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Anthony P Albert - One of the best experts on this subject based on the ideXlab platform.

Lutz Birnbaumer - One of the best experts on this subject based on the ideXlab platform.

  • heteromeric trpv4 trpc1 channels mediate calcium sensing receptor induced relaxations and nitric oxide production in Mesenteric Arteries comparative study using wild type and trpc1 mice
    Channels, 2019
    Co-Authors: Harry Z E Greenberg, Lutz Birnbaumer, Simonette R E Carltoncarew, Alexander Zargaran, Kazi S Jahan, Anthony P Albert
    Abstract:

    We have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit Mesenteric Arteries through activation of heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production. The present study further investigates the role of heteromeric TRPV4/TRPC1 channels in these CaSR-induced vascular responses by comparing responses in Mesenteric Arteries from wild-type (WT) and TRPC1-/- mice. In WT mice, stimulation of CaSR induced endothelium-dependent relaxations of pre-contracted tone and NO generation in endothelial cells (ECs), which were inhibited by the TRPV4 channel blocker RN1734 and the TRPC1 blocking antibody T1E3. In addition, TRPV4 and TRPC1 proteins were colocalised at, or close to, the plasma membrane of endothelial cells (ECs) from WT mice. In contrast, in TRPC1-/- mice, CaSR-mediated vasorelaxations and NO generation were greatly reduced, unaffected by T1E3, but blocked by RN1734. In addition, the TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent vasorelaxations which were blocked by RN1734 and T1E3 in WT mice, but only by RN1734 in TRPC1-/- mice. Moreover, GSK activated cation channel activity with a 6pS conductance in WT ECs but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and NO production in ECs, which are responsible for endothelium-dependent vasorelaxations. This study also suggests that heteromeric TRPV4-TRPC1 channels may form the predominant TRPV4-containing channels in mouse Mesenteric artery ECs. Together, our data further implicates CaSR-induced pathways and heteromeric TRPV4/TRPC1 channels in the regulation of vascular tone.

  • heteromeric trpv4 trpc1 channels mediate calcium sensing receptor induced relaxations and nitric oxide production in Mesenteric Arteries comparative study using wild type and trpc1 mice
    Channels, 2019
    Co-Authors: Harry Z E Greenberg, Lutz Birnbaumer, Simonette R E Carltoncarew, Alexander Zargaran, Kazi S Jahan, Anthony P Albert
    Abstract:

    We have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit Mesenteric Arteries through activation ...

  • transient receptor potential canonical type 3 channels control the vascular contractility of mouse Mesenteric Arteries
    PLOS ONE, 2014
    Co-Authors: Sooin Yeon, Joo Young Kim, Dongsoo Yeon, Joel Abramowitz, Lutz Birnbaumer, Shmuel Muallem, Youngho Lee
    Abstract:

    Transient receptor potential canonical type 3 (TRPC3) channels are non-selective cation channels and regulate intracellular Ca2+ concentration. We examined the role of TRPC3 channels in agonist-, membrane depolarization (high K+)-, and mechanical (pressure)-induced vasoconstriction and vasorelaxation in mouse Mesenteric Arteries. Vasoconstriction and vasorelaxation of endothelial cells intact Mesenteric Arteries were measured in TRPC3 wild-type (WT) and knockout (KO) mice. Calcium concentration ([Ca2+]) was measured in isolated Arteries from TRPC3 WT and KO mice as well as in the mouse endothelial cell line bEnd.3. Nitric oxide (NO) production and nitrate/nitrite concentrations were also measured in TRPC3 WT and KO mice. Phenylephrine-induced vasoconstriction was reduced in TRPC3 KO mice when compared to that of WT mice, but neither high K+- nor pressure-induced vasoconstriction was altered in TRPC3 KO mice. Acetylcholine-induced vasorelaxation was inhibited in TRPC3 KO mice and by the selective TRPC3 blocker pyrazole-3. Acetylcholine blocked the phenylephrine-induced increase in Ca2+ ratio and then relaxation in TRPC3 WT mice but had little effect on those outcomes in KO mice. Acetylcholine evoked a Ca2+ increase in endothelial cells, which was inhibited by pyrazole-3. Acetylcholine induced increased NO release in TRPC3 WT mice, but not in KO mice. Acetylcholine also increased the nitrate/nitrite concentration in TRPC3 WT mice, but not in KO mice. The present study directly demonstrated that the TRPC3 channel is involved in agonist-induced vasoconstriction and plays important role in NO-mediated vasorelaxation of intact Mesenteric Arteries.

