Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions

Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation

Nonanomalous R-symmetry in supersymmetric unified theories of quarks and leptons

A discrete R-symmetry often appears as an exact gauge symmetry in the low energy effective theory of superstring theories. We search for such discrete R-symmetries from a phenomenological point of view and find that Z_{9R} and Z_{18R} are candidates of the nonanomalous R-symmetry in the case of the minimal supersymmetric standard model. We also find Z_{4R} and Z_{20R} in the case that quarks and leptons are embedded in the SU(5) GUT multiplets. Interesting is that in the latter case all the solutions predict some extra matter multiplets and we find that the simplest choice is to take a pair of {\bf 5} and {\bf 5}^* of SU(5)_{GUT} whose mass is of order the SUSY breaking scale \sim 1 TeV. We emphasize that the presence of such extra matters is testable in future collider experiments.Comment: 15 pages, LaTeX, no figure

Natural Effective Supersymmetry

Much heavier sfermions of the first-two generations than the other superparticles provide a natural explanation for the flavor and CP problems in the supersymmetric standard model (SUSY SM). However, the heavy sfermions may drive the mass squareds for the light third generation sfermions to be negative through two-loop renormalization group (RG) equations, breaking color and charge. Introducing extra matters to the SUSY SM, it is possible to construct models where the sfermion masses are RG invariant at the two-loop level in the limit of vanishing gaugino-mass and Yukawa-coupling contributions. We calculate the finite corrections to the light sfermion masses at the two-loop level in the models. We find that the finite corrections to the light-squark mass squareds are negative and can be less than (0.3-1)% of the heavy-squark mass squareds, depending on the number and the parameters of the extra matters. We also discuss whether such models realized by the U(1)_X gauge interaction at the GUT scale can satisfy the constraints from \Delta m_K and \epsilon_K naturally. When both the left- and right-handed down-type squarks of the first-two generations have common U(1)_X charges, the supersymmetric contributions to \Delta m_K and \epsilon_K are sufficiently suppressed without spoiling naturalness, even if the flavor-violating supergravity contributions to the sfermion mass matrices are included. When only the right-handed squarks of the first-two generations have a common U(1)_X charge, we can still satisfy the constraint from \Delta m_K naturally, but evading the bound from \epsilon_K requires the CP phase smaller than 10^{-2}.Comment: 44 pages, Latex, 11 figure

Anomalous U(1) Gauge Symmetry and Lepton Flavor Violation

In recent years, many people have studied the possibility that the anomalous U(1) gauge symmetry is a trigger of SUSY breaking and/or an origin of the fermion mass hierarchy. Though it is interesting that the anomalous U(1) symmetry may explain these two phenomena simultaneously, it causes a negative stop mass squared or a severe fine-tuning in order to avoid the FCNC problem. Recently, it was pointed out that the F-term contribution of the dilaton field can dominate the flavor-dependent contribution from the anomalous U(1) D-term, so that the FCNC problem may be naturally avoided. In this paper, we study the case in which the dilaton is stabilized by the deformation of the K\"ahler potential for the dilaton and find that the order of the ratio of the F-term to the D-term contributions is generally determined. This implies that the branching ratio of \mu \to e \gamma can be found around the present experimental bound.Comment: 23 pages including 5 figures, Latex, references adde

Grand-Unification Scale Generation through the Anomalous U(1) Breaking

We discuss the anomalous U(1) gauge symmetry as a mechanism of generating the grand-unification scale. We conclude that unification to a simple group cannot be realized unless some parameters are ``tuned'', and that models with product gauge groups are preferred. We consider the ``R-invariant natural unification'' model with gauge groups SU(5)_{GUT} \times U(3)_H. In this model the doublet-triplet splitting problem is solved and the unwanted GUT relation m_s = m_\mu is avoided maintaining m_b = m_\tau. Moreover, R-invariance suppresses the dangerous proton decays induced by dimension four and five operators.Comment: 14 pages, Latex, references adde

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京都大学0048新制・課程博士博士(理学)甲第8715号理博第2287号新制||理||1200(附属図書館)UT51-2001-F45京都大学大学院理学研究科物理学・宇宙物理学専攻(主査)教授 静谷 謙一, 教授 九後 太一, 教授 二宮 正夫学位規則第4条第1項該当Doctor of ScienceKyoto UniversityDA