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Khosrow Adeli - One of the best experts on this subject based on the ideXlab platform.
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glucagon like peptide 2 glp 2 stimulates postprandial chylomicron production and postabsorptive release of intestinal triglyceride storage pools via induction of nitric oxide signaling in male hamsters and mice
Endocrinology, 2015Co-Authors: Joanne Hsieh, Sarah Farr, Karin Trajcevski, Chris Baker, Elizabeth J Lake, Jennifer Taher, Jahangir Iqbal, Mahmood M Hussain, Khosrow AdeliAbstract:The intestinal overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles is a common feature of diabetic dyslipidemia and contributes to cardiovascular risk in insulin resistant states. We previously reported that glucagon-like peptide-2 (GLP-2) is a key endocrine stimulator of enterocyte fat absorption and chylomicron output in the postprandial state. GLP-2's stimulatory effect on chylomicron production in the postabsorptive state has been confirmed in human studies. The mechanism by which GLP-2 regulates chylomicron production is unclear, because its receptor is not expressed on enterocytes. We provide evidence for a key role of nitric oxide (NO) in mediating the stimulatory effects of GLP-2 during the postprandial and postabsorptive periods. Intestinal chylomicron production was assessed in GLP-2-treated hamsters administered the pan-specific NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (L-NAME), and in GLP-2-treated Endothelial NOS knockout mice. L-NAME blocked GLP-...
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glucagon like peptide 2 glp 2 stimulates postprandial chylomicron production and postabsorptive release of intestinal triglyceride storage pools via induction of nitric oxide signaling in male hamsters and mice
Endocrinology, 2015Co-Authors: Joanne Hsieh, Sarah Farr, Karin Trajcevski, Elizabeth J Lake, Jennifer Taher, Jahangir Iqbal, Mahmood M Hussain, Christopher Baker, Khosrow AdeliAbstract:The intestinal overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles is a common feature of diabetic dyslipidemia and contributes to cardiovascular risk in insulin resistant states. We previously reported that glucagon-like peptide-2 (GLP-2) is a key endocrine stimulator of enterocyte fat absorption and chylomicron output in the postprandial state. GLP-2's stimulatory effect on chylomicron production in the postabsorptive state has been confirmed in human studies. The mechanism by which GLP-2 regulates chylomicron production is unclear, because its receptor is not expressed on enterocytes. We provide evidence for a key role of nitric oxide (NO) in mediating the stimulatory effects of GLP-2 during the postprandial and postabsorptive periods. Intestinal chylomicron production was assessed in GLP-2-treated hamsters administered the pan-specific NO synthase (NOS) inhibitor L-N(G)-nitroarginine methyl ester (L-NAME), and in GLP-2-treated Endothelial NOS knockout mice. L-NAME blocked GLP-2-stimulated apoB48 secretion and reduced triglycerides (TGs) in the TG-rich lipoprotein (TRL) fraction of the plasma in the postprandial state. Endothelial NOS-deficient mice were resistant to GLP-2 stimulation and secreted fewer large apoB48-particles. When TG storage pools were allowed to accumulate, L-NAME mitigated the GLP-2-mediated increase in TRL-TG, suggesting that NO is required for early mobilization and secretion of stored TG and preformed chylomicrons. Importantly, the NO donor S-nitroso-L-glutathione was able to elicit an increase in TRL-TG in vivo and stimulate chylomicron release in vitro in primary enterocytes. We describe a novel role for GLP-2-mediated NO-signaling as a critical regulator of intestinal lipid handling and a potential contributor to postprandial dyslipidemia.
Vivek Krishna Pulakazhi Venu - One of the best experts on this subject based on the ideXlab platform.
