Occurrence and putative hormone regulatory function of a constitutive heme oxygenase in rat pancreatic islets

1997 ◽  
Vol 273 (2) ◽  
pp. C703-C709 ◽  
Author(s):  
R. Henningsson ◽  
P. Alm ◽  
I. Lundquist
Keyword(s):  
Enzymatic Activity ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Heme Oxygenase ◽  
High Glucose ◽  
Protoporphyrin Ix ◽  
Regulatory Function ◽  
Glucagon Release ◽  
Hormone Release ◽  
Islet Hormone

Recent observations suggest that carbon monoxide (CO) may serve as a neuroendocrine modulator in hypothalamus. Here we provide evidence, for the first time, that the islets of Langerhans contain the constitutive isoform of the CO-producing enzyme heme oxygenase (HO-2), the activity of which was found to modulate islet hormone release. Most insulin and glucagon cells in the rat endocrine pancreas expressed strong immunoreactivity for HO-2. In the exocrine parenchyma, scattered HO-2-positive ganglionic cell bodies were occasionally observed. Furthermore, Western blot analysis revealed the presence of HO-2 in isolated islets but not in acinar cells. Islet homogenates displayed a comparatively high HO-2 enzymatic activity measured as CO formation (approximately 600 pmol CO.min-1.mg islet protein-1). This HO-2 enzymatic activity was greatly suppressed by zincprotoporphyrin-IX (ZnPP-IX), a recognized inhibitor of HO activity. Neither ZnPP-IX nor the HO activator, hemin, influenced basal insulin release from isolated rat islets at low (1 mM) glucose. However, glucagon release at 1 mM glucose was increased by hemin and inhibited by ZnPP-IX. The hemin-induced increase in glucagon secretion was abolished by ZnPP-IX. Furthermore, a series of experiments at high glucose (16.7 mM) revealed that hemin induced a dose-dependent potentiation of glucose-stimulated insulin release. Moreover, glucose-induced insulin release was dose-dependently suppressed by ZnPP-IX but unaffected by protoporphyrin-IX, a compound known not to influence HO-2 activity in other tissues. Similarly, glucagon release at high glucose was dose-dependently increased by hemin and suppressed by ZnPP-IX. Finally, the hemin-induced increase in islet hormone release at high glucose was totally abolished by ZnPP-IX. The data strongly suggest that CO production positively modulates both glucagon and insulin secretion. We propose that CO may serve as a novel messenger molecule within the islets of Langerhans.

Evidence for Nitric Oxide Mediated Effects on Islet Hormone Secretory Phospholipase C Signal Transduction Mechanisms

1998 ◽  
Vol 18 (4) ◽  
pp. 199-213 ◽  
Author(s):  
Björn Åkesson ◽  
Ingmar Lundquist
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Release ◽  
Glucagon Release ◽  
Hormone Release ◽  
Kinase C ◽  
Islet Hormone ◽  
Messenger System ◽  
Nos Inhibitor

