scholarly journals Carbon Monoxide Regulates Macrophage Differentiation and Polarization toward the M2 Phenotype through Upregulation of Heme Oxygenase 1

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3444
Author(s):  
In-Soon Kang ◽  
Rang-Ie Kim ◽  
Chaekyun Kim
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Bone Marrow Cells ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Macrophage Differentiation ◽  
Murine Bone Marrow ◽  
Arginase 1 ◽  
M2 Phenotype

Carbon monoxide (CO) is generated by heme oxygenase (HO), and HO-1 is highly induced in monocytes and macrophages upon stimulation. Monocytes differentiate into macrophages, including pro-inflammatory (M1) and anti-inflammatory (M2) cells, in response to environmental signals. The present study investigated whether CO modulates macrophage differentiation and polarization, by applying the CO-releasing molecule-3 (CORM-3). Results showed that murine bone marrow cells are differentiated into macrophages by CORM-3 in the presence of macrophage colony-stimulating factor. CORM-3 increases expressions of macrophage markers, including F4/80 and CD11b, and alters the cell morphology into elongated spindle-shaped cells, which is a typical morphology of M2 cells. CORM-3 upregulates the expressions of genes and molecules involved in M2 polarization and M2 phenotype markers, such as STAT6, PPARγ, Ym1, Fizz1, arginase-1, and IL-10. However, exposure to CORM-3 inhibits the iNOS expression, suggesting that CO enhances macrophage differentiation and polarization toward M2. Increased HO-1 expression is observed in differentiated macrophages, and CORM-3 further increases this expression. Hemin, an HO-1 inducer, results in increased macrophage differentiation, whereas the HO-1 inhibitor zinc protoporphyrin IX inhibits differentiation. In addition, CORM-3 increases the proportion of macrophages in peritoneal exudate cells and enhances the expression of HO-1 and arginase-1 but inhibits iNOS. Taken together, these results suggest that the abundantly produced CO in activated macrophages enhances proliferation, differentiation, and polarization toward M2. It will probably help clear apoptotic cells, resolve inflammation, and promote wound healing and tissue remodeling.

Roles of Carbon Monoxide in Leukocyte and Platelet Dynamics in Rat Mesentery during Sevoflurane Anesthesia

2001 ◽  
Vol 95 (1) ◽  
pp. 192-199 ◽  
Author(s):  
Hiroshi Morisaki ◽  
Tomihiro Katayama ◽  
Yoshifumi Kotake ◽  
Masaharu Ito ◽  
Takuya Tamatani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Sevoflurane Anesthesia ◽  
Mechanically Ventilated ◽  
Rat Mesentery ◽  
Platelet Dynamics

Background Heme oxygenase 1 (HO-1), induced by a variety of stressors, provides endogenous carbon monoxide (CO) and bilirubin, both of which play consequential roles in organs. The current study aimed to examine whether induction of HO-1 and its by-products modulated endothelial interaction with circulating leukocytes and platelets evoked by sevoflurane anesthesia in vivo. Methods Rats, pretreated with or without hemin, were anesthetized with sevoflurane in 100% O2, and lungs were mechanically ventilated. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester and leukocyte behavior in mesenteric venules were visualized during sevoflurane anesthesia at 1,000 frames/s using intravital ultrahigh-speed intensified fluorescence videomicroscopy. To examine the mechanisms for the effects of HO-1 on leukocyte and platelet behavior, these studies were repeated with superfusion of either CO, bilirubin, or Nomega-nitro-L-arginine methyl ester (L-NAME). Results As reported previously, the elevation of sevoflurane concentration evoked adhesive responses of leukocytes, concurrent with platelet margination and rolling. Pretreatment with hemin, a HO-1 inducer, prevented such sevoflurane-elicited changes in the microvessels. These changes were restored by zinc protoporphyrin IX, a HO inhibitor, and repressed by CO but not by bilirubin. During sevoflurane anesthesia, however, nitric oxide suppression by L-NAME deteriorated microvascular flows irrespective of the presence or absence of the HO-1 induction. Conclusions These results indicate that endogenous CO via HO-1 induction attenuates sevoflurane-induced microvascular endothelial interactions with leukocytes and platelets, although local nitric oxide levels appear to dominate microvascular flow in situ.

