Background Cardiomyocytes (CM) utilize Ca2+ not only in excitation-contraction coupling (ECC), but also as a signaling molecule promoting for example cardiac hypertrophy. It is largely unclear how Ca2+ triggers signaling in CM in the presence of the rapid and large Ca2+ fluctuations that occur during ECC. A potential route is store-operated Ca2+ entry (SOCE), a drug-inducible mechanism for Ca2+ signaling that requires stromal interaction molecule 1 (STIM1). SOCE can also be induced in cardiomyocytes, which prompted us to study STIM1-dependent Ca2+-entry with respect to cardiac hypertrophy in vitro and in vivo. Methods and Results Consistent with earlier reports, we found drug-inducible SOCE in neonatal rat cardiomyocytes, which was dependent on STIM1. While this STIM1-dependent, drug-inducible SOCE was only marginal in adult cardiomyocytes isolated from control hearts, it significantly increased in cardiomyocytes isolated from adult rats that had developed compensated cardiac hypertrophy after abdominal aortic banding. Moreover, we detected an inwardly rectifying current in hypertrophic cardiomyocytes that occurs under native conditions (i.e. in the absence of drug-induced store depletion) and is dependent on STIM1. By manipulating its expression, STIM1 was found to be both sufficient and necessary for cardiomyocyte hypertrophy both in vitro and in the adult heart in vivo. Stim1 silencing by AAV9-mediated gene transfer protected rats from pressure overload-induced cardiac hypertrophy. Conclusions STIM1 promotes cardiac hypertrophy by controlling a previously unrecognized sarcolemmal current.

RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advancedstage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496).

The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or by active efflux transporters, namely the multidrug resistance-associated proteins (MRPs) MRP4 and MRP5. To determine the role of MRP4 and MRP5 in cell signaling, we studied arterial SMCs, in which the effects of cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery SMCs and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to PKA/CREB pathway activation. Here we provide what we believe to be the first evidence that MRP4 acts as an independent endogenous regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus. We also identify MRP4 inhibition as a potentially new way of preventing abnormal VSMC proliferation. Introduction cAMP and cGMP are second messengers that relay external signals to downstream effector proteins. The most common targets are cAMP-dependent PKA and cGMP-dependent PKG, which regulate a large number of processes by phosphorylating target proteins. In addition to PKA, recent evidence has highlighted a major role for guanine-nucleotide exchange factors for Rap proteins (namely EPAC1 and EPAC2) (1) in mediating cAMP signaling. cAMP and cGMP also act by binding certain ion channels (2). Signaling events triggered by extracellular stimuli arise from an ingenious system of regulation that involves the production and elimination of intracellular cyclic nucleotides. Classically, cyclic nucleotide elimination has been attributed to hydrolysis mediated by cyclic nucleotide phosphodiesterases (PDEs). PDEs constitute a large superfamily of enzymes encoded by several genes with tissue-specific expression of a large number of splice variants (3). In several models, including VSMCs, PDEs have been shown to regulate the amplitude and duration of intracellular cyclic nucleotide signaling (4, 5). For instance, sildenafil, a selective PDE5 inhibi-

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Our objective was to study the expression and function of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum protein recently identified as the calcium sensor that regulated Ca(2+)-released activated channels in T cells. STIM1 was found to be upregulated in serum-induced proliferating human coronary artery smooth muscle cells (hCASMCs) as well as in the neointima of injured rat carotid arteries. Growth factors-induced proliferation was significantly lower in hCASMC transfected with STIM1 siRNA than in those transfected with scrambled siRNA (increase relative to 0.1% S: 116 +/- 12% and 184 +/- 16%, respectively, P < 0.01). To assess the role of STIM1 in preventing vascular smooth muscle cells (VSMCs) proliferation in vivo, we infected balloon-injured rat carotid arteries with an adenoviral vector expressing a short hairpin (sh) RNA against rat STIM1 mRNA (Ad-shSTIM1). Intima/media ratios reflecting the degree of restenosis were significantly lower in Ad-shSTIM1- infected arteries than in Ad-shLuciferase-infected arteries (0.34 +/- 0.02 vs. 0.92 +/- 0.11, P < 0.006). Finally, we demonstrated that silencing STIM1 prevents activation of the transcription factor NFAT (nuclear factor of activated T cell). In conclusion, STIM1 appears as a major regulator of in vitro and in vivo VSMC proliferation, representing a novel and original pharmacological target for prominent vascular proliferative diseases.

LM is a severe manifestation of SLE. It can be the first manifestation of the disease or it can occur during followup, in particular in untreated patients. However, the longterm prognosis is typically positive. Patients with less severe disease exhibited good LVEF recovery without CYC.

High anti-CCP2 levels are associated with lung disease in the RA population.

Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The identification of the pivotal role of the mitogen-activated protein kinase (MAPK) pathway has opened new avenues of research and therapeutic approaches. We review the neurologic manifestations of three histiocytic disorders with frequent involvement of the brain and spine: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD) and Destombes-Rosai-Dorfman disease (RDD). Central nervous system (CNS) manifestations occur in 10-25% of LCH cases, with both tumorous or neurodegenerative forms. These subtypes differ by clinical and radiological presentation, pathogenesis, and prognosis. Tumorous or degenerative neurologic involvement occurs in 30-40% of ECD patients and affects the hypothalamopituitary axis, meninges, and brain parenchyma. RDD lesions are typically tumorous with meningeal or parenchymal masses with strong contrast enhancement. Unlike LCH and ECD, neurodegenerative lesions or syndromes have not been described with RDD. Familiarity with principles of evaluation and treatment both shared among and distinct to each these three diseases is critical for effective management. Refractory or disabling neurohistiocytic involvement should prompt the consideration for use of targeted kinase inhibitor therapies.