scholarly journals Angiotensin (1–7) and Mas receptor activation inhibits Aldosterone induced ROS inflammatory responses in neurons of the paraventricular nucleus (PVN).

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Meredith Hay ◽  
Baojian Xue ◽  
Ralph Fred Johnson ◽  
Terry G Beltz ◽  
Alan Kim Johnson
Keyword(s):  
Paraventricular Nucleus ◽  
Inflammatory Responses ◽  
Receptor Activation ◽  
Mas Receptor

Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart

2009 ◽  
Vol 116 (9) ◽  
pp. 731-739 ◽  
Author(s):  
Peter Wilson ◽  
James Morgan ◽  
John W. Funder ◽  
Peter J. Fuller ◽  
Morag J. Young
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Mineralocorticoid Receptor ◽  
Time Course ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Receptor Activation ◽  
Mrna Levels ◽  
Tissue Remodelling ◽  
Perivascular Inflammation

Coronary, vascular and perivascular inflammation in rats following MR (mineralocorticoid receptor) activation plus salt are well-characterized precursors for the appearance of cardiac fibrosis. Endogenous corticosterone, in the presence of the 11βHSD2 (11β hydroxysteroid dehydrogenase type 2) inhibitor CBX (carbenoxolone) plus salt, produces similar inflammatory responses and tissue remodelling via activation of MR. MR-mediated oxidative stress has previously been suggested to account for these responses. In the present study we thus postulated that when 11βHSD2 is inhibited, endogenous corticosterone bound to unprotected MR in the vessel wall may similarly increase early biomarkers of oxidative stress. Uninephrectomized rats received either DOC (deoxycorticosterone), CBX or CBX plus the MR antagonist EPL (eplerenone) together with 0.9% saline to drink for 4, 8 or 16 days. Uninephrectomized rats maintained on 0.9% saline for 8 days served as controls. After 4 days, both DOC and CBX increased both macrophage infiltration and mRNA expression of the p22phox subunit of NADPH oxidase, whereas CBX, but not DOC, increased expression of the NOX2 (gp91phox) subunit. eNOS [endothelial NOS (NO synthase)] mRNA expression significantly decreased from 4 days for both treatments, and iNOS (inducible NOS) mRNA levels increased after 16 days of DOC or CBX; co-administration of EPL inhibited all responses to CBX. The responses characterized over this time course occurred before measurable increases in cardiac hypertrophy or fibrosis. The findings of the present study support the hypothesis that endogenous corticosterone in the presence of CBX can activate vascular MR to produce both inflammatory and oxidative tissue responses well before the onset of fibrosis, that the two MR ligands induce differential but overlapping patterns of gene expression, and that elevation of NOX2 subunit levels does not appear necessary for full expression of MR-mediated inflammatory and fibrogenic responses.

scholarly journals Resveratrol Inhibits Particulate Matter-Induced Inflammatory Responses in Human Keratinocytes

2020 ◽  
Vol 21 (10) ◽  
pp. 3446 ◽  
Author(s):  
Jung-Won Shin ◽  
Hyun-Sun Lee ◽  
Jung-Im Na ◽  
Chang-Hun Huh ◽  
Kyung-Chan Park ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Antioxidant Properties ◽  
Complex Mixture ◽  
Human Keratinocytes ◽  
Receptor Activation ◽  
Air Pollutant ◽  
Cellular Inflammatory Response

Particulate matter (PM), a major air pollutant, is a complex mixture of solid and liquid particles of various sizes. PM has been demonstrated to cause intracellular inflammation in human keratinocytes, and is associated with various skin disorders, including atopic dermatitis, eczema, and skin aging. Resveratrol is a natural polyphenol with strong antioxidant properties, and its beneficial effects against skin changes due to PM remain elusive. Therefore, in the present study, we investigated the effect of resveratrol on PM-induced skin inflammation and attempted to deduce the molecular mechanisms underlying resveratrol’s effects. We found that resveratrol inhibited PM-induced aryl hydrocarbon receptor activation and reactive oxygen species formation in keratinocytes. It also suppressed the subsequent cellular inflammatory response by inhibiting mitogen-activated protein kinase activation. Consequentially, resveratrol reduced PM-induced cyclooxygenase-2/prostaglandin E2 and proinflammatory cytokine expression, including that of matrix metalloproteinase (MMP)-1, MMP-9, and interleukin-8, all of which are known to be central mediators of various inflammatory conditions and aging. In conclusion, resveratrol inhibits the PM-induced inflammatory response in human keratinocytes, and we suggest that resveratrol may have potential for preventing air pollution-related skin problems.

