Polyphenols downregulate PAI-1 gene expression in cultured human coronary artery endothelial cells: Molecular contributor to cardiovascular protection

Pastén, Consuelo; Olave, Nelida; Zhou, Lei; Tabengwa, Edlue M.; Wolkowicz, Paul E.; Grenett, Hernan E.

doi:10.1016/j.thromres.2007.02.001

Cited by 37 publications

(35 citation statements)

References 20 publications

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“…This is in agreement with the molecular formulae C 25 [19] For C 23 H 38 O (4b), the characteristic ions at m/z 57 [(CH 2 ) 3 CH 3 ] C , 83 [CH 3 (CH 2 ) 3 CH 2 ] C , and 97 [CH 3 (CH 2 ) 4 (CH) 2 ] C confirmed the presence of the double bond in the hydrocarbon side chain at D 12' . [19] Thus, the mixture was identified as being two monoene cardanols, 1-hydroxy-3-[(Z)-12'-nonadecenyl] benzene (4a) and 1-hydroxy-3-[(Z)-12'-heptadecenyl] benzene (4b), and two cardanols with saturated side chains, 1-hydroxy-3-heptadecanyl benzene (4c) and 1-hydroxy-3-pentadecanyl benzene (4d).…”

Section: Structure Elucidationsupporting

confidence: 87%

Structure and antioxidant activity of phenolic compounds isolated from the edible fruits and stem bark ofHarpephyllum caffrum

Moodley

Koorbanally

Islam

et al. 2014

Journal of Environmental Science and Health, Part B

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Antioxidant activity in edible fruits is an important characteristic in the choice of fruits for human consumption, and has profound influence on nutrition and health. Two pharmacologically active triterpenoids, β-sitosterol and lupeol, and the powerful flavan-3-ol antioxidant, (+)-catechin, were isolated from the edible fruits of Harpephyllum caffrum while a mixture of cardanols, an alkyl p-coumaric acid ester, and (+)-catechin were isolated from the stem bark. This is the first report of these compounds being isolated from this plant. The antioxidant capacity of (+)-catechin was higher than the other isolated compounds as well as the known antioxidant, ascorbic acid.

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Section: Structure Elucidationsupporting

confidence: 87%

Structure and antioxidant activity of phenolic compounds isolated from the edible fruits and stem bark ofHarpephyllum caffrum

Moodley

Koorbanally

Islam

et al. 2014

Journal of Environmental Science and Health, Part B

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“…We have now shown in both an acute 11,12) and chronic experimental paradigm (present study) that strawberry consumption influences adaptive and compensatory oxidative and inflammatory responses that likely underpin the observed effects on insulin metabolism 5,48) and fibrinolytic/thrombotic activity shown in the present study and by others 44) . The molecular mechanisms supporting these findings are not well described nor are the optimal doses (servings per day) known for maximum benefit; there is therefore much opportunity for research in this area.…”

Section: Discussionsupporting

confidence: 77%

“…Hence, the lower postprandial PAI-1 concentrations observed in this study associated with daily strawberry intake suggest influences on oxidative stressand/or inflammatory-regulated pathways. Candidate pathways include mitogen-activated protein kinase (MAPK) cascades, specifically extracellular signal-regulated kinase (ERK) and jun N-terminal kinase (JNK) signaling pathways, which are redox-sensitive and have been shown to be responsive to polyphenolic anti-oxidant flavonols, catechin and quercetin, in repressing PAI-1 gene expression 44) . Additionally, consensus binding sites for transcription factors in the PAI-1 promoter region include activator protein (AP)-1 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the latter particularly known for its responsiveness to changes in cellular oxidative balance and induction of cytokine production 20,21,45) .…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Meal-Induced Inflammatory and Thrombotic Responses in Overweight Men and Women After 6-Week Daily Strawberry (Fragaria) Intake

Ellis

Edirisinghe

Kappagoda

et al. 2011

JAT

102

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Aim: A pro-thrombotic, pro-inflammatory diet can play a causative role in atherosclerotic-cardiovascular diseases. Dietary intervention studies provide insight into their pathophysiological manifestations and opportunities for prevention and management. We previously showed in an acute-meal setting that a beverage containing polyphenolic-and antioxidant-rich strawberry (Fragaria) vs placebo attenuated postprandial (fed-state) increases in biomarkers of oxidative and inflammatory stress, and insulin concentrations, induced by a high carbohydrate/fat (HCF) meal. In the present study, we aimed to extend our findings and investigate hypotheses related to the effects of chronic/6-week (wk) strawberry consumption on HCF meal-induced increases in glucose, insulin, and indicators of inflammation and hemostasis. Methods: In a crossover design, 14 women and 10 men (mean age, BMI: 50.9 15 years, 29.2 2.3 kg/m 2 , respectively), were randomized to a 6-wk strawberry or placebo beverage followed by an HCF meal with assessments for 6-hours (h) postprandially. Results: HCF meal responses after 6-wk strawberry beverage showed significantly attenuated postprandial PAI-1 concentrations compared to the placebo (p 0.002); the difference was most notable at 6 h. The IL-1 response was attenuated with strawberry compared to the placebo (p 0.05). IL-6 attenuation was apparent but non-significant; IL-6 rose significantly from baseline to 6 h after the HCF meal following a placebo (p ≤ 0.01), although it remained relatively flat following the strawberry beverage from fasting to 6 h. No significant treatment-related differences were apparent for platelet aggregation, hsCRP, TNF-, insulin, or glucose. Conclusion: These data are the first to suggest that regular consumption of strawberry, a polyphenolic-and antioxidant-rich fruit, may provide protection from HCF meal-induced increases in fibrinolytic and inflammatory factors in at-risk men and women.