We have investigated the putative role of nitric oxide (NO) as a modular of islet hormone release, when stimulated by the muscarinic receptor agonist–phospholipase C activator, carbachol, with special regard to whether the IP3-Ca2+ or the diacylglycerol-protein kinase C messenger systems might be involved. It was observed that the NO synthase (NOS) inhibitor NG-nitro-L-arginine methylester (L-NAME) markedly potentiated insulin release and modestly inhibited glucagon release induced by carbachol. Similarly, insulin release induced by the phorbol ester TPA (protein kinase C activator) was markedly potentiated. Glucagon release, however, was unaffected. Dynamic perifusion experiments with 45C2+-loaded islets revealed that the inhibitory action of L-NAME on carbachol-stimulated NO-production was reflected in a rapid and sustained increase in insulin secretion above carbachol controls, whereas the 45Ca2+-efflux pattern was similar in both groups with the exception of a slight elevation of 45C2+ in the L-NAME-carbachol group during the latter part of the perifusion. No difference in either insulin release or 45Ca2+-efflux pattern between the carbachol group and L-NAME-carbachol group was seen in another series of experiments with identical design but performed in the absence of extracellular Ca2+. However, it should be noted that in the absence of extracellular Ca2+ both 45Ca2+-efflux and, especially, insulin release were greatly reduced in comparison with experiments in normal Ca2+. Further, in the presence of diazoxide, a potent K+ATP-channel opener, plus a depolarizing concentration of K+ the NOS-inhibitor L-NAME still markedly potentiated carbachol-induced insulin release and inhibited glucagon release. The enantiomer D-NAME, which is devoid of NOS-inhibitory properties, did not affect carbachol-induced hormone release. TPA-induced hormone release in depolarized islets was not affected by either L-NAME or D-NAME. The pharmacological intracellular NO donor hydroxylamine dose-dependently inhibited insulin release stimulated by TPA. Furthermore, a series of perifusion experiments revealed that hydroxylamine greatly inhibited carbachol-induced insulin release without affecting the 45Ca2+-efflux pattern. In summary, our results suggest that the inhibitory effect of NO on carbachol-induced insulin release is not to any significant extent exerted on the IP3-Ca2+ messenger system but rather through S-nitrosylation of critical thiol-residues in protein kinase C and/or other secretion-regulatory thiol groups. In contrast, the stimulating action of NO on carbachol-induced glucagon release was, at least partially, connected to the IP3-Ca2+ messenger system. The main effects of NO on both insulin and glucagon release induced by carbachol were apparently exerted independently of membrane depolarization events.

scholarly journals Bilin-dependent regulation of chlorophyll biosynthesis by GUN4

2021 ◽  
Vol 118 (20) ◽  
pp. e2104443118
Author(s):  
Weiqing Zhang ◽  
Robert D. Willows ◽  
Rui Deng ◽  
Zheng Li ◽  
Mengqi Li ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Heme Oxygenase ◽  
Chlorophyll Biosynthesis ◽  
Protoporphyrin Ix ◽  
Common Trunk ◽  
Magnesium Chelatase ◽  
Photosynthetic Eukaryotes ◽  
Linear Tetrapyrroles ◽  
Oxygenic Phototrophs ◽  
Binding Component

Biosyntheses of chlorophyll and heme in oxygenic phototrophs share a common trunk pathway that diverges with insertion of magnesium or iron into the last common intermediate, protoporphyrin IX. Since both tetrapyrroles are pro-oxidants, it is essential that their metabolism is tightly regulated. Here, we establish that heme-derived linear tetrapyrroles (bilins) function to stimulate the enzymatic activity of magnesium chelatase (MgCh) via their interaction with GENOMES UNCOUPLED 4 (GUN4) in the model green alga Chlamydomonas reinhardtii. A key tetrapyrrole-binding component of MgCh found in all oxygenic photosynthetic species, CrGUN4, also stabilizes the bilin-dependent accumulation of protoporphyrin IX-binding CrCHLH1 subunit of MgCh in light-grown C. reinhardtii cells by preventing its photooxidative inactivation. Exogenous application of biliverdin IXα reverses the loss of CrCHLH1 in the bilin-deficient heme oxygenase (hmox1) mutant, but not in the gun4 mutant. We propose that these dual regulatory roles of GUN4:bilin complexes are responsible for the retention of bilin biosynthesis in all photosynthetic eukaryotes, which sustains chlorophyll biosynthesis in an illuminated oxic environment.

scholarly journals A Protective Role for Heme Oxygenase Expression in Pancreatic Islets Exposed to Interleukin-1β**This work was supported by NIH Grant DK-25705 (to S.G.L.).

