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Hoyer F.F.,University of Bonn | Steinmetz M.,University of Bonn | Zimmer S.,University of Bonn | Becker A.,University of Bonn | And 4 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2011

Low-dose oral tetrahydrocannabinol (THC) reduces progression of atherosclerosis in mice. THC activates central cannabinoid-1 receptors (CB1) with subsequent psychoactive effects as well as peripheral cannabinoid-2 receptors (CB2). In order to dissect the underlying mechanisms, we performed experiments under selective CB2 stimulation as well as after genetic disruption of the CB2 receptor. Atherosclerosis prone apolipoprotein E-deficient mice were crossed with cannabinoid receptor-2 deficient mice to obtain ApoE -/- CB2 -/- double knockout mice. After 8. weeks of a high-cholesterol diet, immunohistochemical stainings of the aortic root revealed that vascular leukocyte infiltration in atherosclerotic plaques was accelerated in ApoE -/- CB2 -/- mice compared with ApoE -/- mice. This was accompanied by increased release of reactive oxygen species as measured using L012-enhanced chemiluminescence, and by decreased endothelial function as assessed in isolated aortic rings in organ chamber experiments. ApoE -/- mice treated with the selective CB2 agonist JWH 133 during a high-cholesterol diet showed decreased atherosclerotic lesion formation, improved endothelial function and reduced levels of reactive oxygen species. To assess whether CB2 expression in circulating cells influences atherosclerosis, irradiated ApoE -/- mice were repopulated with bone marrow-derived cells from ApoE -/- and ApoE -/- CB2 -/- mice and were fed a high-cholesterol diet for 8. weeks. CB2 deficiency in bone marrow-derived cells increased leukocyte infiltration into the vessel wall, but had no impact on plaque formation. Cell culture experiments revealed that CB2 activation diminishes ROS generation in vascular cells. Selective CB2 receptor stimulation modulates atherogenesis via impact on both circulating proinflammatory and vascular cells. © 2011 Elsevier Ltd.

Beindorff N.,German Primate Center | Einspanier A.,German Primate Center | Einspanier A.,Institute of Physiological Chemistry
Reproduction | Year: 2010

In early pregnant primates, relaxin (RLX) is highly upregulated within the corpus luteum (CL), suggesting that RLX may have an important role in the implantation of the blastocyst. Therefore, the aim of the present study was to investigate the local effects of RLX and gonadotrophins on the maintenance of the CL using an in vitro microdialysis system. CLs of common marmoset monkeys were collected by luteectomy during different stages of the luteal phase and early pregnancy. Each CL was perfused with either Ringer's solution alone or Ringer's solution supplemented with either porcine RLX (250, 500 and 1000 ng/ml) or gonadotrophins (50 IU/ml). Application of RLX provoked a significant luteal response of progesterone (P4) and oestradiol (E2) secretions during the mid-luteal phase (500 ng/ml: P4 54±42%, E2 24±11%; 1000 ng/ml: E2 16±13%), and especially during the late luteal phase (250 ng/ml: P4 53±10%; 500 ng/ml: P4 44±15%; 1000 ng/ml: P4 62±15%, E2 18±7%). The effects of RLX on steroid secretion were irrespective of the RLX dosages. While treatment with human chorionic gonadotrophin did not affect luteal steroid or RLX secretion, the application of FSH resulted in a significant increase in the secretion of both P4 (20±8%) and E2 (37±28%), and a prominent rise in RLX during early pregnancy. In conclusion, our results demonstrate that RLX and FSH have a luteotrophic function in the marmoset monkeys; moreover, FSH has a function beyond its traditional role just as a follicle-stimulating hormone. © 2010 Society for Reproduction and Fertility.