Harry Z E Greenberg - One of the best experts on this subject based on the ideXlab platform.

Sookyoung Choi - One of the best experts on this subject based on the ideXlab platform.

  • adiporon adiponectin receptor agonist improves vascular function in the Mesenteric Arteries of type 2 diabetic mice
    PLOS ONE, 2020
    Co-Authors: Sookyoung Choi, Youngin Kwon, Seonhee Byeon, Chae Eun Haam, Youngho Lee
    Abstract:

    Background An orally active synthetic adiponectin receptor agonist, AdipoRon has been suggested to ameliorate insulin resistance, and glucose tolerance. However, the chronic effect of AdipoRon in the vascular dysfunction in type 2 diabetes has not been studied yet. Thus, in this study, we examined whether AdipoRon improves vascular function in type 2 diabetes. Methods Type 2 diabetic (db-/db-) mice were treated with AdipoRon (10 mg/kg/everyday, by oral gavage) for 2 weeks. Body weight and blood glucose levels were recorded every other day during the experimental period. Diameter of Mesenteric Arteries was measured. And western blot analysis was performed with Mesenteric Arteries. Results Pressure-induced myogenic response was significantly increased while endothelium-dependent relaxation was reduced in the Mesenteric Arteries of db-/db- mice. Treatment of AdipoRon normalized potentiated myogenic response, whereas endothelium-dependent relaxation was not affected by treatment of AdipoRon. The expression levels of AdiR1, AdiR2, APPL1, and APPL 2 were increased in the Mesenteric Arteries of db-/db- mice and treatment of AdipoRon did not affect them. Interestingly, AdipoRon treatment increased the phospho-AMPK and decreased MYPT1 phosphorylation in db-/db- mice while there was no change in the level of eNOS phosphorylation. Conclusion The treatment of AdipoRon improves vascular function in the Mesenteric Arteries of db-/db- mice through endothelium-independent mechanism. We suggest that MLCP activation through reduced phosphorylation of MYPT1 might be the dominant mechanism in the AdipoRon-induced vascular effect.

  • adiporon adiponectin receptor agonist improves vascular function in the Mesenteric Arteries of type 2 diabetic mice
    Journal of Infectious Diseases and Therapy, 2019
    Co-Authors: Sookyoung Choi
    Abstract:

