CSN was stimulated daily for 10 min, during nine days, in unanesthetized animals. On the eighth day, a catheter was inserted into the left femoral artery and, in the next day, the arterial pressure was recorded. Effectiveness of the CNS electrical stimulation was confirmed by hypotensive responses, which was followed by the collection of a blood sample, gingival tissue, and jaw. Long-term (9 days) electrical stimulation of the CSN attenuated bone loss and the histological damage around the first molar. In addition, the CSN stimulation also reduced the gingival and plasma pro-inflammatory cytokines induced by periodontitis. Thus, CSN stimulation has a protective effect on the development of periodontal disease mitigating alveolar bone loss and inflammatory processes.
The mechanisms involved in NOX5 activation in atherosclerotic processes are not completely understood. The present study tested the hypothesis that lysophosphatidylcholine (LPC), a proatherogenic ...component of oxLDL, induces endothelial calcium influx, which drives NOX5-dependent reactive oxygen species (ROS) production, oxidative stress, and endothelial cell dysfunction.
Human aortic endothelial cells (HAEC) were stimulated with LPC (10-5 M, for different time points). Pharmacological inhibition of NOX5 (Melittin, 10-7 M) and NOX5 gene silencing (siRNA) was used to determine the role of NOX5-dependent ROS production in endothelial oxidative stress induced by LPC. ROS production was determined by lucigenin assay and electron paramagnetic spectroscopy (EPR), calcium transients by Fluo4 fluorimetry, and NOX5 activity and protein expression by pharmacological assays and immunoblotting, respectively.
LPC increased ROS generation in endothelial cells at short (15 min) and long (4 h) stimulation times. LPC-induced ROS was abolished by a selective NOX5 inhibitor and by NOX5 siRNA. NOX1/4 dual inhibition and selective NOX1 inhibition only decreased ROS generation at 4 h. LPC increased HAEC intracellular calcium, important for NOX5 activation, and this was blocked by nifedipine and thapsigargin. Bapta-AM, selective Ca2+ chelator, prevented LPC-induced ROS production. NOX5 knockdown decreased LPC-induced ICAM-1 mRNA expression and monocyte adhesion to endothelial cells.
These results suggest that NOX5, by mechanisms linked to increased intracellular calcium, is key to early LPC-induced endothelial oxidative stress and pro-inflammatory processes. Since these are essential events in the formation and progression of atherosclerotic lesions, the present study highlights an important role for NOX5 in atherosclerosis.
Introduction
Erectile dysfunction (ED) is associated with risk factors for the development of cardiovascular diseases such as hypertension. Increased activity of the immune system is closely linked ...to the development of hypertension and ED. Arterial hypertension is strongly influenced by pro‐inflammatory effects of NLRP3. NLRP3 activity promotes vascular changes, cardiac and renal hypertrophy and increase in blood pressure. In addition, NLRP3 is involved in the recruitment of cells of the immune system. Increasing evidence shows that increased lymphocyte infiltrate is involved in the genesis and/or aggravation of various cardiovascular diseases.
Hypothesis
NLRP3 increases lymphocyte infiltrate, promotes impairment of corpora cavernosa (CC) reactivity and ED in DOCA/salt hypertensive mice.
Objective
Evaluate the role of NLRP3 in lymphocyte recruitment in CC, impairment of erectile function and changes in CC reactivity in DOCA/salt mice.
Methods
(CEUA 213/2016). Male C57BL/6 (WT) and NLRP3 deficient mice (NLRP3−/−) were either treated with vehicle or induced to DOCA/salt hypertension. Fluorescence to FAM‐FLICA and histochemistry were performed to analyze respectively the caspase‐1 activity and the number of lymphocytes in CC. The intracavernous pressure (ICP) was measured. Reactivity of CC to acetylcholine (ACh) and sodium nitroprusside (SNP) was performed.
Results
DOCA/salt hypertension increased the caspase‐1 activity in the CC. In addition, we observed increased lymphocyte infiltrate in the CC (WTsham: 18.5 ± 1.0; WTdoca: 33.5 ± 1.4, n=6), impaired erectile function (decreased ICP in WTdoca in the frequencies of 4, 8, 12 and 16 Hz) and reduced relaxation for ACh (pD2 WTsham: 7.2 ± 0.08, n=7; WTdoca: 6.5 ± 0.12, n=7) and SNP (pD2 WTsham: 7.2 ± 0.07, n=6; WTdoca: 6.7 ± 0.06, n=7) in the CC of WT mice. The absence of NLRP3 prevented the increase in the caspase‐1 activity and in the lymphocyte infiltrate (NLRP3−/−sham: 12.0 ± 1.2; NLRP3−/−doca: 17.6 ± 1.9, n=5) in the CC. Furthermore, NLRP3 absence normalized the erectile function, the reactivity to ACh (pD2 NLRP3−/−sham: 7.0 ± 0,14, n=6; NLRP3−/−doca: 6.9 ± 0.16, n=7) and to SNP (pD2 NLRP3−/−sham: 8.2 ± 0.08, n=6; NLRP3−/−doca: 8.5 ± 0.07, n=7) in DOCA/salt hypertension.