Endocrinology ◽  
1998 ◽  
Vol 139 (10) ◽  
pp. 4155-4163 ◽  
Author(s):  
Jing Ye ◽  
Suzanne G. Laychock
Keyword(s):  
Nitric Oxide ◽  
Protective Effect ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Heme Oxygenase ◽  
Protoporphyrin Ix ◽  
Interleukin 1Β ◽  
Zinc Protoporphyrin ◽  
Inhibitory Effects ◽  
Isolated Pancreatic Islets

Abstract Heme oxygenase (HO)-1 expression was investigated in rat isolated pancreatic islets. Freshly isolated islets showed no evidence of HO-1 expression. After a 20-h culture, there was a small increase in HO-1 in control islets, and interleukin-1β (IL-1β) induced HO-1 expression above control levels. NG-monomethyl-l-arginine inhibited the IL-1β-induced increase in HO-1. Sodium nitroprusside-generated nitric oxide also increased HO-1 expression. CoCl2 induced a concentration- and time-dependent increase in HO-1, but not heat shock protein 70, expression. Cobalt chloride (CoCl2) protected islets from the inhibitory effects of IL-1β on glucose-stimulated insulin release and glucose oxidation. Nickel chloride did not mimic the effects of CoCl2. An inhibitor of HO-1 activity, zinc-protoporphyrin IX (ZnPP), prevented the protective effect of CoCl2 on insulin release with IL-1β but did not affect HO-1 expression or the inhibitory response to IL-1β alone. ZnPP also inhibited the protective effect of hemin in IL-1β-treated islets. CoCl2 inhibited the marked increase in islet nitrite production in response to IL-1β. Cobalt-protoporphyrin IX (CoPP), which increased HO expression and activity, also protected islets from the inhibitory effects of IL-1β, even though IL-1β largely blocked the CoPP-induced increase in HO-1 expression. In βHC9 cells, CoCl2 increased HO-1 expression and HO activity, whereas CoPP directly activated HO. ZnPP inhibited basal and CoCl2-stimulated HO activity. Thus, increased HO-1 expression and/or HO activity in response to CoCl2, CoPP, and hemin, seems to mediate protective responses of pancreatic islets against IL-1β. HO-1 may be protective of β-cells because of the scavenging of free heme, the antioxidant effects of the end-product bilirubin, or the generation of carbon monoxide, which might have insulin secretion-promoting effects and inhibitory effects on nitric oxide synthase.

Effects of flavonoids on insulin secretion and 45Ca2+ handling in rat islets of Langerhans

1985 ◽  
Vol 107 (1) ◽  
pp. 1-8 ◽  
Author(s):  
C.S.T. Hii ◽  
S.L. Howell
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Hormone Release ◽  
Short Term ◽  
Rat Islets ◽  
Naturally Occurring ◽  
Isolated Rat Islets ◽  
Rat Islets Of Langerhans ◽  
Isolated Rat

ABSTRACT The effects of some flavonoids, a group of naturally occurring pigments one of which has been claimed to possess antidiabetic activities, on insulin release and 45Ca2+ handling have been studied in isolated rat islets of Langerhans. Insulin release was enhanced by approximately 44–70% when islets were exposed to either (−)epicatechin (0·8 mmol/l) or quercetin (0·01–0·1 mmol/l); others such as naringenin (0·1 mmol/l) and chrysin (0·08 mmol/l) inhibited hormone release by approximately 40–60%. These effects were observed only in the presence of 20 mmol glucose/l. Quercetin (0·01 mmol/l) and (−)epicatechin (0·8 mmol/l) both inhibited 45Ca2+ efflux in the presence and absence of extracellular Ca2+. In the presence of 20 mmol glucose/l both the short-term (5 min) and steady-state (30 min) uptake of 45Ca2+ were significantly increased by either quercetin or (−)epicatechin. These results suggest that the stimulatory compounds such as quercetin and (−)epicatechin may, at least in part, exert their effects on insulin release via changes in Ca2+ metabolism. J. Endocr. (1985) 107, 1–8

Islet constitutive nitric oxide synthase: biochemical determination and regulatory function

1996 ◽  
Vol 270 (6) ◽  
pp. C1634-C1641 ◽  
Author(s):  
A. Salehi ◽  
M. Carlberg ◽  
R. Henningson ◽  
I. Lundquist
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Insulin Release ◽  
Glucagon Secretion ◽  
Isolated Islets ◽  
Regulatory Function ◽  
No Production ◽  
Glucagon Release ◽  
Constitutive Nitric Oxide Synthase ◽  
Oxide Synthase