    Adiponectin is one of the most abundant adipokines secreted from adipose tissue. An orally active synthetic adiponectin receptor agonist, adipoRon has been suggested to ameliorate insulin resistance, myocardial apoptosis, and pancreatic tumor. It has been reported that adiponectin directly induces vascular relaxation however; the chronic effect of adipoRon in the vascular dysfunction in type 2 diabetes has not been studied yet. Thus, in this study, we examined whether adipoRon improves vascular function in type 2 diabetes and what mechanism is involved. Ten to 12-week old male type 2 diabetic (db-/ db-) mice were treated with adiponectin receptor agonist (adipoRon, 10 mg/kg/everyday by oral gavage) for 2 weeks. Isolated Mesenteric Arteries were mounted in the arteriography and arterial diameter was measured. And western blot analysis was assessed. Pressure-induced myogenic response was significantly increased, whereas endothelium-dependent relaxation was significantly reduced in the Mesenteric Arteries from type 2 diabetic mice. Interestingly, treatment of adipoRon normalized potentiated myogenic response. However, endothelium-dependent relaxation was not affected by treatment of adipoRon. The expression levels of adiponectin receptor 1, 2 and APPL 1, 2 were increased in the Mesenteric Arteries from Type 2 diabetic mice and treatment of adipoRon did not affect them. Interestingly, adipoRon treatment increased the phosphorylation level of AMPK and decreased phosphorylation of MYPT1 in the type 2 diabetic mice while there was no change in the level of eNOS phosphorylation. The treatment of adipoRon improves vascular function in the Mesenteric Arteries from type 2 diabetic mice through endothelium-independent mechanism. It is suggested that MLCP activation through reduced phosphorylation of MYPT1 might be the dominant mechanism in the adipoRon-induced vascular effect. Stoutness is characterized as an extreme and irregular fat collection to apply wellbeing concerns. Heftiness is viewed as the main consideration in the advancement of different malady, for example, type 2 diabetes, hypertension, cardiovascular ailment, respiratory illness, and osteo-joint inflammation . Collecting proof shows that heftiness every now and again happens with type 2 diabetes and is viewed as a solid hazard factor for the advancement of type 2 diabetes . Heftiness and type 2 diabetes effectsly affect vascular capacity and make conditions that favor cardiovascular illness .Adiponectin is a significant and copious adipokine emitted from adipocyte and directs insulin affectability and vitality homeostasis. The low centralization of adiponectin is related with different infection, for example, weight, diabetes, cardiovascular sicknesses. Late examinations revealed plasma adiponectin level was diminished in the patients with type 2 diabetes, and thiazolidinedione (TZD) organization expanded the adiponectinlevel . A trial study indicated that insulin opposition was enhanced by the renewal of adiponectin in mice . In this way adiponectin has been engaged as likely restorative objective for the treatment of type 2 diabetes .Adiponectin directs cell work by means of two explicit receptors, adiponectin receptor 1 (AdiR1) and adiponectin receptor 2 (AdiR2) . Connector protein containing a pleckstrin homology (PH) space, phosphotyrosine-official (PTB) area, and leucine zipper theme 1 (APPL1) is the primary recognized connector protein to emphatically intervene intracellular adiponectin flagging. APPL1 straightforwardly ties to the intracellular area of adiponectin receptor and decidedly intervenes the motioning to the AMP-initiated protein kinase (AMPK), p38 mitogen enacted protein kinase (MAPK), and peroxisome proliferator-actuated receptor α (PPARα) . Then again APPL2, an isoform of APPL1, squares APPL1-intervened insulin-sharpening impact of adiponectin and in this way adversely directs adiponectinflagging .   As of late, an orally dynamic adiponectin receptor agonist, AdipoRon, has been created and demonstrated comparative impacts to adiponectin. Like adiponectin, AdipoRon ties to both AdiR1 and AdiR2 at a low atomic focus and enacts AMPK, PPAR, and peroxisome proliferator–initiated receptor gamma coactivator 1–alpha (PGC1α). AdipoRon improved insulin affectability and glucose resilience and lipid digestion in refined cells and mice. Moreover, treatment of AdipoRon improved metabolic capacity and broadened life range in type 2 diabetic mice. Ten-to 12-week-old male sort 2 diabetic mice (db−/db−) and age-coordinated heterozygote control mice (db−/db+) were acquired from Jackson Laboratories. Mice were housed in an AAALAC endorsed creature office at Yonsei University. Quickly, mice were housed in plastic enclosures with hardened steel framework tops at 23~24°C with a 12-hour light/dim cycle and permitted access to business rat chow and water not indispensable. Absolute 30 diabetic mice and 20 control mice were utilized in this examination. Mice were separated into 4 gatherings: (1) control mice rewarded with vehicle for about fourteen days (control mice); (2) control mice rewarded with AdipoRon (10 mg/kg/ordinarily, by oral gavage) for about fourteen days; (3) diabetic mice rewarded with vehicle for about fourteen days (diabetic mice); (4) diabetic mice rewarded with AdipoRon (10 mg/kg/regularly, by oral gavage) for about fourteen days. Body weight and blood glucose levels were recorded each other day during the trial time frame. Toward the finish of the treatment time frame, mice were euthanized with isoflurane (5%) trailed by the CO2 inward breath. To affirm demise, we checked mice for the few signs, for example, no rising and falling of chest, no reaction to toe squeeze, no substantial heartbeat, shading change obscurity in eyes. After we affirm the passing, the heart was expelled quickly and tissue tests were gotten. To confine Mesenteric supply route, the Mesenteric little vein beds were expelled and set in super cold Krebs-Henseleit (K-H) arrangement (creation in mmol/L: NaCl, 119; CaCl2, 2.5; NaHCO3, 25; MgSO4, 1.2; KH2PO4, 1.2; KCl, 4.6; and glucose, 11.1). The third part of Mesenteric veins (120–150 μm, inward distance across at 40 mmHg) were confined and sliced into 2-to 3-mm sections for ensuing examination. As of late, an orally dynamic adiponectin receptor agonist, AdipoRon, has been created and demonstrated comparable impacts to adiponectin. Like adiponectin, AdipoRon ties to both AdiR1 and AdiR2 at a low atomic fixation and enacts AMPK, PPAR, and peroxisome proliferator–actuated receptor gamma coactivator 1–alpha (PGC1α). AdipoRon improved insulin affectability and glucose resistance and lipid digestion in refined cells and mice . Moreover, treatment of AdipoRon improved metabolic capacity and expanded life expectancy in type 2 diabetic mice. In spite of the fact that impacts of AdipoRon have been researched in different pathophysiological states, the impacts of AdipoRon on vascular capacity, explicitly in type 2 diabetes have not yet been contemplated. Along these lines, the targets of the current investigation were to explain whether adiponectin receptor agonist, AdipoRon, improves vascular capacity in the Mesenteric supply routes of type 2 diabetic mice and, provided that this is true, to decide the systems in question.

