Publications by authors named "Jacqueline M Cale"

Article Synopsis
  • PAI-1 is a key inhibitor of plasminogen activators and is linked to various health issues, making it a valuable target for new drugs.
  • Researchers discovered five new polyphenolic compounds that are significantly more effective at inhibiting PAI-1 than existing options, with enhanced potencies of 10-1000 times.
  • These new compounds not only work in the presence of vitronectin but also showed promising results in lab tests and in mice, suggesting potential cardiovascular benefits from dietary polyphenols through PAI-1 inactivation.
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Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of tissue-type and urokinase-type plasminogen activators (tPA and uPA, respectively). PAI-1 also interacts with non-proteinase targets such as vitronectin, heparin, and several endocytic receptors of the low-density lipoprotein-receptor family, including the low-density lipoprotein-receptor related protein (LRP) and the very low-density lipoprotein receptor (VLDLr). PAI-1 is a multifunctional protein that is not only a physiologic regulator of fibrinolysis and cell migration but is also associated with several acute and chronic pathologic conditions.

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The serine proteinase inhibitor, plasminogen activator inhibitor type-1 (PAI-1), binds to the adhesion protein vitronectin with high affinity at a site that is located directly adjacent to the vitronectin RGD integrin binding sequence. The binding of PAI-1 to vitronectin sterically blocks integrin access to this site and completely inhibits the binding of purified integrins to vitronectin; however, its inhibition of endothelial and smooth muscle cell adhesion to vitronectin is at most 50-75%. Because PAI-1 binds vitronectin with approximately 10-100-fold higher affinity than purified integrins, we have analyzed the mechanism whereby these cells are able to overcome this obstacle.

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The inactivation of plasminogen activator inhibitor-1 (PAI-1) by the small molecule PAI-1 inhibitor PAI-039 (tiplaxtinin) has been investigated using enzymatic analysis, direct binding studies, site-directed mutagenesis, and molecular modeling studies. Previously PAI-039 has been shown to exhibit in vivo activity in various animal models, but the mechanism of inhibition is unknown. PAI-039 bound specifically to the active conformation of PAI-1 and exhibited reversible inactivation of PAI-1 in vitro.

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eNOS (endothelial nitric oxide synthase) activity is post-translationally regulated in a complex fashion by acylation, protein-protein interactions, intracellular trafficking and phosphorylation, among others. Signalling pathways that regulate eNOS activity include phosphoinositide 3-kinase/Akt, cyclic nucleotide-dependent kinases [PKA (protein kinase A) and PKG], PKC, as well as ERKs (extracellular-signal-regulated kinases). The role of ERKs in eNOS activation remains controversial.

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Pregnancy enhanced nitric oxide production by uterine artery endothelial cells (UAEC) is the result of reprogramming of both Ca(2+) and kinase signaling pathways. Using UAEC derived from pregnant ewes (P-UAEC), as well as COS-7 cells transiently expressing ovine endothelial nitric oxide synthase (eNOS), we investigated the role of phosphorylation of five known amino acids following treatment with physiological calcium-mobilizing agent ATP and compared with the effects of PMA (also known as TPA) alone or in combination with ATP. In P-UAEC, ATP stimulated eNOS activity and phosphorylation of eNOS S617, S635, and S1179.

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Although pregnancy is clearly associated with refractoriness to infused angiotensin II (AII) in the uteroplacental unit, there is still dispute over the mechanism by which angiotensin type 1 and type 2 receptors (AT1R and AT2R) may mediate this response in the uterine artery. This is in large part due to incomplete knowledge of levels of AT1R and AT2R expression and function in uterine artery endothelium (UA Endo) in the nonpregnant (NP) and pregnant (P) states, combined with the disagreement on whether AII may act through release of adrenomedullary catecholamines. The authors have previously described an increase in AT1R in UA Endo but not UA vascular smooth muscle (VSM) during pregnancy as compared to the nonpregnant intact ewe.

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While studies of human and bovine endothelial nitric oxide synthase (eNOS) demonstrate activation by Ca(2+)/calmodulin, recent progress demonstrates that eNOS phosphorylation can alter sensitivity to intracellular free calcium ([Ca(2+)](i)). The sheep, however, is widely used as a model for cardiovascular adaptation to pregnancy and ovine uterine artery endothelial cell (UAEC) eNOS undergoes pregnancy-specific (P) enhancement of activity associated with increased Ca(2+) and protein kinase signaling in response to a number of agonists, including adenosine triphosphate (ATP). The degree of homology between the ovine and human full-length cDNAs was not previously known and yet is necessary to determine the validity in using an ovine model to study human physiology.

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Objective: Third-trimester human placentas from normal and preeclamptic pregnancies were evaluated for possible changes in gene expression patterns by microarray analysis.

Methods: Placentas from four normal pregnancies and four pregnancies complicated by preeclampsia were studied. In a preliminary effort to identify possible differences between the two groups, complementary DNA (cDNA) probes were prepared from pooled total RNA by reverse transcription in the presence of (33)P-dCTP.

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Commercially available human complementary DNA microarrays were used to compare differential expression in the livers of Atlantic salmon ( Salmo salar) infected with Aeromonas salmonicida and of healthy fish. Complementary DNA probes were prepared from total RNA isolated from livers of control salmon and infected salmon by reverse transcription in the presence of (33)P-dCTP and independently hybridized to human GENE-FILTERS GF211 microarrays. Of the 4131 known genes on the microarray, 241 spots gave clearly detectable signals using labeled RNA from the control salmon liver.

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