Angiotensin-(1–7) Induces Peripheral Antinociception through Mas Receptor Activation in an Opioid-Independent Pathway

Pharmacology ◽  
2012 ◽  
Vol 89 (3-4) ◽  
pp. 137-144 ◽  
Author(s):  
Aline C.O. Costa ◽  
Lenice K. Becker ◽  
Éder R. Moraes ◽  
Thiago R.L. Romero ◽  
Luciana Guzzo ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Mas Receptor

scholarly journals MMP13 Expression Is Increased Following Mutant α-Synuclein Exposure and Promotes Inflammatory Responses in Microglia

2020 ◽  
Vol 14 ◽  
Author(s):  
Kathryn Sánchez ◽  
Kathleen Maguire-Zeiss
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Receptor Activation ◽  
Proinflammatory Response ◽  
Molecular Pattern ◽  
Lewy Body Pathology ◽  
Acid Protein

α-Synuclein is a 140-amino acid protein that readily misfolds and is associated with the Lewy body pathology found in sporadic and genetic forms of Parkinson's disease. We and others have shown that wild-type α-synuclein is a damage-associated molecular pattern that directly elicits a proinflammatory response in microglia through toll-like receptor activation. Here we investigated the direct effect of oligomeric mutant α-synuclein (A53T) on microglia morphology and activation. We found that misfolded A53T increased quantitative measures of amoeboid cell morphology, NFκB nuclear translocation and the expression of prototypical proinflammatory molecules. We also demonstrated that A53T increased expression of MMP13, a matrix metalloproteinase that remodels the extracellular matrix. To better understand the role of MMP13 in synucleinopathies, we further characterized the role of MMP13 in microglial signaling. We showed exposure of microglia to MMP13 induced a change in morphology and promoted the release of TNFα and MMP9. Notably, IL1β was not released indicating that the pathway involved in MMP13 activation of microglia may be different than the A53T pathway. Lastly, MMP13 increased the expression of CD68 suggesting that the lysosomal pathway might be altered by this MMP. Taken together this study shows that mutant α-synuclein directly induces a proinflammatory phenotype in microglia, which includes the expression of MMP13. In turn, MMP13 directly alters microglia supporting the need for multi-target therapies to treat Parkinson's disease patients.

scholarly journals Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

2015 ◽  
Vol 113 (5) ◽  
pp. 1302-1309 ◽  
Author(s):  
Sean D. Stocker ◽  
Kathryn W. Gordon
Keyword(s):  
Paraventricular Nucleus ◽  
Excitatory Amino Acid ◽  
Isotonic Saline ◽  
Nmda Antagonist ◽  
Receptor Activation ◽  
Hypothalamic Paraventricular Nucleus ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Drug Treatments ◽  
Change In Mean

The sympathoexcitatory response to insulin is mediated by neurons in the arcuate nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. Therefore, the purpose of the present study was to determine whether glutamatergic neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male Sprague-Dawley rats (275–400 g) were infused with isotonic saline or insulin (3.75 mU·kg−1·min−1) plus 50% dextrose to maintain euglycemia. Intravenous infusion of insulin significantly increased lumbar SNA without a significant change in mean ABP, renal SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with insulin. Similarly, a cocktail of the NMDA antagonist dl-2-amino-5-phosphonopentanoic acid (AP5) and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced lumbar SNA and mean ABP during infusion of insulin. In a final experiment, bilateral PVH injection of AP5 only, but not CNQX, lowered lumbar SNA and mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or AP5 alone. These drug treatments did not alter any variable in animals infused with saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission in the PVH contributes to insulin-induced sympathoexcitation.

Abstract P135: Deletion of the Mas Receptor Aggravates Vascular Dysfunction and the Development of Atherosclerosis Through a NO-dependent Mechanism in Apolipoprotein E-deficient Mice

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Guang Yang ◽  
Katharina Grave ◽  
Manuel Thieme ◽  
Ulrike Hendgen-Cotta ◽  
Lars C Rump ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Vascular Dysfunction ◽  
Atherosclerotic Lesion ◽  
Receptor Activation ◽  
Lesion Area ◽  
Mas Receptor ◽  
Apoe Ko Mice ◽  
Apoe Ko ◽  
Dependent Mechanism ◽  
Nitrite Content