Owen L Woodman - One of the best experts on this subject based on the ideXlab platform.

  • 3,4-dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat Mesenteric Arteries
    2016
    Co-Authors: Chen Huei Leo, Joanne L Hart, Owen L Woodman
    Abstract:

    Background: 3’,4’-Dihydroxyflavonol (DiOHF) is an effective antioxidant that acutely preserves nitric oxide (NO) activity in the presence of elevated reactive oxygen species (ROS). We hypothesized that DiOHF treatment (7 days, 1 mg/kg per day s.c.) would improve relaxation in Mesenteric Arteries from diabetic rats where endothelial dysfunction is associated with elevated oxidant stress. Methodology/Principal Findings: In Mesenteric Arteries from diabetic rats there was an increase in ROS, measured by L-012 and 2’,7’-dichlorodihydrofluorescein diacetate fluorescence. NADPH oxidase-derived superoxide levels, assayed by lucigenin chemiluminescence, were also significantly increased in diabetic Mesenteric Arteries (diabetes, 48926946 counts/mg versus normal 24866344 counts/mg, n = 7–10, p,0.01) associated with an increase in Nox2 expression but DiOHF (20946300 counts/mg, n = 10, p,0.001) reversed that effect. Acetylcholine (ACh)-induced relaxation of Mesenteric Arteries was assessed using wire myography (pEC50 = 7.9460.13 n = 12). Diabetes significantly reduced the sensitivity to ACh and treatment with DiOHF prevented endothelial dysfunction (pEC50, diabetic 6.8660.12 versus diabetic+DiOHF, 7.4960.13, n = 11, p,0.01). The contribution of NO versus endothelium-derived hyperpolarizing factor (EDHF) to ACh-induced relaxation was assessed by evaluating responses in the presence of TRAM-34+apamin+iberiotoxin or N-nitro-L-arginine+ODQ respectively. Diabetes impaired the contribution of both NO (maximum relaxation, Rmax diabetic 246

  • the dpp 4 inhibitor linagliptin and the glp 1 receptor agonist exendin 4 improve endothelium dependent relaxation of rat Mesenteric Arteries in the presence of high glucose
    Pharmacological Research, 2015
    Co-Authors: Salheen M Salheen, Usha Panchapakesan, Carol A Pollock, Owen L Woodman
    Abstract:

    Abstract The aim of the study was to investigate the effects of the DPP-4 inhibitors and GLP-1R agonist, exendin-4 on the mechanism(s) of endothelium-dependent relaxation in rat Mesenteric Arteries exposed to high glucose concentration (40 mM). Organ bath techniques were employed to investigate vascular endothelial function in rat Mesenteric Arteries in the presence of normal (11 mM) or high (40 mM) glucose concentrations. Pharmacological tools (1 μM TRAM-34, 1 μM apamin, 100 nM Ibtx, 100 μM l -NNA, 10 μM ODQ) were used to distinguish between NO and EDHF-mediated relaxation. Superoxide anion levels were assessed by L-012 and lucigenin enhanced-chemiluminescence techniques. Incubation of Mesenteric rings with high glucose for 2 h caused a significant increase in superoxide anion generation and a significant impairment of endothelium-dependent relaxation. Exendin-4 and DPP-4 inhibitor linagliptin, but not sitagliptin or vildagliptin, significantly reduced vascular superoxide and improved endothelium-dependent relaxation in the presence of high glucose. The beneficial actions of exendin-4, but not linagliptin, were attenuated by the GLP-1R antagonist exendin fragment (9–39). Further experiments demonstrated that the presence of high glucose impaired the contribution of both nitric oxide and endothelium-dependent hyperpolarisation to relaxation and that linagliptin improved both mechanisms involved in endothelium-dependent relaxation. These findings demonstrate that high glucose impaired endothelium-dependent relaxation can be improved by exendin-4 and linagliptin, likely due to their antioxidant activity and independently of any glucose lowering effect.