Conclusion
NLRP3 mediates the lymphocyte recruitment, impairment in erectile function and CC reactivity, promoted by DOCA/salt hypertension.
Support or Funding Information
Financial support: FAPESP, CNPq, CAPES, CRID.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Butyrate is a 4-carbon fatty acid that has antiinflammatory and antioxidative properties. It has been demonstrated that butyrate is able to reduce atherosclerotic development in animal models by ...reducing inflammatory factors. However, the contribution of its antioxidative effects of butyrate on atherogenesis has not yet been studied. We investigated the influence of butyrate on oxidative status, reactive oxygen species (ROS) release and oxidative enzymes (NADPH oxidase and iNOS) in atherosclerotic lesions of ApoE−/− mice and in oxLDL-stimulated peritoneal macrophages and endothelial cells (EA.hy926). The lesion area in aorta was reduced while in the aortic valve, although lesion area was unaltered, superoxide production and protein nitrosylation were reduced in butyrate-supplemented mice. Peritoneal macrophages from the butyrate group presented a lower free radical release after zymosan stimulus. When endothelial cells were pretreated with butyrate before oxLDL stimulus, the CCL-2 and superoxide ion productions and NADPH oxidase subunit p22phox were reduced. In macrophage cultures, in addition to a reduction in ROS release, nitric oxide and iNOS expression were down-regulated. The data suggest that one mechanism related to the effect of butyrate on atherosclerotic development is the reduction of oxidative stress in the lesion site. The reduction of oxidative stress related to NADPH oxidase and iNOS expression levels associated to butyrate supplementation attenuates endothelium dysfunction and macrophage migration and activation in the lesion site.
Studies suggest that sodium butyrate reduces obesity-associated inflammation and insulin resistance in in vitro and in vivo models. Apo E−/− mice have high basal oxidative stress and naturally ...develop dyslipidemia and atherosclerosis. Because these disorders are present in obesity, the aim of this study was to determine whether Apo E−/− mice could be a more realistic model for studying obesity and insulin resistance.
We evaluated the action of orally administered sodium butyrate on adipose tissue expansion and insulin resistance using diet-induced obese Apo E−/− mice.
Findings from the present study demonstrated that obese mice fed a sodium butyrate–supplemented diet presented a modest reduction of weight gain associated with reduction of adipocyte expansion, induction of adipogenesis and angiogenesis, and adiponectin production. Sodium butyrate also improved insulin sensitivity, by increasing insulin receptor expression associated with activation of Akt signaling pathway. These results were associated with increased peroxisome proliferator-activated receptor-γ expression and nuclear factor-κB downregulation.
These results suggested that oral supplementation of butyrate could be useful as an adjuvant in the treatment of obesity, metabolic syndrome, and insulin resistance.
Vascular Stress Signaling in Hypertension Cicalese, Stephanie M; da Silva, Josiane Fernandes; Priviero, Fernanda ...
Circulation research,
04/2021, Letnik:
128, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Cells respond to stress by activating a variety of defense signaling pathways, including cell survival and cell death pathways. Although cell survival signaling helps the cell to recover from acute ...insults, cell death or senescence pathways induced by chronic insults can lead to unresolved pathologies. Arterial hypertension results from chronic physiological maladaptation against various stressors represented by abnormal circulating or local neurohormonal factors, mechanical stress, intracellular accumulation of toxic molecules, and dysfunctional organelles. Hypertension and aging share common mechanisms that mediate or prolong chronic cell stress, such as endoplasmic reticulum stress and accumulation of protein aggregates, oxidative stress, metabolic mitochondrial stress, DNA damage, stress-induced senescence, and proinflammatory processes. This review discusses common adaptive signaling mechanisms against these stresses including unfolded protein responses, antioxidant response element signaling, autophagy, mitophagy, and mitochondrial fission/fusion, STING (signaling effector stimulator of interferon genes)-mediated responses, and activation of pattern recognition receptors. The main molecular mechanisms by which the vasculature copes with hypertensive and aging stressors are presented and recent advancements in stress-adaptive signaling mechanisms as well as potential therapeutic targets are discussed.
