Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth

Reactive oxygen species (ROS) are implicated in coronary collateral growth (CCG). We evaluated the requirement for ROS in human coronary artery endothelial cell (HCAEC) tube formation, CCG in vivo, and signaling (p38 MAP kinase) by which ROS may stimulate vascular growth. The flavin-containing oxidase inhibitor diphenyleneiodonium (DPI) or the superoxide dismutase inhibitor diethyldithiocarbamate (DETC) blocked vascular endothelial growth factor-induced HCAEC tube formation in Matrigel. We assessed the effect of DPI and DETC on CCG in a rat model of repetitive ischemia (RI) (40 s left anterior descending coronary artery occlusion every 20 min for 2 h 20 min, 3 times/day, 10 days). DPI or DETC was given intraperitoneally, or the NAD(P)H oxidase inhibitor apocynin was given in drinking water. Collateral-dependent flow (measured by using microspheres) was expressed as a ratio of normal and ischemic zone flows. In sham-operated rats, collateral flow in the ischemic zone was 18 ± 6% of normal zone; in the RI group, collateral flow in the ischemic zone was 83 ± 5% of normal zone. DPI prevented the increase in collateral flow after RI (25 ± 4% of normal zone). Similar results were obtained with apocynin following RI (32 ± 7% of that in the normal zone). DETC achieved similar results (collateral flow after RI was 21 ± 2% of normal zone). DPI and DETC blocked RI-induced p38 MAP kinase activation in response to vascular endothelial growth factor and RI. These results demonstrate a requirement for optimal ROS concentration in HCAEC tube formation, CCG, and p38 MAP kinase activation. p38 MAP kinase inhibition prevented HCAEC tube formation and partially blocked RI-induced CCG (42 ± 7% of normal zone flow), indicating that p38 MAP kinase is a critical signaling mediator of CCG.

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p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts

Journal of Endocrinology ◽

10.1677/joe.0.1700629 ◽

2001 ◽

Vol 170 (3) ◽

pp. 629-638 ◽

Cited By ~ 16

Author(s):

H Tokuda ◽

O Kozawa ◽

M Miwa ◽

T Uematsu

Keyword(s):

Map Kinase ◽

Cholera Toxin ◽

Prostaglandin E1 ◽

Specific Inhibitor ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Kinase Activation ◽

Protein Map ◽

Mitogen Activated Protein ◽

Endothelial Growth Factor

We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.

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HSP22 (HSPB8) positively regulates PGF2α-induced synthesis of interleukin-6 and vascular endothelial growth factor in osteoblasts

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02209-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Gen Kuroyanagi ◽

Go Sakai ◽

Takanobu Otsuka ◽

Naohiro Yamamoto ◽

Kazuhiko Fujita ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Map Kinase ◽

Interleukin 6 ◽

Prostaglandin F2α ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Mitogen Activated Protein ◽

Endothelial Growth Factor ◽

Vegf Release

Abstract Background Heat shock protein 22 (HSP22) belongs to class I of the small HSP family that displays ubiquitous expression in osteoblasts. We previously demonstrated that prostaglandin F2α (PGF2α), a potent bone remodeling factor, induces the synthesis of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether HSP22 is implicated in the PGF2α-induced synthesis of IL-6 and VEGF and the mechanism of MC3T3-E1 cells. Methods MC3T3-E1 cells were transfected with HSP22-siRNA. IL-6 and VEGF release was assessed by ELISA. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was detected by Western blotting. Results The PGF2α-induced release of IL-6 in HSP22 knockdown cells was significantly suppressed compared with that in the control cells. HSP22 knockdown also reduced the VEGF release by PGF2α. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was attenuated by HSP22 downregulation. Conclusions Our results strongly suggest that HSP22 acts as a positive regulator in the PGF2α-induced synthesis of IL-6 and VEGF in osteoblasts.

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p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells

Oncogene ◽

10.1038/sj.onc.1201380 ◽

1997 ◽

Vol 15 (18) ◽

pp. 2169-2177 ◽

Cited By ~ 598

Author(s):

Simon Rousseau ◽

François Houle ◽

Jacques Landry ◽

Jacques Huot

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Cell Migration ◽

Growth Factor ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Human Endothelial Cells ◽

Actin Reorganization ◽

Kinase Activation ◽

Endothelial Growth Factor

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Involvement of SAPK/JNK in basic fibroblast growth factor-induced vascular endothelial growth factor release in osteoblasts

Journal of Endocrinology ◽

10.1677/joe.0.1770101 ◽

2003 ◽

Vol 177 (1) ◽

pp. 101-107 ◽

Cited By ~ 41

Author(s):

H Tokuda ◽

K Hirade ◽

X Wang ◽

Y Oiso ◽

O Kozawa

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Map Kinase ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Fibroblast Growth ◽

Endothelial Growth Factor ◽

Vegf Release

We previously reported that basic fibroblast growth factor (FGF-2) activates p44/p42 mitogen-activated protein (MAP) kinase resulting in the stimulation of vascular endothelial growth factor (VEGF) release in osteoblast-like MC3T3-E1 cells and that FGF-2-activated p38 MAP kinase negatively regulates VEGF release. In the present study, we investigated the involvement of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in FGF-2-induced VEGF release in these cells. FGF-2 markedly induced the phosphorylation of SAPK/JNK. SP600125, an inhibitor of SAPK/JNK, markedly reduced the FGF-2-induced VEGF release. SP600125 suppressed the FGF-2-induced phosphorylation of SAPK/JNK without affecting the phosphorylation of p44/p42 MAP kinase or p38 MAP kinase induced by FGF-2. PD98059, an inhibitor of upstream kinase of p44/p42 MAP kinase, or SB203580, an inhibitor of p38 MAP kinase, failed to affect the FGF-2-induced phosphorylation of SAPK/JNK. A combination of SP600125 and SB203580 suppressed the FGF-2-stimulated VEGF release in an additive manner. These results strongly suggest that FGF-2 activates SAPK/JNK in osteoblasts, and that SAPK/JNK plays a part in FGF-2-induced VEGF release.