Schnedl W.J.,General Practice for General Internal Medicine | Krause R.,Medical University of Graz | Tafeit E.,Institute of Physiological Chemistry | Tillich M.,Diagnostikum Sued West | And 2 more authors.
Nature Reviews Gastroenterology and Hepatology | Year: 2011

Epiploic appendagitis is a rare cause of abdominal pain. Diagnosis of epiploic appendagitis, although infrequent, is easily made with CT or ultrasonography in experienced hands. As reported in the literature, most patients with primary epiploic appendagitis are treated conservatively without surgery, with or without anti-inflammatory drugs. A small number of patients are treated with antibiotics and some patients require surgical intervention to ensure therapeutic success. Symptoms of primary epiploic appendagitis usually resolve with or without treatment within a few days. A correct diagnosis of epiploic appendagitis with imaging procedures enables conservative and successful outpatient management of the condition and avoids unnecessary surgical intervention and associated additional health-care costs. Gastroenterologists and all medical personnel should be aware of this rare disease, which mimics many other intra-abdominal acute and subacute conditions, such as diverticulitis, cholecystitis and appendicitis. This article reviews epiploic appendagitis and includes discussion of clinical findings, pathophysiology, diagnosis and therapeutic possibilities. © 2011 Macmillan Publishers Limited. All rights reserved.

Hermann M.-R.,Max Planck Institute of Biochemistry | Jakobson M.,Max Planck Institute of Biochemistry | Colo G.P.,Max Planck Institute of Biochemistry | Rognoni E.,Max Planck Institute of Biochemistry | And 3 more authors.
Journal of Cell Science | Year: 2016

Integrin-mediated activation of small GTPases induces the polymerisation of G-actin into various actin structures and the release of the transcriptional co-activator MRTF from G-actin. Here we report that pan-integrin-null fibroblasts seeded on fibronectin and expressing β1- and/or aV-class integrin contained different G-actin pools, nuclear MRTF-A (also known as MKL1 or MAL) levels and MRTF-A-SRF activities. The nuclear MRTF-A levels and activities were highest in cells expressing both integrin classes, lower in cells expressing β1 integrins and lowest in cells expressing the αV integrins. Quantitative proteomics and transcriptomics analyses linked the differential MRTF-A activities to the expression of the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), which is known to modify focal adhesion and cytoskeletal proteins. The malignant breast cancer cell line MDA-MB-231 expressed high levels of β1 integrins, ISG15 and ISGylated proteins, which promoted invasive properties, whereas non-invasive MDA-MB-468 and MCF-7 cell lines expressed low levels of β1 integrins, ISG15 and ISGylated proteins. Our findings suggest that integrin-adhesion-induced MRTF-A-SRF activation and ISG15 expression constitute a newly discovered signalling circuit that promotes cell migration and invasion. © 2016. Published by The Company of Biologists Ltd | Journal of Cell Science.

Crnkovic S.,Institute of Molecular Biology and Biochemistry | Crnkovic S.,University Clinic for Anesthesiology and Intensive Care Medicine | Riederer M.,Institute of Molecular Biology and Biochemistry | Lechleitner M.,Institute of Molecular Biology and Biochemistry | And 8 more authors.
Free Radical Biology and Medicine | Year: 2012

Proliferation of vascular smooth muscle cells is a characteristic of pathological vascular remodeling and represents a significant therapeutic challenge in several cardiovascular diseases. Docosahexaenoic acid (DHA), a member of the n-3 polyunsaturated fatty acids, was shown to inhibit proliferation of numerous cell types, implicating several different mechanisms. In this study we examined the molecular events underlying the inhibitory effects of DHA on proliferation of primary human smooth muscle cells isolated from small pulmonary artery (hPASMCs). DHA concentration-dependently inhibited hPASMC proliferation, induced G1 cell cycle arrest, and decreased cyclin D1 protein expression. DHA activated the unfolded protein response (UPR), evidenced by increased mRNA expression of HSPA5, increased phosphorylation of eukaryotic initiation factor 2α, and splicing of X-box binding protein 1. DHA altered cellular lipid composition and led to increased reactive oxygen species (ROS) production. DHA-induced ROS were dependent on both intracellular Ca 2+ release and entry of extracellular Ca 2+ . Overall cellular ROS and mitochondrial ROS were decreased by RU360, a specific inhibitor of mitochondrial Ca 2+ uptake. DHA-induced mitochondrial dysfunction was evidenced by decreased mitochondrial membrane potential and decreased cellular ATP content. DHA triggered apoptosis as found by increased numbers of cleaved caspase-3- and TUNEL-positive cells. The free radical scavenger Tempol counteracted DHA-induced ROS, cell cycle arrest, induction of UPR, and apoptosis. We conclude that Ca 2+-dependent oxidative stress is the central and initial event responsible for induction of UPR, cell cycle arrest, and apoptosis in DHA-treated hPASMCs. © 2012 Elsevier Inc. All rights reserved.

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