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heat shock protein 27 and sex selective regulation of muscarinic and proteinase activated receptor 2 mediated vasodilatation differential sensitivity to Endothelial NOS inhibition
British Journal of Pharmacology, 2018Co-Authors: Vivek Krishna Pulakazhi Venu, Mahmoud Saifeddine, Koichiro Mihara, Mahmoud Eldaly, Darrell D Elke, Jonatha L E Dea, Edward R Obrie, Simo A HirotaAbstract:BACKGROUND AND PURPOSE: Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human Endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-Endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature Endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on Endothelial NOS (eNOS)/NO-dependent relaxation induced by ACh and the coagulation pathway-activated receptor, proteinase-activated receptor 2 (PAR2). EXPERIMENTAL APPROACH: Aorta rings from male and female wild-type, HSPB1-null and HSPB1 overexpressing (HSPB1o/e) mice were contracted with phenylephrine, and NOS-dependent relaxation responses to ACh and PAR2 agonist, 2-furoyl-LIGRLO-NH2 , were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 and then used for bioassay as above. Furthermore, oestrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice. KEY RESULTS: Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation induced by activation of either PAR2 or muscarinic ACh receptors that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy did not affect NO sensitivity, supporting an oestrogen-independent role for HSPB1. CONCLUSIONS AND IMPLICATIONS: HSPB1 can regulate intact vascular Endothelial function to affect NO-mediated vascular relaxation, especially in females.
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heat shock protein 27 and sex selective regulation of muscarinic and proteinase activated receptor 2 mediated vasodilatation differential sensitivity to Endothelial NOS inhibition
British Journal of Pharmacology, 2018Co-Authors: Vivek Krishna Pulakazhi Venu, Mahmoud Saifeddine, Koichiro Mihara, Mahmoud Eldaly, Darrell D Belke, Jonathan L E Dean, Edward R Obrien, Simo A HirotaAbstract:Background and Purpose Previously, we demonstrated that exogenous Heat Shock Protein 27 (HSP27/gene, HSPB1) treatment of human Endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-Endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 could also affect mature Endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on eNOS/NO-dependent relaxation caused by acetylcholine and the coagulation pathway-activated receptor, proteinase-activated receptor-2 (PAR2). Experimental Approach/ResultsMethods Aorta rings from male and female wild-type, HSPB1-null, and HSPB1 over-expressing (HSPB1o/e) mice were contracted with phenylephrine (PE) and NOS-dependent relaxation responses to acetylcholine and a PAR2 agonist, 2-furoyl-LIGRLO-NH2 (2-fLI), were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 (rHSP27) and then used for bioassay as above. Furthermore, estrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice. Results Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation caused by activation either PAR2 or the muscarinic acetylcholine receptor, that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy didn’t affect NO-sensitivity, supporting an estrogen-independent role for HSPB1. Conclusion HSPB1 can regulate intact vascular Endothelial function to affect NO-mediated vascular relaxation, especially in females.
Joanne Hsieh - One of the best experts on this subject based on the ideXlab platform.
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glucagon like peptide 2 glp 2 stimulates postprandial chylomicron production and postabsorptive release of intestinal triglyceride storage pools via induction of nitric oxide signaling in male hamsters and mice
Endocrinology, 2015Co-Authors: Joanne Hsieh, Sarah Farr, Karin Trajcevski, Chris Baker, Elizabeth J Lake, Jennifer Taher, Jahangir Iqbal, Mahmood M Hussain, Khosrow AdeliAbstract:The intestinal overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles is a common feature of diabetic dyslipidemia and contributes to cardiovascular risk in insulin resistant states. We previously reported that glucagon-like peptide-2 (GLP-2) is a key endocrine stimulator of enterocyte fat absorption and chylomicron output in the postprandial state. GLP-2's stimulatory effect on chylomicron production in the postabsorptive state has been confirmed in human studies. The mechanism by which GLP-2 regulates chylomicron production is unclear, because its receptor is not expressed on enterocytes. We provide evidence for a key role of nitric oxide (NO) in mediating the stimulatory effects of GLP-2 during the postprandial and postabsorptive periods. Intestinal chylomicron production was assessed in GLP-2-treated hamsters administered the pan-specific NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (L-NAME), and in GLP-2-treated Endothelial NOS knockout mice. L-NAME blocked GLP-...