  • 3 4 dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat Mesenteric Arteries
    PLOS ONE, 2011
    Co-Authors: Chen Huei Leo, Joanne L Hart, Owen L Woodman
    Abstract:

    Background: 3’,4’-Dihydroxyflavonol (DiOHF) is an effective antioxidant that acutely preserves nitric oxide (NO) activity in the presence of elevated reactive oxygen species (ROS). We hypothesized that DiOHF treatment (7 days, 1 mg/kg per day s.c.) would improve relaxation in Mesenteric Arteries from diabetic rats where endothelial dysfunction is associated with elevated oxidant stress. Methodology/Principal Findings: In Mesenteric Arteries from diabetic rats there was an increase in ROS, measured by L-012 and 2’,7’-dichlorodihydrofluorescein diacetate fluorescence. NADPH oxidase-derived superoxide levels, assayed by lucigenin chemiluminescence, were also significantly increased in diabetic Mesenteric Arteries (diabetes, 48926946 counts/mg versus normal 24866344 counts/mg, n=7–10, p,0.01) associated with an increase in Nox2 expression but DiOHF (20946300 counts/mg, n=10, p,0.001) reversed that effect. Acetylcholine (ACh)-induced relaxation of Mesenteric Arteries was assessed using wire myography (pEC50=7.9460.13 n=12). Diabetes significantly reduced the sensitivity to ACh and treatment with DiOHF prevented endothelial dysfunction (pEC50, diabetic 6.8660.12 versus diabetic+DiOHF, 7.4960.13, n=11, p,0.01). The contribution of NO versus endothelium-derived hyperpolarizing factor (EDHF) to ACh-induced relaxation was assessed by evaluating responses in the presence of TRAM-34+apamin+iberiotoxin or N-nitro-Larginine+ODQ respectively. Diabetes impaired the contribution of both NO (maximum relaxation, Rmax diabetic 2467 versus normal, 68610, n=9–10, p,0.01) and EDHF (pEC50, diabetic 6.6360.15 versus normal, 7.1460.12, n=10–11, p,0.01) to endothelium-dependent relaxation. DiOHF treatment did not significantly affect the EDHF contribution but enhanced NO-mediated relaxation (Rmax 6966, n=11, p,0.01). Western blotting demonstrated that diabetes also decreased expression and increased uncoupling of endothelial NO synthase (eNOS). Treatment of the diabetic rats with DiOHF significantly reduced vascular ROS and restored NO-mediated endothelium-dependent relaxation. Treatment of the diabetic rats with DiOHF also increased eNOS expression, both in total and as a dimer. Conclusions/Significance: DiOHF improves NO activity in diabetes by reducing Nox2-dependent superoxide production and preventing eNOS uncoupling to improve endothelial function.

  • impairment of both nitric oxide mediated and edhf type relaxation in small Mesenteric Arteries from rats with streptozotocin induced diabetes
    British Journal of Pharmacology, 2011
    Co-Authors: Chen Huei Leo, Joanne L Hart, Owen L Woodman
    Abstract:

    BACKGROUND AND PURPOSE To investigate whether diabetes affects either or both nitric oxide (NO)-mediated and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation in endothelium-dependent relaxation of Mesenteric Arteries from streptozotocin-induced diabetic rats. EXPERIMENTAL APPROACH Wire myography was employed to examine endothelial function of Mesenteric Arteries. Superoxide levels were measured by L-012 and lucigenin-enhanced chemiluminescence. Western blotting was used to quantify protein expression levels. KEY RESULTS Superoxide levels were significantly increased in diabetic Mesenteric Arteries compared with normal Arteries. Diabetes significantly reduced the sensitivity to the endothelium-dependent relaxant, acetylcholine (ACh) in Mesenteric Arteries. When the contribution of NO to relaxation was abolished by N-nitro-L-arginine (L-NNA) + a soluble guanylate cyclase inhibitor (ODQ), the sensitivity to ACh was significantly decreased in the diabetic Arteries compared with normal Arteries, indicating an impaired EDHF-type relaxation despite increased expression of intermediate- and small-conductance calcium-activated potassium channels. Conversely, when the contribution of EDHF was inhibited with TRAM-34 + apamin + iberiotoxin, maximum relaxations to ACh were significantly decreased in diabetic compared with normal Arteries, suggesting that the contribution of NO was also impaired by diabetes. Basal levels of NO release, indicated by contraction to L-NNA, were also significantly decreased in diabetic Arteries. Western blot analysis demonstrated that diabetic Arteries had an increased expression of Nox2, decreased pSer473Akt and a reduced proportion of endothelial NO synthase (eNOS) expressed as a dimer, indicating uncoupling. CONCLUSION AND IMPLICATIONS The contribution of both NO and EDHF-type relaxations was impaired in diabetes and was caused by increased oxidative stress, decreased pSer473Akt and/or eNOS uncoupling.