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      Altered transforming growth factor-beta signaling in a murine model of thoracic aortic aneurysm.

      Journal of Vascular Research
      Animals, Aorta, Thoracic, metabolism, pathology, Aortic Aneurysm, Thoracic, genetics, Disease Models, Animal, Female, Gene Expression Profiling, methods, Male, Mice, Mice, Inbred C57BL, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Time Factors, Tumor Necrosis Factor-alpha

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          Abstract

          Thoracic aortic aneurysms (TAAs) develop by a multifactorial process involving maladaptive signaling pathways that alter the aortic vascular environment. Transforming growth factor-beta (TGF-beta) has been implicated in regulating the structure and composition of the extracellular matrix by differential activation of various intracellular signaling pathways. However, whether and to what degree TGF-beta signaling contributes to TAA development remains unclear. Accordingly, the hypothesis that alterations in TGF-beta signaling occur during aneurysm formation was tested in a murine model of TAA. TAAs were surgically induced in mice (C57BL/6J) and aortas were analyzed at predetermined time points (1, 2, and 4 weeks post-TAA induction). Quantitative real-time PCR (QPCR) was performed to evaluate the expression of 84 relevant TGF-beta superfamily genes, and the protein levels of key signaling intermediates were measured by immunoblotting. Results were compared to unoperated reference control mice. QPCR revealed increased expression of TGF-beta superfamily ligands (Gdf-2, -6, -7, Inhba), ligand inhibitors (Bmper, Chrd, Gsc), and transcriptional regulators (Dlx2, Evi1), among other genes (Cdkn2b, Igf1, IL-6). Protein levels of TGF-beta receptor(II), Smad2, Smad1/5/8, phospho-Smad1/5/8, and Smurf1 were increased from control values post-TAA induction. Both TGF-beta receptor(I) and Smad4 were decreased from control values, while ALK-1 levels remained unchanged. These alterations in the TGF-beta pathway suggest a mechanism by which primary signaling is switched from a TGF-betaR(I)/Smad2-dependent response, to an ALK-1/Smad1/5/8 response, representing a significant change in signaling outcome, which may enhance matrix degradation. Copyright 2008 S. Karger AG, Basel.

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          Most cited references34

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          A comparison of rate control and rhythm control in patients with atrial fibrillation.

          There are two approaches to the treatment of atrial fibrillation: one is cardioversion and treatment with antiarrhythmic drugs to maintain sinus rhythm, and the other is the use of rate-controlling drugs, allowing atrial fibrillation to persist. In both approaches, the use of anticoagulant drugs is recommended. We conducted a randomized, multicenter comparison of these two treatment strategies in patients with atrial fibrillation and a high risk of stroke or death. The primary end point was overall mortality. A total of 4060 patients (mean [+/-SD] age, 69.7+/-9.0 years) were enrolled in the study; 70.8 percent had a history of hypertension, and 38.2 percent had coronary artery disease. Of the 3311 patients with echocardiograms, the left atrium was enlarged in 64.7 percent and left ventricular function was depressed in 26.0 percent. There were 356 deaths among the patients assigned to rhythm-control therapy and 310 deaths among those assigned to rate-control therapy (mortality at five years, 23.8 percent and 21.3 percent, respectively; hazard ratio, 1.15 [95 percent confidence interval, 0.99 to 1.34]; P=0.08). More patients in the rhythm-control group than in the rate-control group were hospitalized, and there were more adverse drug effects in the rhythm-control group as well. In both groups, the majority of strokes occurred after warfarin had been stopped or when the international normalized ratio was subtherapeutic. Management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy, and there are potential advantages, such as a lower risk of adverse drug effects, with the rate-control strategy. Anticoagulation should be continued in this group of high-risk patients. Copyright 2002 Massachusetts Medical Society
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            Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus

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              How cells read TGF-beta signals.

              Cell proliferation, differentiation and death are controlled by a multitude of cell-cell signals, and loss of this control has devastating consequences. Prominent among these regulatory signals is the transforming growth factor-beta (TGF-beta) family of cytokines, which can trigger a bewildering diversity of responses, depending on the genetic makeup and environment of the target cell. What are the networks of cell-specific molecules that mould the TGF-beta response to each cell's needs?
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