Identification and Localization of a Fatty Acid Response Region in the Human Plasminogen Activator Inhibitor-1 Gene

Chen, Yabing; Billadello, Joseph J.; Schneider, David J.

doi:10.1161/01.atv.20.12.2696

Cited by 48 publications

(34 citation statements)

References 28 publications

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“…2 Ketogenic diets enhance the liver supply of FFA from adipose tissues, and fatty acid accumulation seems to contribute to kDa-induced PAI-1 expression in the liver, because fatty acids induce PAI-1 gene expression in human hepatoma HepG2 cells. 27,28 We showed that hepatic PAI-1 mRNA significantly correlates with blood FFA levels in fasting mice. 29 A range of fatty acids and their derivatives regulate target gene expression via the activation of peroxisome proliferator-activated receptor ␣ (PPAR␣), a nuclear hormone receptor that is both a sensor and an effector for kDa.…”

Section: Discussionmentioning

confidence: 92%

Ketogenic Diet Disrupts the Circadian Clock and Increases Hypofibrinolytic Risk by Inducing Expression of Plasminogen Activator Inhibitor-1

Oishi

Uchida

Ohkura

et al. 2009

ATVB

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Objectives-Metabolic disorders such as diabetes and obesity are considered risk factors for cardiovascular diseases by increasing levels of blood plasminogen activator inhibitor-1 (PAI-1). Ketogenic diets (KDs) have been used as an approach to weight loss in both obese and nonobese individuals. We examined circadian changes in plasma PAI-1 and its mRNA expression levels in tissues from mice fed with a KD (KD mice), to evaluate its effects on fibrinolytic functions. Methods and Results-Two weeks on the kDa increased plasma levels of free fatty acids and ketones accompanied by hypoglycemia in mice. Plasma PAI-1 concentrations were extremely elevated in accordance with mRNA expression levels in the heart and liver, but not in the kidneys of KD mice. Circadian expression of PAI-1 mRNA was phase-advanced for 4.7, 7.9, and 7.8 hours in the heart, kidney, and adipose tissues, respectively, as well as that of circadian genes mPer2 and DBP in KD mice, suggesting that peripheral clocks were phase-advanced by ketosis despite feeding ad libitum under a periodic light-dark cycle. The circadian clock that regulates behavioral activity rhythms was also phase-advanced, and its free-running period was significantly shortened in KD mice. Conclusions-Our

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Section: Discussionmentioning

confidence: 92%

Ketogenic Diet Disrupts the Circadian Clock and Increases Hypofibrinolytic Risk by Inducing Expression of Plasminogen Activator Inhibitor-1

Oishi

Uchida

Ohkura

et al. 2009

ATVB

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“…[42][43][44] Recently, it was shown that the PAI-1 promoter contains sequences able to bind free fatty acids or VLDL response elements. 45,46 Thus, free fatty acids might induce PAI-1 gene expression in the liver directly.…”

Section: Discussionmentioning

confidence: 99%

Plasma PAI-1 Levels Are More Strongly Related to Liver Steatosis Than to Adipose Tissue Accumulation

Alessi

Bastelica

Mavri

et al. 2003

ATVB

170

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Objective-Because obesity and insulin resistance (IR) are strongly associated with liver steatosis (LS), we investigated the relation between the degree of LS and plasminogen activator inhibitor-1 (PAI-1) in ob/ob mice, in C57/BL6 mice with alcoholic LS, and in severely obese humans. Methods and Results-In both mouse models, plasma PAI-1 levels were associated with PAI-1 expression in the liver and with the degree of LS. Liver PAI-1 antigen was associated with the tumor necrosis factor receptor-II (TNFRII) antigen, whereas association with TNF antigen content was found in ob/ob mice only. No significant correlation between plasma PAI-1 and PAI-1 expression in adipose tissue of ob/ob mice was observed. Furthermore, the relation between plasma PAI-1 levels and body weight was positive in ob/ob mice but negative in C57/BL6 mice (both PϽ0.001). In humans, PAI-1 levels were correlated with the degree of LS, and 26% of plasma PAI-1 activity was independently explained by LS and serum insulin levels. Conclusions-Plasma PAI-1 levels are more closely related to fat accumulation and PAI-1 expression in the liver than in adipose tissue. In steatotic liver, PAI-1 antigen content is associated with those of TNF and TNFRII. Therefore, we suggest that TNF pathway dysregulation in LS could be involved in increased plasma PAI-1 in obesity with IR. Key Words: liver steatosis Ⅲ PAI-1 Ⅲ adipose tissue Ⅲ insulin resistance P lasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of fibrinolysis. PAI-1 modulates the development of atherosclerosis in mice, 1,2 and an elevated plasma PAI-1 concentration is predictive for myocardial infarction in humans. 3,4 Interestingly, the predictive value of circulating PAI-1 levels is highly dependent on the insulin resistance syndrome. 4,5 Despite several efforts in the last few years, the mechanism of increased plasma PAI-1 concentration in insulin resistance associated with android obesity is not completely understood. PAI-1 is expressed in murine as well as in human adipose tissue, 6 -9 and its expression in adipose tissue is correlated positively with body mass index (BMI). 9 -11 Human visceral adipose tissue expresses more PAI-1 than does subcutaneous abdominal adipose tissue. 7,12 Furthermore, PAI-1 expression in only abdominal, but not in femoral subcutaneous adipose tissue, is associated with the features of insulin resistance. 11 Therefore, it has been postulated that in the insulin resistance syndrome with central obesity, abdominal adipose tissue is an important source of plasma PAI-1. Of note, an increase in plasma PAI-1 is also observed in lipodystrophy associated with antiretroviral treatment in HIV patients. These patients typically have prominent, peripheral fat wasting and maintained or decreased visceral fat depots and are insulin resistant. Interestingly, the difference in plasma PAI-1 levels between HIV patients and healthy controls was independent of HIV infection status and was not affected after adjustment for visceral fat estimation but was rather explained by...