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HSP22 (HSPB8) positively regulates PGF2α-induced synthesis of interleukin-6 and vascular endothelial growth factor in osteoblasts

10.21203/rs.3.rs-32089/v2 ◽

2020 ◽

Author(s):

Gen Kuroyanagi ◽

Go Sakai ◽

Takanobu Otsuka ◽

Naohiro Yamamoto ◽

Kazuhiko Fujita ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Map Kinase ◽

Interleukin 6 ◽

Prostaglandin F2α ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Mitogen Activated Protein ◽

Endothelial Growth Factor ◽

Vegf Release

Abstract Background: Heat shock protein 22 (HSP22) belongs to class I of the small HSP family that displays ubiquitously expression including in osteoblasts. We previously demonstrated that prostaglandin F2α (PGF2α), a potent bone remodeling factor, induces the synthesis of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether HSP22 is implicated in the PGF2α-induced synthesis of IL-6 and VEGF, and the mechanism in MC3T3-E1 cells. Methods: MC3T3-E1 cells were transfected with HSP22-siRNA. IL-6 and VEGF release was assessed by ELISA. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was detected by Western blotting. Results: The PGF2α-induced release of IL-6 in HSP22 knockdown cells was significantly suppressed compared with that in the control cells. HSP22 knockdown also reduced the VEGF release by PGF2α. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was attenuated by HSP22 down-regulation. Conclusions: Our results strongly suggest that HSP22 acts as a positive regulator in the PGF2α-induced synthesis of IL-6 and VEGF in osteoblasts.

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Regulation by intracellular glutathione of TNF-α-induced p38 MAP kinase activation and RANTES production by human pulmonary vascular endothelial cells

Allergy ◽

10.1034/j.1398-9995.2000.00455.x ◽

2000 ◽

Vol 55 (5) ◽

pp. 463-468 ◽

Cited By ~ 9

Author(s):

S. Hashimoto ◽

Y. Gon ◽

K. Matsumoto ◽

I. Takeshita ◽

Y. Asai ◽

...

Keyword(s):

Endothelial Cells ◽

Map Kinase ◽

Vascular Endothelial Cells ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Kinase Activation ◽

Tnf Α ◽

Intracellular Glutathione ◽

Rantes Production

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HSP22 (HSPB8) positively regulates PGF2α-induced synthesis of interleukin-6 and vascular endothelial growth factor in osteoblasts

10.21203/rs.3.rs-32089/v1 ◽

2020 ◽

Author(s):

Gen Kuroyanagi ◽

Go Sakai ◽

Takanobu Otsuka ◽

Naohiro Yamamoto ◽

Kazuhiko Fujita ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Map Kinase ◽

Interleukin 6 ◽

Prostaglandin F2α ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Mitogen Activated Protein ◽

Endothelial Growth Factor ◽

Vegf Release

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Expression of Vascular Endothelial Growth Factor in Human Monocyte/Macrophages Stimulated with Lipopolysaccharide

Thrombosis and Haemostasis ◽

10.1055/s-0037-1612921 ◽

2001 ◽

Vol 85 (01) ◽

pp. 171-176 ◽

Cited By ~ 48

Author(s):

Hiroyuki Itaya ◽

Hidemi Yoshida ◽

Masayuki Koyama ◽

Sohei Suzuki ◽

Kei Satoh ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Map Kinase ◽

Human Monocyte ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Vegf Expression ◽

Vegf Mrna ◽

Endothelial Growth Factor

SummaryVascular endothelial growth factor (VEGF) is a mitogen for endothelial cells. We have studied the production of VEGF by human macrophages in response to lipopolysaccharide (LPS). Macrophages stimulated with LPS expressed VEGF mRNA and protein in concentration- and time-dependent manners. The LPS-induced expression of VEGF was inhibited by cycloheximide pretreatment, which suggested that synthesis of certain factor(s) is required for the LPS activity. The induction of VEGF was also suppressed by SB203580, an inhibitor of p38 mitogen-activated protein (MAP) kinase. These results suggest that the LPS-induced VEGF expression depends on the p38-mediated expression of c-Jun, which constitutes the AP-1 complex and binds to the AP-1 site in the VEGF promoter. Pretreatment of the cells with dexamethasone did not affect the LPS-induced upregulation of VEGF mRNA but strongly inhibited VEGF protein production, and the involvement of posttranscriptional regulation on VEGF expression by dexamethasone was suggested. The conditioned medium of LPS-stimulated macrophages enhanced the growth of cultured endothelial cells and it was inhibited by an antibody against VEGF. We conclude that macrophages produce VEGF in response to the stimulation with LPS, which may be partly mediated by the p38 MAP kinase pathway.

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