scholarly journals Upregulation of Plasminogen Activator Inhibitor-1 in Irradiated Recipient Arteries and Veins from Free Tissue Transfer Reconstruction in Cancer Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Bjorn O. Eriksson ◽  
Caroline Gahm ◽  
Martin Halle
Keyword(s):  
Gene Expression ◽  
Vascular Disease ◽  
Free Tissue Transfer ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Unirradiated Control ◽  
Human Arteries ◽  
Arteries And Veins ◽  
Activator Inhibitor ◽  
Pai 1

Background. Clinical studies have shown that radiotherapy can induce vascular disease at the site of exposure but is usually not clinically evident until years after treatment. We have studied irradiated human arteries and veins to better understand the underlying biology in search of future treatments. The aim was to investigate whether radiotherapy contributed to a sustained expression of plasminogen activator inhibitor-1 (PAI-1) in human arteries and veins. Methods. Irradiated arteries and veins were harvested, together with unirradiated control vessels, from patients undergoing free tissue transfer reconstruction at a median time of 90 weeks [5–650] following radiation exposure. Differential gene expression of PAI-1 was analysed, together with immunohistochemistry (IHC) and immunofluorescence (IF). Results. PAI-1 gene expression was increased in both arteries (p=0.012) and veins (p<0.001) in irradiated compared to unirradiated control vessels. IHC and IF indicated that cells expressing PAI-1 were located in the adventitia of both arteries and veins and colocalized with cells positive for CD68, CD45, and α-SMA in arteries and with CD45 and α-SMA in veins. Conclusion. The current study shows a sustained upregulation of PAI-1 in both arteries and veins after exposure to ionizing radiation, indicating a chronic inflammation mainly in the adventitia. We believe that the results contribute to further understanding of radiation-induced vascular disease, where targeting PAI-1 may be a potential treatment.

Regional Variation in Plasminogen Activator Inhibitor-1 Expression in Adipose Tissue from Obese Individuals

2000 ◽  
Vol 83 (04) ◽  
pp. 545-548 ◽  
Author(s):  
Vanessa Van Harmelen ◽  
Johan Hoffstedt ◽  
Per Lundquist ◽  
Hubert Vidal ◽  
Veronika Stemme ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Subcutaneous Adipose Tissue ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Visceral Adipose ◽  
Subcutaneous Adipose ◽  
Activator Inhibitor ◽  
Pai 1

SummaryHigh plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity and adipose tissue has recently been suggested to be a source of circulating PAI-1 in humans. In the present study, differences in adipose tissue gene expression and protein secretion rate of PAI-1 between subcutaneous and visceral adipose tissue was analysed in specimens obtained from 22 obese individuals. The secretion rate of PAI-1 was two-fold higher in subcutaneous adipose tissue than in visceral adipose tissue (292 ± 50 vs 138 ± 24 ng PAI-1/107 cells, P <0.05). In accordance with the secretion data, subcutaneous adipose tissue contained about three-fold higher levels of PAI-1 mRNA than visceral adipose tissue (2.43 ± 0.37 vs 0.81 ± 0.12 attomole PAI-1 mRNA/µg total RNA, P <0.001). PAI-1 secretion from subcutaneous but not from visceral adipose tissue correlated significantly with cell size (r = 0.43, P <0.05). In summary, subcutaneous adipose tissue secreted greater amounts of PAI-1 and had a higher PAI-1 gene expression than visceral adipose tissue from the same obese individuals. Bearing in mind that subcutaneous adipose tissue is the largest fat depot these finding may be important for the coagulation abnormalities associated with obesity.

Critical Roles of Rho Kinase and Mek/Erk Pathways for Angiotensin Ii-Induced Plasminogen Activator Inhibitor-1 Gene Expression

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 721-721
Author(s):  
Kotaro Takeda ◽  
Toshihiro Ichiki ◽  
Tomotake Tokunou ◽  
Satoshi Fujii ◽  
Akira Kitabatake ◽  
...  
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Plasminogen Activator ◽  
Rho Kinase ◽  
Plasminogen Activator Inhibitor ◽  
Luciferase Assay ◽  
Ang Ii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

P157 Plasminogen activator inhibitor-1 (PAI-1) plays an integral role not only in the regulation of plasminogen activity and fibrinolytic system but also in the pathogenesis of atherosclerosis and hypertension. Because angiotensin II (Ang II) is also involved in these processes, we investigated its role in the intracellular signaling cascade leading to PAI-1 gene expression in vascular smooth muscle cells (VSMC). Ang II increased the PAI-1 mRNA and protein levels through Ang II type 1 receptor. Although PAI-1 mRNA stability was not increased by Ang II, PAI-1 gene promoter activity, which was measured by luciferase assay, was significantly increased by Ang II. This process did not require de novo protein synthesis. BAPTA-AM, genistein and AG1478 completely inhibited the Ang II-induced PAI-1 mRNA upregulation, suggesting that intracellular calcium, tyrosine kinase and epidermal growth factor (EGF) receptor transactivation were involved in this process. However, inhibition of protein kinase C (PKC) by calphostin C, GF109203, or prolonged exposure to PMA failed to abolish the Ang II-induced PAI-1 upregulation, suggesting PKC pathway was not involved. PD98059 suppressed Ang II-induced PAI-1 upregulation, whereas SB203580 did not, suggesting that MEK/ERK1/2 pathway rather than p38 MAP kinase pathway was crucial in this process. Furthermore, adenovirus-mediated expression of dominant negative form of Rho kinase or Rho kinase inhibitor Y27632 also completely suppressed PAI-1 induction by Ang II without affecting Ang II-induced ERK1/2 activation. These data suggest that activation of both MEK/ERK1/2 and Rho kinase pathways will be necessary for the upregulation of PAI-1 gene expression and these two pathways may act synergically to promote PAI-1 gene transcription at least at the downstream of ERK1/2 in VSMC. These findings are important biological and therapeutical implications for the evolution of arterial wall thrombus and the pathogenesis of atherosclerosis by Ang II.