Protease-activated receptor (PAR)2 has been implicated in mediating allergic airway inflammation. We investigate the role of PAR2 in lung inflammation and neutrophil and eosinophil recruitment into ...the lungs in a mouse model of short-term acute allergic inflammation. Allergic lung inflammation was induced in sensitized BALB/c mice through intranasal instillations of ovalbumin (OVA), and mice were pretreated with the PAR2 antagonist ENMD1068 or with the PAR2-activating peptide (PAR2-AP) 1 hour before each OVA challenge. Bronchoalveolar lavage fluid (BALF) was collected, and the lungs, trachea and lymph nodes were removed after the last challenge to analyze the airway inflammation. PAR2 blockade reduced OVA-induced eosinophil and neutrophil counts, CXCL1, CCL5, amphiregulin, and interleukin (IL)-6 and 13 levels. Moreover, PAR2 blockade reduced OVA-induced PAR2 expression in cells present in BALF 2 hour after OVA challenge, and PAR2-AP acted synergistically with OVA promoting eosinophil recruitment into BALF and increased IL-4 and IL-13 levels in lymph nodes. Conversely, PAR2 blockade increased IL-10 levels when compared with OVA-treated mice. Our results provide evidence for a mechanism by which PAR2 meditates acute lung inflammation triggered by multiple exposures to allergen through a modulatory role on cytokine production and vascular permeability implicated in the lung diseases such as asthma.
To evaluate the performance of comprehensive care for older adults in primary care services in the Brazilian Unified Health System in the state of São Paulo, Brazil.
A total of 157 primary care ...services from five health regions in midwestern São Paulo responded, from October to December 2014, the pre-validated 2014 questionnaire for primary care services assessment and monitoring. We selected 155 questions, based on national policies and guidelines on this theme. The responses indicate the service performance in older adults' care, clustered into three areas of analysis: health care for active and healthy aging (45 indicators, d1), chronic noncommunicable diseases care (89 indicators, d2), and support network in aging care (21 indicators, d3). Performance was measured by the sum of positive (value 1) or negative (value 0) responses for each indicator. Services were clustered according to k-means of the performance scores of each domain. After weighting the domains (Z tests), we estimated the associations between the scores of each domain and independent management variables (typology, planning and evaluation of services), with simple and multiple linear regression.
Chronic noncommunicable diseases care (d2) showed, for all clusters, better average performance (55.7) than domains d1 (35.4) and d3 (39.2). Service performance in the general area of planning and evaluation associates with the performance of older adults' care.
The evaluated services had incipient implementation of comprehensive care for older adults. The evaluation framework can contribute to processes to improve the quality of primary health care.
Despite all the development of modern medicine, around 100 compounds derived from natural products were undergoing clinical trials only at the end of 2013. Among these natural substances in clinical ...trials, we found the resveratrol (RES), a pharmacological multi-target drug. RES analgesic properties have been demonstrated, although the bases of these mechanisms have not been fully elucidated. The aim of this study was to evaluate the involvement of opioid and cannabinoid systems in RES-induced peripheral antinociception. Paw withdrawal method was used and hyperalgesia was induced by carrageenan (200 μg/paw). All drugs were given by intraplantar injection in male Swiss mice (n = 5). RES (100 μg/paw) administered in the right hind paw induced local antinociception that was antagonized by naloxone, non-selective opioid receptor antagonist, and clocinnamox, μOR selective antagonist. Naltrindole and nor-binaltorfimine, selective antagonists for δOR and kOR, respectively, did not reverse RES-induced peripheral antinociception. CB1R antagonist AM251, but not CB2R antagonist AM630, antagonized RES-induced peripheral antinociception. Peripheral antinociception of RES intermediate-dose (50 μg/paw) was increased by: (i) bestatin, inhibitor of endogenous opioid degradation involved-enzymes; (ii) MAFP, inhibitor of anandamide amidase; (iii) JZL184, inhibitor of 2-arachidonoylglycerol degradation involved-enzyme; (iv) VDM11, endocannabinoid reuptake inhibitor. Acute and peripheral administration of RES failed to affect the amount of μOR, CB1R and CB2R. Experimental data suggest that RES induces peripheral antinociception through μOR and CB1R activation by endogenous opioid and endocannabinoid releasing.
Display omitted
•Resveratrol induced local antinociception.•Resveratrol induces peripheral antinociception through μOR.•Resveratrol induces peripheral antinociception through CB1R.•Resveratrol antinociception by opioid and cannabinoid releasing.
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