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“…Previously, the sequences of PAI-1 promoter which functionally responds to the stimulation of TGF-␤, Ang II, glucose, glucosamine, and fatty acid, were reported. 50,[52][53][54]63 However, the sequence that mediates the response of PAI-1 to Ang II stimulation in VSMCs was not reported, partially because of low transfection efficiency of primary cell culture by cationic lipid reagents such as Lipofectamine, about 5% maximum based on estimate from transfected GFP-expressing cells (data not shown), and could only generate less than 50% response to Ang II stimulation during transient transfection. 17 By using adenoviral vectors we were able to infect more than 80% of cells with PAI-1/Luc reporter constructs and show that the effect of Ang II on the MRE region is comparable to its effect on endogenous PAI-1 mRNA.…”

Section: Discussionmentioning

confidence: 99%

MEK1,2 response element mediates angiotensin II—stimulated plasminogen activator inhibitor-1 promoter activation

Chen

Feener

2004

Blood

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IntroductionPlasminogen activator inhibitor-1 (PAI-1) is the major regulator of both tissue and urokinase plasminogen activators. 1,2 Inhibition of plasminogen activation by PAI-1 reduces the generation of plasmin and thereby impairs fibrinolysis. In addition, PAI-1 has also been suggested to reduce plasmin-mediated activation of matrix metalloproteases 3 and compete with cellular ␣v␤3 integrin matrix interactions, which contribute to cellular migration. 4 Overexpression of PAI-1 in transgenic mice or by adenovirus-mediated gene transfer increases thrombosis, 5,6 and PAI-1 deficiency enhances fibrinolysis and neointimal remodeling. 7,8 Increased levels of PAI-1 have been demonstrated in vascular lesions induced by balloon catheter injury and atherosclerosis. [9][10][11][12] Within these vascular lesions, PAI-1 expression is prominently increased in neointimal smooth muscle cells. 9,13 In previous animal studies using angiotensin-converting enzyme inhibition, angiotensin type 1 receptor antagonism and systemic angiotensin II (Ang II) infusion, our group and others have demonstrated that the Ang II/AT 1 pathway plays an important role in regulating vascular PAI-1 gene expression in vivo. 9,[14][15][16] A host of agonists, including Ang II, transforming growth factor-␤ (TGF-␤), very low density lipoprotein (VLDL), and phorbol ester, require the activity of MAPK/ERK kinase1 and 2 (MEK1,2) to induce PAI-1 mRNA expression. [17][18][19][20] Although the MEK/ERK pathway plays a key role in controlling PAI-1 mRNA levels, the mechanism(s) that mediates the effects of MEK1,2 on PAI-1 transcription have not been identified. Previous reports have demonstrated that the MEK/ERK pathway can affect phosphorylation, nuclear transport, and transactivation of a number of transcription factors, including Elk-1, Sma-and Mad-related protein (SMAD), c-Jun, Sp1, and signal transducer and activator of transcription 3 (STAT3). [21][22][23][24][25] In addition, Ras/MEK/ERK activation can lead to increased expression of intermediate-early response genes, such as c-fos, egr-1, and junB. 26 Although the promoter of the PAI-1 gene contains an array of potential response elements for these transcription factors, 27-29 the contributions of these transcriptional elements to the effects of MEK1,2 on the PAI-1 promoter activity have not yet been elucidated.Given the importance of PAI-1 in vascular physiology and its possible contribution to vasculopathies, further understanding of how the MAP kinase pathways affect PAI-1 expression in vascular smooth muscle cells (VSMCs) is of considerable importance. In this study, we identified and characterized the MEK1,2 response element in the 5Ј flanking region of PAI-1 gene in VSMCs. These studies identified 2 adjacent cis-acting AP-1-like and Sp1-like sequences that functionally cooperate in MEK-induced PAI-1 promoter activation. These results establish a mechanistic link between the MEK/ERK pathway and the activation of the PAI-1 promoter. Materials and methods MaterialsDominant-negative AP-1 (A-Fos), and ...

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Identification and Localization of a Fatty Acid Response Region in the Human Plasminogen Activator Inhibitor-1 Gene

Cited by 48 publications

References 28 publications

Ketogenic Diet Disrupts the Circadian Clock and Increases Hypofibrinolytic Risk by Inducing Expression of Plasminogen Activator Inhibitor-1

Ketogenic Diet Disrupts the Circadian Clock and Increases Hypofibrinolytic Risk by Inducing Expression of Plasminogen Activator Inhibitor-1

Plasma PAI-1 Levels Are More Strongly Related to Liver Steatosis Than to Adipose Tissue Accumulation

MEK1,2 response element mediates angiotensin II—stimulated plasminogen activator inhibitor-1 promoter activation

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