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glucagon like peptide 2 glp 2 stimulates postprandial chylomicron production and postabsorptive release of intestinal triglyceride storage pools via induction of nitric oxide signaling in male hamsters and mice
Endocrinology, 2015Co-Authors: Joanne Hsieh, Sarah Farr, Karin Trajcevski, Elizabeth J Lake, Jennifer Taher, Jahangir Iqbal, Mahmood M Hussain, Christopher Baker, Khosrow AdeliAbstract:The intestinal overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles is a common feature of diabetic dyslipidemia and contributes to cardiovascular risk in insulin resistant states. We previously reported that glucagon-like peptide-2 (GLP-2) is a key endocrine stimulator of enterocyte fat absorption and chylomicron output in the postprandial state. GLP-2's stimulatory effect on chylomicron production in the postabsorptive state has been confirmed in human studies. The mechanism by which GLP-2 regulates chylomicron production is unclear, because its receptor is not expressed on enterocytes. We provide evidence for a key role of nitric oxide (NO) in mediating the stimulatory effects of GLP-2 during the postprandial and postabsorptive periods. Intestinal chylomicron production was assessed in GLP-2-treated hamsters administered the pan-specific NO synthase (NOS) inhibitor L-N(G)-nitroarginine methyl ester (L-NAME), and in GLP-2-treated Endothelial NOS knockout mice. L-NAME blocked GLP-2-stimulated apoB48 secretion and reduced triglycerides (TGs) in the TG-rich lipoprotein (TRL) fraction of the plasma in the postprandial state. Endothelial NOS-deficient mice were resistant to GLP-2 stimulation and secreted fewer large apoB48-particles. When TG storage pools were allowed to accumulate, L-NAME mitigated the GLP-2-mediated increase in TRL-TG, suggesting that NO is required for early mobilization and secretion of stored TG and preformed chylomicrons. Importantly, the NO donor S-nitroso-L-glutathione was able to elicit an increase in TRL-TG in vivo and stimulate chylomicron release in vitro in primary enterocytes. We describe a novel role for GLP-2-mediated NO-signaling as a critical regulator of intestinal lipid handling and a potential contributor to postprandial dyslipidemia.
Kenneth D Bloch - One of the best experts on this subject based on the ideXlab platform.
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hypertension in mice lacking the gene for Endothelial nitric oxide synthase
Nature, 1995Co-Authors: Paul L Huang, Kenneth D Bloch, Zhihong Huang, Michael A Moskowitz, Hiroshi Mashimo, John A Bevan, Mark C FishmanAbstract:Nitric oxide (NO), a potent vasodilator produced by Endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in Endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of Endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-Endothelial isoforms of NOS may be involved in maintaining blood pressure.
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cloning and expression of a cdna encoding human endothelium derived relating factor nitric oxide synthase
Journal of Biological Chemistry, 1992Co-Authors: Stefan Janssens, A Simouchi, Thomas Quertermous, D Bloch, Kenneth D BlochAbstract:Abstract Nitric oxide, which accounts for the biological activity of endothelium-derived relaxing factor (EDRF), is synthesized in Endothelial cells from L-arginine by nitric oxide synthase (NOS). We report here the cloning and functional expression of a cDNA encoding human Endothelial NOS. Oligonucleotides corresponding to amino acid sequences shared by cytochrome P450 reductase and the recently identified brain NOS were synthesized to amplify a partial cDNA encoding a bovine Endothelial cell NOS-related protein. This partial cDNA was used to isolate a cDNA encoding a human vascular Endothelial NOS. The translated human protein is 1294 amino acids long and shares 52% of its amino acid sequence with brain NOS. Using RNA blot hybridization, abundant Endothelial NOS mRNA was detected in unstimulated human umbilical vein Endothelial cells. To determine the functional activity of the Endothelial protein, we ligated the cDNA into an expression vector and transfected it into NIH3T3 cells. Cells expressing this cDNA contained abundant NADPH diaphorase activity, a histochemical marker for NOS. In co-culture assays, nitric oxide production by transfected cells increased guanylate cyclase activity in reporter rat fetal lung fibroblasts. In addition, NOS-catalyzed conversion of arginine to citrulline in transfected cells was significantly increased by A23187, a calcium ionophore. Isolation of a cDNA encoding a calcium-regulated, constitutively expressed human Endothelial NOS, capable of producing EDRF in blood vessels, will accelerate the characterization of the role of this enzyme in normal and abnormal Endothelial regulation of vascular tone.