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“…Of particular relevance to PAI-1 are the proposed mechanisms by which dietary polyphenols may regulate hemostasis and prevent cardiovascular disease. In ex vivo and cell culture studies, dietary polyphenols have been shown to reduce tissue factor expression (51), increase plasminogen activator levels (52), and decrease PAI-1 via changes in gene expression (53). These effects are observed at micromolar concentrations of the compounds, a dose range that is well within the effective concentrations of the polyphenols identified in our study.…”

Section: Discussionsupporting

confidence: 76%

Characterization of a Novel Class of Polyphenolic Inhibitors of Plasminogen Activator Inhibitor-1

Cale

Warnock

et al. 2010

Journal of Biological Chemistry

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Plasminogen activator inhibitor type 1, (PAI-1) the primary inhibitor of the tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, has been implicated in a wide range of pathological processes, making it an attractive target for pharmacologic inhibition. Currently available small-molecule inhibitors of PAI-1 bind with relatively low affinity and do not inactivate PAI-1 in the presence of its cofactor, vitronectin. To search for novel PAI-1 inhibitors with improved potencies and new mechanisms of action, we screened a library selected to provide a range of biological activities and structural diversity. Five potential PAI-1 inhibitors were identified, and all were polyphenolic compounds including two related, naturally occurring plant polyphenols that were structurally similar to compounds previously shown to provide cardiovascular benefit in vivo. Unique second generation compounds were synthesized and characterized, and several showed IC 50 values for PAI-1 between 10 and 200 nM. This represents an enhanced potency of 10 -1000-fold over previously reported PAI-1 inactivators. Inhibition of PAI-1 by these compounds was reversible, and their primary mechanism of action was to block the initial association of PAI-1 with a protease. Consistent with this mechanism and in contrast to previously described PAI-1 inactivators, these compounds inactivate PAI-1 in the presence of vitronectin. Two of the compounds showed efficacy in ex vivo plasma and one blocked PAI-1 activity in vivo in mice. These data describe a novel family of high affinity PAI-1-inactivating compounds with improved characteristics and in vivo efficacy, and suggest that the known cardiovascular benefits of dietary polyphenols may derive in part from their inactivation of PAI-1. Plasminogen activator inhibitor type 1 (PAI-1)3 is the primary physiologic inhibitor of uPA and tPA with a well characterized role in fibrinolysis (1). PAI-1 also plays a role in many physiologic processes, including angiogenesis, wound healing, and cell migration (2-6), and has been implicated in fibrotic diseases of the kidney and lung, and in tumor metastasis (7-11). More recently, PAI-1 has been linked to obesity and metabolic syndrome (12-16), and to the development of vascular diseases such as venous thrombosis and atherosclerosis (17)(18)(19). The prospect that PAI-1 may play a direct role in the early development of a variety of diseases has made it an attractive target for drug development (20,21). However, the structural complexity of PAI-1 has made the identification and development of PAI-1 inhibitors challenging. This is due in part to the metastable structure of PAI-1, which can adopt several different conformations, including active, latent, cleaved, and protease complexed (1). These different forms of PAI-1 provide conformational control of PAI-1 interactions and dictate its localization to either matrix or the cell surface and control its activity in cell signaling events (22, 23).Active PAI-1 inhibits protease targets and is associated with vitron...

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Polyphenols downregulate PAI-1 gene expression in cultured human coronary artery endothelial cells: Molecular contributor to cardiovascular protection

Cited by 37 publications

References 20 publications

Structure and antioxidant activity of phenolic compounds isolated from the edible fruits and stem bark ofHarpephyllum caffrum

Structure and antioxidant activity of phenolic compounds isolated from the edible fruits and stem bark ofHarpephyllum caffrum

Attenuation of Meal-Induced Inflammatory and Thrombotic Responses in Overweight Men and Women After 6-Week Daily Strawberry (Fragaria) Intake

Characterization of a Novel Class of Polyphenolic Inhibitors of Plasminogen Activator Inhibitor-1

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