Expression and function of heme oxygenase-1 in human gastric cancer

2012 ◽  
Vol 237 (4) ◽  
pp. 362-371 ◽  
Author(s):  
Yujing Yin ◽  
Qingjun Liu ◽  
Bo Wang ◽  
Gan Chen ◽  
Li Xu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Heme Oxygenase ◽  
Close Association ◽  
Protoporphyrin Ix ◽  
Clinicopathological Characteristics ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Human Gastric Cancer ◽  
Cobalt Protoporphyrin ◽  
And Function

Heme oxygenase-1 (HO-1) potently influences tumor growth and metastasis. To date, no study has been performed on HO-1 expression pattern and its clinicopathological significance in human gastric cancer (GC) cases. In this study, the expression of HO-1 in human GC tissues ( n = 74) and matched non-tumoral adjacent parenchyma ( n = 46) was investigated by immunohistochemistry. The correlation of HO-1 with the clinicopathological characteristics was analyzed. Results showed that HO-1 was expressed in 62 GC tissues from 74 cases (83.8%), which is significantly higher than non-tumoral adjacent parenchyma (20/46, 43.8%, P < 0.05). A high HO-1 expression rate showed a close association with well/moderate histological differentiation and negative lymph node metastasis ( P < 0.05). The expression of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor A (VEGF-A) as well as chemosensitivity to cisplatin of MKN-45 cell lines with genetically altered HO-1 status were then determined by realtime polymerase chain reaction and 3-(4,5 dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), respectively. Whether the induction or inhibition of HO-1 by cobalt-protoporphyrin-IX (CoPP) or zinc-protoporphyrin-IX (ZnPP) could affect the sensitivity of MKN-45 cells to cisplatin was also studied. Results showed that the expression of MMP9 and VEGF-A were up-regulated in MKN-45 cells overexpressing HO-1, and down-regulated in HO-1 interfered cells. HO-1 overexpression could lead to an increased resistance to cisplatin, whereas down-regulation of HO-1 expression by siRNA or chemical inhibition of HO-1 could lead to increased chemosensitivity to cisplatin in MKN-45 cells. HO-1 may have multiple effects on protection against carcinogenesis and progression in GC.

cAMP induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle

1997 ◽  
Vol 273 (1) ◽  
pp. H317-H323 ◽  
Author(s):  
W. Durante ◽  
N. Christodoulides ◽  
K. Cheng ◽  
K. J. Peyton ◽  
R. K. Sunahara ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Heme Oxygenase ◽  
Muscle Cells ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Intracellular Camp

Recent studies indicate that vascular smooth muscle cells generate carbon monoxide (CO) via the action of heme oxygenase (HO). Because adenosine 3',5'-cyclic monophosphate (cAMP) is an important intracellular signaling molecule in the regulation of vascular cell function, we examined whether this second messenger modulates the expression of HO and the production of CO by rat aortic smooth muscle cells. Treatment of smooth muscle cells with the membrane-permeable cAMP derivative dibutyryl cAMP or with compounds that increase intracellular cAMP levels (isoproterenol and forskolin) resulted in a concentration- and time-dependent increase in the levels of HO-1 mRNA and protein, whereas the expression of HO-2 remained unchanged. Both actinomycin D and cycloheximide blocked the basal expression of HO-1 mRNA and protein and prevented the cAMP-mediated induction of HO-1. Incubation of platelets with cAMP-treated smooth muscle cells resulted in a significant increase in platelet cGMP concentration that was partially reversed by treatment of smooth muscle cells with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine or the HO blocker zinc protoporphyrin-IX. However, the combined addition of these two inhibitors to cAMP-treated smooth muscle cells or the addition of the CO and NO scavenger hemoglobin to platelets completely blocked the stimulatory effect on platelet cGMP levels. These results demonstrate that cAMP induces the expression of the HO-1 gene and stimulates the formation of CO and NO in vascular smooth muscle cells. The capacity of cAMP to induce the synthesis of guanylate cyclase-stimulatory CO from smooth muscle cells may represent a novel mechanism by which this nucleotide regulates vascular tone.

Upregulation of heme oxygenase-1 potentiates EDH-type relaxations in the mesenteric artery of the spontaneously hypertensive rat

2013 ◽  
Vol 305 (10) ◽  
pp. H1471-H1483 ◽  
Author(s):  
Zhuoming Li ◽  
Yu Wang ◽  
Ricky Y. K. Man ◽  
Paul M. Vanhoutte
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Spontaneously Hypertensive Rat ◽  
Combined Treatment ◽  
Antioxidant Properties ◽  
Mesenteric Arteries ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Spontaneously Hypertensive

Heme oxygenase (HO) converts heme to carbon monoxide, bilirubin, and free iron. The present study investigated whether or not HO-1 induction improves vascular relaxations attributable to endothelium-dependent hyperpolarization (EDH). Thirty-six-week-old spontaneously hypertensive rats were treated with the HO-1 inducer hemin, the HO inhibitor zinc protoporphyrin IX (II) (ZnPP), the antioxidant apocynin, or combinations of these compounds. Isolated mesenteric arteries were prepared for measurement of isometric tension, protein presence, and production of reactive oxygen species (ROS). Hemin potentiated acetylcholine-evoked EDH-type relaxations in the presence of Nω-nitro-l-arginine methyl ester (l-NAME) and indomethacin, while the combined treatment with ZnPP plus hemin prevented these improvements. The intermediate conductance Ca2+-activated K+ channel (IKCa) blocker TRAM-34 and the Na+-K+-ATPase blocker ouabain significantly impaired these hemin-potentiated relaxations. NS309-induced TRAM-34- and ouabain-sensitive relaxations were enhanced by hemin. K+-induced ouabain-sensitive relaxations and the expression of Na+-K+-ATPase were increased by hemin. Thus HO-1 induction improves EDH-type relaxations by augmented activation of IKCa and the downstream Na+-K+-ATPase. Treatment with apocynin showed a similar effect as hemin in impairing ROS production, enhancing K+-induced relaxations, and increasing Na+-K+-ATPase expression, without affecting the expression of HO-1. The effects of hemin and apocynin were not additive. These observations suggest that the effect of HO-1 induction on EDH-type relaxations is possibly due to its antioxidant properties. In vitro treatment with bilirubin, but not carbon monoxide, enhanced EDH-type relaxations and K+-induced ouabain-sensitive relaxations, suggesting that the production of bilirubin may be also involved. The present findings reveal that HO-1 may be a potential vascular-specific therapeutic strategy for endothelial dysfunction in hypertension.

