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Vascular pharmacology

Qian Lu, Jihong Wang, Junshu Jiang, Shengnan Wang, Qilan Jia, Yue Wang, Weiping Li, Qin Zhou, Li Lv, Qingwei Li
BACKGROUND: The RGD-toxin protein Lj-RGD3 is a naturally occurring 118 amino acid peptide that can be obtained from the salivary gland of the Lampetra japonica fish. This unique peptide contains 3 RGD (Arg-Gly-Asp) motifs in its primary structure. Lj-RGD3 is available in recombinant form (rLj-RGD3) and can be produced in large quantities using DNA recombination techniques. The pharmacology of the three RGD motif-containing peptides has not been studied. This study investigated the protective effects of rLj-RGD3, a novel polypeptide, against ischemia/reperfusion-induced damage to the brain caused by middle cerebral artery occlusion (MCAO) in a rat stroke model...
2016: PloS One
Pirow Bekker, Daniel Dairaghi, Lisa Seitz, Manmohan Leleti, Yu Wang, Linda Ertl, Trageen Baumgart, Sarah Shugarts, Lisa Lohr, Ton Dang, Shichang Miao, Yibin Zeng, Pingchen Fan, Penglie Zhang, Daniel Johnson, Jay Powers, Juan Jaen, Israel Charo, Thomas J Schall
The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood...
2016: PloS One
Alessandro Rubini, Vincenzo Catena, Daniele Del Monte, Gerardo Bosco
CONTEXT: Calcium channel blockers may theoretically exhibit relaxing effects not only on vascular smooth muscle but also on airway smooth muscle. OBJECTIVE: To investigate possible effects of nifedipine on respiratory mechanics in the rat. METHODS: Respiratory system mechanical parameters were measured by the end-inflation occlusion method in the rat in vivo before and after the intraperitoneal administration of nifedipine. RESULTS: We found that nifedipine affects respiratory mechanics, inducing a reduction of airway resistance and of respiratory system elastance, probably because of a relaxing action on airway and parenchimal smooth muscle cells...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Szczepan Mogilski, Monika Kubacka, Dorota Łażewska, Małgorzata Więcek, Monika Głuch-Lutwin, Małgorzata Tyszka-Czochara, Karolina Bukowska-Strakova, Barbara Filipek, Katarzyna Kieć-Kononowicz
OBJECTIVE AND DESIGN: Histamine H4 receptor (H4R) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of H4R with particular reference to their anti-inflammatory and analgesic activity. MATERIALS AND SUBJECTS: We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test...
October 20, 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Constanze Hantel, Igor Shapiro, Giada Poli, Costanza Chiapponi, Martin Bidlingmaier, Martin Reincke, Michaela Luconi, Sara Jung, Felix Beuschlein
In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy...
October 15, 2016: Oncotarget
Claire Peghaire, Marie Lise Bats, Raj Sewduth, Sylvie Jeanningros, Beatrice Jaspard, Thierry Couffinhal, Cécile Duplàa, Pascale Dufourcq
OBJECTIVE: Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/β-catenin canonical pathway and Notch signaling. APPROACH AND RESULTS: Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation...
October 6, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Jingjiang Pi, Ting Tao, Tao Zhuang, Huimin Sun, Xiaoli Chen, Jie Liu, Yu Cheng, Zuoren Yu, Helen H Zhu, Wei-Qiang Gao, Yuanzhen Suo, Xunbin Wei, Paul Chan, Xiangjian Zheng, Ying Tian, Edward Morrisey, Lin Zhang, Yuzhen Zhang
RATIONALE: Angiogenic hypersprouting and leaky vessels are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs of miR302-367cluster in angiogenesis and tumors has not yet been fully evaluated. OBJECTIVE: To investigate the functions of miR302-367 in developmental angiogenesis and tumor angiogenesis and explore the molecular mechanisms of microRNA for the treatment of pathological neovascularization-related diseases...
October 18, 2016: Circulation Research
Masahiro Nezu, Tomokazu Souma, Lei Yu, Hiroki Sekine, Takashi Moriguchi, Nobuyuki Takahashi, Sadayoshi Ito, Norio Suzuki, Masayuki Yamamoto
OBJECTIVE: Placental activation of the renin-angiotensin system (RAS) plays an important role in pathogenesis of preeclampsia. RAS induces reactive oxygen species (ROS) production by activating NADPH oxidases. Keap1-Nrf2 system is a critical regulator for cellular anti-oxidative stress response through controlling transcription of antioxidant genes. This study has explored the relationship between RAS-induced ROS signaling and Keap1-Nrf2 system in preeclampsia. DESIGN AND METHOD: To examine the contribution of Keap1-Nrf2 system to preeclampsia pathology, we generated transgenic mouse models of preeclampsia/pregnancy-associated hypertension (PAH mice), in which RAS is activated selectively in late pregnancy, under deficient, normal or active Nrf2 conditions...