scholarly journals Glucocorticoid-modulated gene expression of tissue- and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2.

1988 ◽  
Vol 106 (3) ◽  
pp. 971-978 ◽  
Author(s):  
R L Medcalf ◽  
E Van den Berg ◽  
W D Schleuning
Keyword(s):  
Gene Expression ◽  
Plasminogen Activator ◽  
Protein Biosynthesis ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Northern Blot Hybridization ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Activator Inhibitor ◽  
Pai 1

Constitutive gene expression of four components of plasminogen activating enzyme system, urinary and tissue-type plasminogen activator (u-PA and t-PA), plasminogen activator inhibitor 1 (PAI-1) and PAI-2 in HT-1080 human fibrosarcoma cells, was modulated by the synthetic glucocorticoid dexamethasone (Dex, 10(-7) M). More than 90% of u-PA, t-PA and PAI-1 antigen was found in conditioned medium, whereas PAI-2 was mainly cell associated. In 48-h culture supernatants (expressed per 10(6) cells) PAI-1 antigen increased from 350 to 3,300 ng and t-PA from 19 to 38 ng. u-PA and PAI-2 in the same samples decreased from 380 to 46 ng and from 3.5 to 1.8 ng, respectively. Northern blot hybridization and nuclear "Run-on" transcription assays demonstrated that the increase of t-PA and PAI-1 and the decrease of u-PA were associated with equivalent changes of gene template activity. Modulation of u-PA, t-PA and PAI-1 gene expression by Dex was completely blocked by the glucocorticoid antagonist RU 38486, suggesting that all effects were mediated through the glucocorticoid receptor. Cycloheximide, an inhibitor of protein biosynthesis induced a rapid transient increase of t-PA, u-PA and PAI-1 mRNA and a sustained increase of PAI-2 mRNA, but blocked the more long term effects of Dex, suggesting that both constitutive and hormonally regulated maintenance of mRNA steady state levels required protein biosynthesis.

scholarly journals Endogenous Aldosterone Contributes to Acute Angiotensin II-Stimulated Plasminogen Activator Inhibitor-1 and Preproendothelin-1 Expression in Heart But Not Aorta

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2229-2236 ◽  
Author(s):  
James M. Luther ◽  
Zuofei Wang ◽  
Ji Ma ◽  
Natalia Makhanova ◽  
Hyung-Suk Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Plasminogen Activator ◽  
Plasma Renin ◽  
Plasminogen Activator Inhibitor ◽  
Renin Activity ◽  
Ang Ii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

To test the hypothesis that angiotensin (Ang) II induces profibrotic gene expression through endogenous aldosterone, we measured the effect of 4 h infusion (600 ng/kg · min) of Ang II on tissue mRNA expression of plasminogen activator inhibitor 1 (PAI-1), preproendothelin-1 (ppET-1), TGF-β, and osteopontin in wild-type (WT), aldosterone synthase-deficient (AS−/−), and AS−/− mice treated with aldosterone (either 500 ng/d for 7 d or 250 ng as a concurrent 4 h infusion). Ang II increased aldosterone in WT (P &lt; 0.001) but not in AS−/− mice. Aldosterone (7 d) normalized basal aldosterone concentrations in AS−/− mice; however, there was no further effect of Ang II on aldosterone (P = NS). Basal cardiac and aortic PAI-1 and ppET-1 expression were similar in WT and AS−/− mice. Ang II-stimulated PAI-1 (P &lt; 0.001) and ppET-1 expression (P = 0.01) was diminished in the heart of AS−/− mice; treatment with aldosterone for 4 h or 7 d restored PAI-1 and ppET-1 mRNA responsiveness to Ang II in the heart. Ang II increased PAI-1 (P = 0.01) expression in the aorta of AS−/− as well as WT mice. In the kidney, basal PAI-1, ppET-1, and TGF-β mRNA expression was increased in AS−/− compared with WT mice and correlated with plasma renin activity. Ang II did not stimulate osteopontin or TGF-β expression in the heart or kidney. Endogenous aldosterone contributes to the acute stimulatory effect of Ang II on PAI-1 and ppET-1 mRNA expression in the heart; renin activity correlates with basal profibrotic gene expression in the kidney.

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