scholarly journals Terminalia Chebulanin Attenuates Psoriatic Skin Lesion via Regulation of Heme Oxygenase-1

2016 ◽  
Vol 39 (2) ◽  
pp. 531-543 ◽  
Author(s):  
Jingang An ◽  
Tian Li ◽  
Yingying Dong ◽  
Zhengxiao Li ◽  
Jia Huo
Keyword(s):  
Heme Oxygenase ◽  
Therapeutic Option ◽  
Protoporphyrin Ix ◽  
Psoriatic Skin ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Keratinocyte Proliferation ◽  
Factor Α ◽  
Psoriatic Lesions

Background/Aims: Psoriasis is one of the most common inflammatory skin disorders, affecting 3% of the general population. Terminalia chebulanin (TC) is a polyphenolic compound that possesses antioxidant and anti-inflammatory activities. The current study was designed to investigate the effect of TC on psoriatic lesions. Methods: We examined the protective effect of TC against psoriatic lesions in mice and keratinocyte proliferation in HaCaT cells. Results: We found that TC exhibited potent anti-psoriatic activities, as evidenced by improvement of erythema and scaling scores, decrease of epidermal, ear and skinfold thickening, decrease of tumor necrosis factor α (TNFα), interleukin (IL)-17A, IL-23 and matrix metalloproteinase (MMP)-9 expression, and decrease of TBARS content and increase of GSH content in IMQ-treated mice, and decrease of keratinocyte proliferation, TNFα, IL-17A and IL-23 expression, and ROS level in M5-treated cells. All those effects induced by TC were inhibited by zinc protoporphyrin IX (ZnPP), an inhibitor of heme oxygenase (HO)-1, indicating that HO-1 was responsible the anti-psoriatic effect of TC. Moreover, TC inhibited the upregulation of p65 NF-κB under in vitro psoriatic condition. ZnPP suppressed TC-induced inhibition of p65 NF-κB expression. Overexpression of p65 NF-κB significantly suppressed TC-induced decrease of TNFα, IL-17A and IL-23 expression and keratinocyte proliferation, indicating that HO-1-mediated downregulation of NF-κB was involved in the anti-psoriatic effect of TC. Conclusions: The data demonstrate that TC may serve as a potential therapeutic option for psoriatic patients.

scholarly journals Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice

2006 ◽  
Vol 120 (3) ◽  
pp. 500-505 ◽  
Author(s):  
Kaeko Hirai ◽  
Tomonori Sasahira ◽  
Hitoshi Ohmori ◽  
Kiyomu Fujii ◽  
Hiroki Kuniyasu
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Heme Oxygenase ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
C57bl Mice

scholarly journals Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Simon C. M. Kwok
Keyword(s):  
Stress Response ◽  
Protein Kinase ◽  
Heme Oxygenase ◽  
Kinase Inhibitors ◽  
Protoporphyrin Ix ◽  
Competitive Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Transcriptional Level

Zinc protoporphyrin IX (ZnPP), a naturally occurring molecule formed in iron deficiency or lead poisoning, is a potent competitive inhibitor of heme oxygenase-1 (HO-1). It also regulates expression of HO-1 at the transcriptional level. However, the effect of ZnPP on HO-1 expression is controversial. It was shown to induce HO-1 expression in some cells, but suppress it in others. The objective of this study is to investigate the effect of ZnPP on HO-1 expression in prostate cancer PC-3 cells. Incubation of PC-3 cells with 10 μM ZnPP for 4 h showed only a slight induction of HO-1 mRNA and protein, but the induction was high after 16 h and was maintained through 48 h of incubation. Of all the known responsive elements in the HO-1 promoter, ZnPP activated mainly the stress response elements. Of the various protein kinase inhibitors and antioxidant tested, only Ro 31-8220 abrogated ZnPP-induced HO-1 expression, suggesting that activation of HO-1 gene by ZnPP may involve protein kinase C (PKC). The involvement of PKCα,β,δ,η,θ, andζisoforms was ruled out by the use of specific inhibitors. The isoform of PKC involved and participation of other transcription factors remain to be studied.

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