Recently, we have shown that chronic Ang-(1-7) treatment acting through the Mas receptor improves vascular dysfunction in atherosclerotic apolipoprotein E-deficient (apoE-KO) mice by increasing NO bioavailability. To test whether deletion of the Mas receptor aggravates atherosclerosis and to examine the underlying mechanism, we generated apoE/Mas-KO mice. 12 weeks old ApoE-KO and apoE/Mas-KO mice fed on a lipid-rich Western diet were treated via osmotic minipumps with either saline or Ang-(1-7) (82 μg/kg/h) for 6 weeks. Aortae were stained with red oil and quantified for atherosclerosis. To examine whether Ang-(1-7) modulates the development of atherosclerosis through a NO dependent mechanism, 8 weeks old apoE-KO mice treated with L-NAME (20mg/kg/d) were infused either with Ang-(1-7) or saline for 6 weeks. Tissue nitrite, a marker for NO generation was measured by HPLC. Endothelial dependent vasodilation and atherosclerosis was significantly impaired in apoE/Mas-KO mice compared to apoE-KO (relative lesion area of the aortic arch: 38.7±3.0 vs. 25.4±2.0%; P<0.01; specific lesion area 11.7±0.9 vs. 8.1±1.0mm2 P<0.01). Moreover, nitrotyrosin and urinary 8-Isoprostane levels, both markers for oxidative stress were significantly increased in apoE/Mas-KO compared to apoE-KO mice. In contrast, chronic Ang-(1-7) treatment attenuated atherosclerotic lesion in apoE-KO (11.1±2.6% vs. 25.4±2.0, P<0.01 and 3.1±0.8mm2 vs. 8.1±1.0, P<0.01) but not in apoE/Mas-KO mice (38.7±3.0 vs. 38.0±14.2% and 11.7±0.9 vs. 11.4±5.0mm2). Additionally, aortic nitrite content was increased in Ang-(1-7) treated apoE-KO compared to untreated apoE-KO mice (180±31 vs. 311±47μM/g, P<0.05). L-NAME treatment increased blood pressure (BP) and reduced aortic nitrite content significantly compared to sham-treated apoE-KO mice. However, Ang-(1-7) treatment did not affect BP (127±3 vs. 128±3mmHg), aortic nitrite (861±16 vs. 1004±174 μM/g) content and the development of atherosclerosis in L-NAME treated apoE-KO mice. In conclusion, our findings indicate that Ang-(1-7) improves atherosclerosis via Mas receptor activation. Moreover, these effects seems to mediated through a NO-dependent mechanism as Ang-(1-7) failed to affect atherosclerosis in L-NAME treated mice.

Abstract 258: Angiotensin 1-7 Attenuates Endothelin-1-Induced Endothelial Cell Inflammation and Growth Through Nitric Oxide Production and Activation of Mas and EndothelinB Receptors

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Hiba Yusuf ◽  
Augusto C Montezano ◽  
Glaucia E Callera ◽  
Aurille Nguyen Dinh Cat ◽  
Robson A Santos ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
No Production ◽  
Beneficial Effects ◽  
Mas Receptor ◽  
Mediated Effects ◽  
Endothelin System ◽  
Etb Receptor

In pulmonary hypertension, where the endothelin system plays a major role, the vasoprotective axis of the rennin angiotensin system (ACE2-Ang (1-7)-Mas) seems to be protective. However, the exact mechanisms are still elusive and whether Ang 1-7 counterbalancing effects are beyond interactions with Ang II system is unknown. In this study, we assessed whether Ang 1-7 influences/interacts with the ET-1 system in endothelial cells. Cultured human microvascular endothelial cells (HMEC) were studied. HMEC were stimulated with ET-1 (10-7 mol/L) in the absence and presence of Ang 1-7 (10-7 mol/L), BQ788 (an ETBR antagonist), BQ 123 (an ETAR antagonist) and A779 (Mas receptor inhibitor) (10-6 mol/L). Expression of pro-inflammatory mediator (VCAM-1), cell growth marker (PCNA), Mas, ETBR expression and eNOS activation was determined by immunoblotting. ET-1 significantly increased expression of VCAM-1 (138.90% vs control, p<0.05) and PCNA (125% vs control, p<0.05). Ang 1-7 alone did not modulate pro-inflammatory and growth mediators, but significantly inhibited the effects of ET-1 on VCAM-1 (95.55%) and PCNA (103.83%) expression, an effect mediated by Mas receptor activation (after A779: VCAM-1: 226.15%; PCNA: 120% vs control, p<0.05). Ang 1-7 increased NO production (Ctl: 7.5 vs Ang 1-7: 20 RFU/ug of protein, by microfluorescence). Inhibition of Ang 1-7-induced NO production by L-NAME, inhibited Ang 1-7-mediated effects on ET-1-induced VCAM-1 (160%) and PCNA (125%), p<0.05. Ang 1-7 significantly increased expression of ETB receptors (175.63% vs control, p<0.05), an effect attenuated by A779. Ang 1-7 (166.94% vs control, p<0.05) and ET-1 (146.04% vs control, p<0.05) increased eNOS phosphorylation in HMEC. Blockade of Mas and ETB receptor inhibited Ang 1-7 and ET-1 effects on eNOS activation. BQ123, but not BQ788, blocked ET-1-stimulated inflammation/growth in HMEC (VCAM-1: 75%, PCNA: 100%, p<0.05). In conclusion, Ang 1-7 negatively modulates proinflammatory and mitogenic actions of ET-1, through crosstalk between Mas and ETB receptors, and increase in NO production. These data highlight some molecular mechanisms whereby Ang 1-7 may exert beneficial effects in pulmonary hypertension and suggests a novel mechanism for Ang 1-7 signalling in HMEC.

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