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Abstract-Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pathophysiology.Subtypes of vascular smooth muscle cells with specific morphology, growth, or apoptotic features have been isolated. Here, we investigated the effects of angiotensin II on apoptosis of 2 morphologically different rat aortic smooth muscle cell phenotypes. Key Words: angiotensin II Ⅲ apoptosis Ⅲ calcium Ⅲ muscle, smooth, vascular Ⅲ cells V ascular smooth muscle cells (VSMCs) maintain vascular tone mainly through coordinated contraction/relaxation, and they play a role in arterial wall remodeling through proliferation, hypertrophy, and apoptosis. 1 The arterial tree exhibits heterogeneity in response to vasoactive stimuli and in alterations induced by hypertension or atherosclerosis. The concept that distinct VSMC subtypes may play specific roles, at different locations or pathophysiological situations, is well documented in animals, 2-6 and VSMC heterogeneity also exists in human arteries. 7 In the rat arterial model, 2 major VSMC subtypes have been discerned on the basis of stable distinct morphologies in culture: spindle versus epithelioid. 2,8,9 They also differ in growth properties or protein synthesis 2,8 -11 ; however, their responses to vasoactive stimuli are barely known. 12 Angiotensin (Ang) II, the main effector peptide of the renin-angiotensin system, plays an important role in normal vascular physiology and cardiovascular diseases, 13 mostly through the Ang II type 1 (AT 1 ) receptor and partly through the Ang II type 2 (AT 2 ) receptor. AT 1 receptor-mediated intracellular calcium concentration ([Ca 2ϩ ] i ) signaling is a major determinant of VSMC contraction. 14 Ang II is a modulator of VSMC growth with proliferative/hypertrophic effects mediated by the AT 1 receptor through complex, partly calcium-dependent, signaling. 14 Heterogeneity exists in Ang II calcium signaling 14 -16 and long-term responses 17-19 between individual VSMCs, arteries, or arterial layers. In vivo, Ang II can induce a delayed apoptosis through AT 1 receptor activation. 20,21 Inversely, in vitro, Ang II induces apoptosis through AT 2 receptor activation in AT 2 -transfected VSMCs, 22 whereas AT 1 receptors might also protect native VSMCs against acute NO-induced apoptosis. 23 The question of whether the diversity in Ang II biological effects could originate from variations in the different VSMC subtypes has not been addressed. Therefore, the aim of the present study was to investigate whether VSMC subtypes responded differently to Ang II in [Ca 2ϩ ] i signaling and long-term survival. We used 2 stable cell lines, Sp-SMC and Ep-SMC, as respective models of spindle and epithelioid rat arterial VSMC subtypes. The results show dramatically different Ang II responses in the 2 VSMC lines. A delayed AT 1 receptor-mediated calcium-dependent apoptosis was

Natural thymic T regulatory (tTreg) cells maintain tolerance to self-antigen. These cells are generated in the thymus, but how this generation occurs is still controversial. Furthermore, the contribution of thymus epithelial cells to this process is still unclear, especially in humans. Using an exceptional panel of human thymic samples, we demonstrated that medullary thymus epithelial cells (mTECs) promote the generation of tTreg cells and favor their function. These effects were mediated through soluble factors and were mTEC specific since other cell types had no such effect. By evaluating the effects of mTECs on the absolute number of Treg cells and their state of proliferation or cell death, we conclude that mTECs promote the proliferation of newly generated CD25+ cells from CD4+CD25− cells and protect Treg cells from cell death. This observation implicates Bcl-2 and mitochondrial membrane potential changes, indicating that the intrinsic cell death pathway is involved in Treg protection by mTECs. Interestingly, when the mTECs were cultured directly with purified Treg cells, they were able to promote their phenotype but not their expansion, suggesting that CD4+CD25− cells have a role in the expansion process. To explore the mechanisms involved, several neutralizing antibodies were tested. The effects of mTECs on Treg cells were essentially due to interleukin (IL)-2 overproduction by thymus CD4+ T cells. We then searched for a soluble factor produced by mTECs able to increase IL-2 production by CD4+ cells and could identify the inducible T-cell costimulator ligand (ICOSL). Our data strongly suggest a « ménage à trois »: mTEC cells (via ICOSL) induce overproduction of IL-2 by CD25− T cells leading to the expansion of tTreg cells. Altogether, these results demonstrate for the first time a role of mTECs in promoting Treg cell expansion in the human thymus and implicate IL-2 and ICOSL in this process.

Recently, it was demonstrated that CD8(+) T cells are important for the response against Chlamydia pneumoniae. By use of the human monocytic cell line U937 and human monocytes taken from peripheral blood, we investigated the effect of infection on various molecules critical for CD8(+) T cell function. A strong secretion of interleukin (IL)-10 by infected cells was observed, together with an inhibited expression of major histocompatibility complex (MHC) class I antigens, but without significant alteration of tumor growth factor-beta secretion or MHC class II expression. Recombinant IL-10 added to uninfected U937 cells decreased the expression of MHC class I, whereas blocking antibodies to IL-10 and its receptor abolished the C. pneumoniae-induced inhibition of MHC class I expression. Analysis of our data provides evidence that IL-10 secretion induced by C. pneumoniae infection of monocytic cells down-regulates the expression of MHC class I molecules and thereby might reduce the presentation of bacterial epitopes by MHC. This would decrease the ability of CD8(+) T cells to eliminate infected cells.

C. pneumoniae infection enhances the inflammatory action of oxLDLs in the vascular wall, leading to cell necrosis rather than apoptosis.

Apoptosis plays an essential role in atherosclerosis. Oxidized low-density lipoproteins (oxLDL) and activated T lymphocytes are present in atherosclerotic lesions, and we have previously reported that oxLDL induce apoptosis of activated T lymphocytes. We now show that this is preceded by an increase of Fas and FasL expression. Fas and FasL overexpression was dependent on reactive oxygen species (ROS) production as well as ERK and JNK activation. In addition, oxLDL triggered an early production of soluble FasL by T lymphocytes. Blocking anti-Fas antibody or Fas-Fc protein, but also antioxidant molecules and inhibitors of ERK and JNK, decreased oxLDL-mediated apoptosis. Moreover, PHA-activated murine lymphocytes lacking a functional Fas receptor were partially resistant to oxLDL. Finally, Jurkat T cells deficient for FADD, an adaptor protein required for Fas signaling, resisted oxLDL-induced apoptosis. OxLDL triggered caspase 8 and 3 activation as well as ceramide production in PHA-activated lymphocytes and in Jurkat cells. Caspase activation was completely impaired in FADD-deficient cells, but ceramide production was not affected. Altogether, our results highlight the putative role of both membrane-bound and soluble FasL in oxLDL-induced Fas and FADD-dependent apoptosis of T lymphocytes and suggest an involvement of ROS, ERK, and JNK in this process.

All of the patients with an isolated anti-HBc profile who did not have an anti-HBs titer of >100 mIU/mL 4 weeks after a single recall dose of HBV vaccine should be further vaccinated with a reinforced triple double-dose scheme.