Simo A Hirota - One of the best experts on this subject based on the ideXlab platform.
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heat shock protein 27 and sex selective regulation of muscarinic and proteinase activated receptor 2 mediated vasodilatation differential sensitivity to Endothelial NOS inhibition
British Journal of Pharmacology, 2018Co-Authors: Vivek Krishna Pulakazhi Venu, Mahmoud Saifeddine, Koichiro Mihara, Mahmoud Eldaly, Darrell D Elke, Jonatha L E Dea, Edward R Obrie, Simo A HirotaAbstract:BACKGROUND AND PURPOSE: Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human Endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-Endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature Endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on Endothelial NOS (eNOS)/NO-dependent relaxation induced by ACh and the coagulation pathway-activated receptor, proteinase-activated receptor 2 (PAR2). EXPERIMENTAL APPROACH: Aorta rings from male and female wild-type, HSPB1-null and HSPB1 overexpressing (HSPB1o/e) mice were contracted with phenylephrine, and NOS-dependent relaxation responses to ACh and PAR2 agonist, 2-furoyl-LIGRLO-NH2 , were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 and then used for bioassay as above. Furthermore, oestrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice. KEY RESULTS: Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation induced by activation of either PAR2 or muscarinic ACh receptors that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy did not affect NO sensitivity, supporting an oestrogen-independent role for HSPB1. CONCLUSIONS AND IMPLICATIONS: HSPB1 can regulate intact vascular Endothelial function to affect NO-mediated vascular relaxation, especially in females.
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heat shock protein 27 and sex selective regulation of muscarinic and proteinase activated receptor 2 mediated vasodilatation differential sensitivity to Endothelial NOS inhibition
British Journal of Pharmacology, 2018Co-Authors: Vivek Krishna Pulakazhi Venu, Mahmoud Saifeddine, Koichiro Mihara, Mahmoud Eldaly, Darrell D Belke, Jonathan L E Dean, Edward R Obrien, Simo A HirotaAbstract:Background and Purpose Previously, we demonstrated that exogenous Heat Shock Protein 27 (HSP27/gene, HSPB1) treatment of human Endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-Endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 could also affect mature Endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on eNOS/NO-dependent relaxation caused by acetylcholine and the coagulation pathway-activated receptor, proteinase-activated receptor-2 (PAR2). Experimental Approach/ResultsMethods Aorta rings from male and female wild-type, HSPB1-null, and HSPB1 over-expressing (HSPB1o/e) mice were contracted with phenylephrine (PE) and NOS-dependent relaxation responses to acetylcholine and a PAR2 agonist, 2-furoyl-LIGRLO-NH2 (2-fLI), were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 (rHSP27) and then used for bioassay as above. Furthermore, estrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice. Results Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation caused by activation either PAR2 or the muscarinic acetylcholine receptor, that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy didn’t affect NO-sensitivity, supporting an estrogen-independent role for HSPB1. Conclusion HSPB1 can regulate intact vascular Endothelial function to affect NO-mediated vascular relaxation, especially in females.