Recent immunohistochemical findings suggested that a constitutive nitric oxide synthase (cNOS) resides in endocrine pancreas. Here we provide direct biochemical evidence for the presence of cNOS activity in isolated islets. The regulating influence of this nitric oxide synthase (NOS) activity for islet hormone release was also investigated. We observed that cNOS activity could be quantitated in islet homogenates by monitoring the formation of L-citrulline from L-arginine using an Amprep CBA cation-exhange minicolumn before derivatization with o-phthaldialdehyde and subsequent high-performance liquid chromatography analysis. The islet NOS was dependent on both Ca2+ and calmodulin and suppressed by the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). This effect was enantiomerically specific. Islet insulin release induced by a mixture of L-arginine and glucose was enhanced by L-NAME, whereas L-arginine-induced glucagon release was inhibited. The effect of L-NAME on insulin release was dose dependently potentiated by increasing glucose concentrations, suggesting that glucose is an important regulator of islet NO production. Complementary in vivo studies showed similar results, i.e., the insulin secretory response to a mixture of glucose and L-arginine was extremely enhanced by pretreatment with L-NAME, whereas L-arginine-stimulated glucagon response was suppressed. Finally, in isolated islets, the intracellular nitric oxide (NO) donor hydroxylamine suppressed insulin release and increased glucagon release. In summary, the islets of Langerhans contain a constitutive, Ca2+/calmodulin-dependent isoform of NOS. Islet NO suppressed insulin but enhanced glucagon secretion. The data also suggest a negative feedback by NO on glucose-induced insulin release. The islet NO system is a novel and important regulatory factor in insulin and glucagon secretion.

Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release

2000 ◽  
Vol 279 (1) ◽  
pp. E95-E107 ◽  
Author(s):  
Ragnar Henningsson ◽  
Per Alm ◽  
Erik Lindström ◽  
Ingmar Lundquist
Keyword(s):  
Insulin Release ◽  
Hormone Secretion ◽  
No Synthase ◽  
No Production ◽  
Hormone Release ◽  
Compensatory Mechanisms ◽  
Nos Inhibitors ◽  
Islet Hormone

Islet production of nitric oxide (NO) and CO in relation to islet hormone secretion was investigated in mice given the NO synthase (NOS) inhibitor N G-nitro-l-arginine methyl ester (l-NAME) in their drinking water. In these mice, the total islet NO production was paradoxically increased, reflecting induction of inducible NOS (iNOS) in background of reduced activity and immunoreactivity of constitutive NOS (cNOS). Unexpectedly, normal mice fasted for 24 h also displayed iNOS activity, which was further increased in l-NAME-drinking mice. Glucose-stimulated insulin secretion in vitro and in vivo was increased in fasted but unaffected in fed mice after l-NAME drinking. Glucagon secretion was increased in vitro. Control islets incubated with different NOS inhibitors at 20 mM glucose displayed increased insulin release and decreased cNOS activity. These NOS inhibitors potentiated glucose-stimulated insulin release also from islets ofl-NAME-drinking mice. In contrast, glucagon release was suppressed. In islets from l-NAME-drinking mice, cyclic nucleotides were upregulated, and forskolin-stimulated hormone release, CO production, and heme oxygenase (HO)-2 expression increased. In conclusion, chronic NOS blockade evoked iNOS-derived NO production in pancreatic islets and elicited compensatory mechanisms against the inhibitory action of NO on glucose-stimulated insulin release by inducing upregulation of the islet cAMP and HO-CO systems.

scholarly journals Red Yeast Rice Protects Circulating Bone Marrow-Derived Proangiogenic Cells against High-Glucose-Induced Senescence and Oxidative Stress: The Role of Heme Oxygenase-1

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Jung-Tung Liu ◽  
Huey-Yi Chen ◽  
Wen-Chi Chen ◽  
Kee-Ming Man ◽  
Yung-Hsiang Chen
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Heme Oxygenase ◽  
High Glucose ◽  
Protoporphyrin Ix ◽  
Vascular Complications ◽  
Heme Oxygenase 1 ◽  
Red Yeast Rice ◽  
And Oxidative Stress

