Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies have demonstrated the therapeutic potential of estrogen metabolite 2-methoxyestradiol (2ME2) in several cardiovascular disorders, including hypertension. However, the exact mechanism(s) remains unknown. In this study, primary rat aortic smooth muscle cells (RASMCs) were exposed to 2ME2, and angiotensin type 1 receptor (AT1R) expression, function, and associated signaling pathways were evaluated. In RASMCs, 2ME2 downregulated AT1R expression in a concentration- and time-dependent manner, which was correlated with reduced mRNA expression. The 2ME2 effect was through G protein-coupled receptor 30 (GPR30) that inhibits second messenger cAMP. Moreover, 2ME2 exposure phosphorylated ERK1/2 that was sensitive to MEK inhibitor PD98059. Selective epidermal growth factor receptor (EGFR) inhibitor AG1478 blocked 2ME2-induced EGFR transactivation and attenuated subsequent phosphorylation of ERK1/2 preventing AT1R downregulation. The transactivation was dependent on 2ME2-induced release of matrix metalloproteinase 9 (MMP9) and epidermal growth factor demonstrated by ELISA. Furthermore, transfection with small interfering (si) RNA targeting MMP9 impeded ERK1/2 activation and AT1R downregulation in response to 2ME2 and G1 stimulation. Interestingly, under similar conditions, stimulation of GPR30 with the selective agonist G1 elicited similar signaling pathways and downregulated the AT1R expression that was reversed by GPR30 antagonist G15. Furthermore, 2ME2 and G1 inhibited angiotensin II (ANG II) induced Ca2+ release, a response consistent with AT1R downregulation. Collectively, our study demonstrates for the first time that 2ME2 binding to GPR30 induces MMP9 specific transactivation of EGFR that mediates ERK1/2-dependent downregulation of AT1R in RASMCs. The study provides critical insights into the newly discovered role and signaling pathways of 2ME2 in the regulation of AT1R in vascular cells and its potential to be developed as a therapeutic agent that ameliorates hypertension.
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PMID:2-Methoxyestradiol causes matrix metalloproteinase 9-mediated transactivation of epidermal growth factor receptor and angiotensin type 1 receptor downregulation in rat aortic smooth muscle cells. 2936 74

The ability to accurately measure multiple proteins simultaneously in a single assay has the potential to markedly improve the efficiency of clinical tests composed of multiple biomarkers. We investigated the diagnostic accuracy of the two multiplex protein array platforms for detecting a bladder-cancer-associated diagnostic signature in samples from a cohort of 80 subjects (40 with bladder cancer). Banked urine samples collected from Kyoto and Nara Universities were compared to histologically determined bladder cancer. The concentrations of the 10 proteins (A1AT; apolipoprotein E-APOE; angiogenin-ANG; carbonic anhydrase 9-CA9; interleukin 8-IL-8; matrix metalloproteinase 9-MMP-9; matrix metalloproteinase 10-MMP10; plasminogen activator inhibitor 1-PAI-1; syndecan-SDC1; and vascular endothelial growth factor-VEGF) were monitored using two prototype multiplex array platforms and an enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's technical specifications. The range for detecting each biomarker was improved in the multiplex assays, even though the lower limit of quantification (LLOQ) was typically lower in the commercial ELISA kits. The area under the receiver operating characteristics (AUROC) of the prototype multiplex assays was reported to be 0.97 for the multiplex bead-based immunoassay (MBA) and 0.86 for the multiplex electrochemoluminescent assay (MEA). The sensitivities and specificities for MBA were 0.93 and 0.95, respectively, and for MEA were 0.85 and 0.80, respectively. Accuracy, positive predictive values (PPV), and negative predictive values (NPV) for MBA were 0.94, 0.95, and 0.93, respectively, and for MEA were 0.83, 0.81, and 0.84, respectively. Based on these encouraging preliminary data, we believe that a multiplex protein array is a viable platform that can be utilized as an efficient and highly accurate tool to quantitate multiple proteins within biologic specimens.
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PMID:Comparison of Commercial ELISA Kits, a Prototype Multiplex Electrochemoluminescent Assay, and a Multiplex Bead-Based Immunoassay for Detecting a Urine-Based Bladder-Cancer-Associated Diagnostic Signature. 3167 75