The inflammation and oxidative stress of bone marrow-derived proangiogenic cells (PACs), also named endothelial progenitor cells, triggered by hyperglycemia contributes significantly to vascular dysfunction. There is supporting evidence that the consumption of red yeast rice (RYR; Monascus purpureus-fermented rice) reduces the vascular complications of diabetes; however, the underlying mechanism remains unclear. This study aimed to elucidate the effects of RYR extract in PACs, focusing particularly on the role of a potent antioxidative enzyme, heme oxygenase-1 (HO-1). We found that treatment with RYR extract induced nuclear factor erythroid-2-related factor nuclear translocation and HO-1 mRNA and protein levels in PACs. RYR extract inhibited high-glucose-induced (30 mM) PAC senescence and the development of reactive oxygen species (ROS) in a dose-dependent manner. The HO-1 inducer cobalt protoporphyrin IX also decreased high-glucose-induced cell senescence and oxidative stress, whereas the HO-1 enzyme inhibitor zinc protoporphyrin IX and HO-1 small interfering RNA significantly reversed RYR extract-caused inhibition of senescence and reduction of oxidative stress in high-glucose-treated PACs. These results suggest that RYR extract serves as alternative and complementary medicine in the treatment of these diseases, by inducing HO-1, thereby decreasing the vascular complications of diabetes.

scholarly journals Nitric oxide inhibits, and carbon monoxide activates, islet acid α-glucoside hydrolase activities in parallel with glucose-stimulated insulin secretion

2006 ◽  
Vol 190 (3) ◽  
pp. 681-693 ◽  
Author(s):  
Henrik Mosén ◽  
Albert Salehi ◽  
Ragnar Henningsson ◽  
Ingmar Lundquist
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Insulin Secretion ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Direct Effect ◽  
Appreciable Effect ◽  
Intact Mouse ◽  
Glucose Stimulated Insulin Secretion ◽  
Glucoside Hydrolases

We have studied the influence of nitric oxide (NO) and carbon monoxide (CO), putative messenger molecules in the brain as well as in the islets of Langerhans, on glucose-stimulated insulin secretion and on the activities of the acid α-glucoside hydrolases, enzymes which we previously have shown to be implicated in the insulin release process. We have shown here that exogenous NO gas inhibits, while CO gas amplifies glucose-stimulated insulin secretion in intact mouse islets concomitant with a marked inhibition (NO) and a marked activation (CO) of the activities of the lysosomal/vacuolar enzymes acid glucan-1,4-α-glucosidase and acid α-glucosidase (acid α-glucoside hydrolases). Furthermore, CO dose-dependently potentiated glucose-stimulated insulin secretion in the range 0.1–1000 μM. In intact islets, the heme oxygenase substrate hemin markedly amplified glucose-stimulated insulin release, an effect which was accompanied by an increased activity of the acid α-glucoside hydrolases. These effects were partially suppressed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. Hemin also inhibited inducible NO synthase (iNOS)-derived NO production probably through a direct effect of CO on the NOS enzyme. Further, exogenous CO raised the content of both cGMP and cAMP in parallel with a marked amplification of glucose-stimulated insulin release, while exogenous NO suppressed insulin release and cAMP, leaving cGMP unaffected. Emiglitate, a selective inhibitor of α-glucoside hydrolase activities, was able to markedly inhibit the stimulatory effect of exogenous CO on both glucose-stimulated insulin secretion and the activityof acid glucan-1,4-α-glucosidase and acid α-glucosidase, while no appreciable effect on the activities of other lysosomal enzyme activities measured was found. We propose that CO and NO, both produced in significant quantities in the islets of Langerhans, have interacting regulatory roles on glucose-stimulated insulin secretion. This regulation is, at least in part, transduced through the activity of cGMP and the lysosomal/vacuolar system and the associated acid α-glucoside hydrolases, but probably also through a direct effect on the cAMP system.

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