September 2016: Journal of Hypertension
Jolanta Malyszko, Dominika Musialowska, Edyta Zbroch, Ewa Koc-Zorawska, Jacek Malyszko
OBJECTIVE: Endocan, human endothelial cell-specific molecule, which is expressed by the vascular endothelium may play role in endothelium-dependent inflammatory process leading to the development of hypertension.The aim of the study was to estimate endocan concentration in 121 patients with primary hypertension and proper renal function as also in healthy individuals from the control group and to estimate endocan levels in subgroups with proper blood pressure control and without. DESIGN AND METHOD: The endocan concentration was estimated in 121 hypertensive patients (median age 56 min-19, max-85)...
September 2016: Journal of Hypertension
Karima Ait-Aissa, Joseph Hockenberry, David Gutterman, Aron Geurts, Andreas Beyer
OBJECTIVE: Flow mediated dilation (FMD) is the most physiological relevant form of endothelial-mediated vasodilation. Our laboratory has previously shown that telomerase, a ribo-nucleoprotein that counteracts telomere shortening, has a protective effect on endothelial function under conditions of oxidative stress in the human microcirculation. In the presence of coronary artery disease, decreased telomerase activity contributes to a shift in the mediator of FMD from atheroprotective nitric oxide (NO) to pro-inflammatory and atherogenic hydrogen peroxide (H2O2)...
September 2016: Journal of Hypertension
Jeganathan Manivannan, Manjunath Prashanth, Venkatesan Saravana Kumar, Manickaraj Shairam, Jayachandran Subburaj
Since there is no precise therapy for treating vascular calcification by directly targeting the vascular wall, we aim to unveil novel drug targets through mining the molecular effect of a high phosphate environment on vascular cells through computational methods. Here, we hypothesize that manipulation of the vascular pathogenic network by small molecule therapeutics predicted from prior knowledge might offer great promise. With this, we intend to understand the publicly available transcriptomic data of vascular smooth muscle cells and endothelial cells exposed to the high phosphate induced vascular calcification milieu and to re-examine the above published experiments for reasons different from those examined in the previous studies through multilevel systems biological understanding...
October 18, 2016: Molecular BioSystems
Estelle R Simo-Cheyou, George Vardatsikos, Ashok K Srivastava
We have previously demonstrated that the non-receptor protein tyrosine kinase (NR-PTK) c-Src is an upstream regulator of endothelin-1 (ET-1) and angiotensin II-induced activation of protein kinase B (PKB) signaling in vascular smooth muscle cells (VSMCs). We have also demonstrated that ET-1 potently induces the expression of the early growth response protein-1 (Egr-1), a zinc finger transcription factor that is overexpressed in models of vascular diseases, such as atherosclerosis. However, the involvement of c-Src in ET-1‑induced Egr-1 expression has not yet been investigated and its role in mitogen-activated protein kinase (MAPK) signaling remains controversial...
October 6, 2016: International Journal of Molecular Medicine
Domenico Maurizio Toraldo, Michele De Benedetto, Luana Conte, Francesco De Nuccio
Obstructive sleep apnea (OSA) is characterized by repetitive interruptions of breathing, causing a Chronic Intermittent Hypoxia (CIH) that can be a key step in the development and progression of cardiovascular diseases. Nowadays, in fact, there is scientific evidence showing the close relationship between OSA and atherosclerosis, even in those patients who do not show co-morbidities such as hypertension, diabetes, high levels of low-density lipoprotein (LDL), cigarette smoking and obesity, which normally are able to activate the endothelium...
October 7, 2016: Current Vascular Pharmacology
Kady Fischer, Dominik P Guensch, Nancy Shie, Julie Lebel, Matthias G Friedrich
BACKGROUND: Breathing maneuvers can elicit a similar vascular response as vasodilatory agents like adenosine; yet, their potential diagnostic utility in the presence of coronary artery stenosis is unknown. The objective of the study is to investigate if breathing maneuvers can non-invasively detect inducible ischemia in an experimental animal model when the myocardium is imaged with oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR). METHODS AND FINDINGS: In 11 anesthetised swine with experimentally induced significant stenosis (fractional flow reserve <0...
2016: PloS One
Kerstin Kick, Katharina Nekolla, Markus Rehberg, Angelika M Vollmar, Stefan Zahler
OBJECTIVE: Cell-matrix interactions are crucial for regulating cellular activities, such as migration. This is of special importance for morphogenic processes, such as angiogenesis (the development of new blood vessels). Most of our understanding of cell migration relies on 2-dimensional (2D) experiments. However, the awareness that 3D settings might elicit different results has increased. Knowledge about endothelial cell (EC) behavior in 3D environments and the influence of matrix composition on EC migration, in particular, is still limited...
October 13, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Verena Zoller, Jan-Bernd Funcke, Michaela Keuper, Muad Abd El Hay, Klaus-Michael Debatin, Martin Wabitsch, Pamela Fischer-Posovszky
Tumor necrosis factor-α (TNFα) and other ligands of the TNF superfamily are potent regulators of adipose tissue metabolism and play a crucial role in the obesity-induced inflammation of adipose tissue. Adipose tissue expression levels of TRAIL (TNF-related apoptosis-inducing ligand) and its receptor were shown to be upregulated by overfeeding and decreased by fasting in mice. In the present study we aimed to elucidate the impact of TRAIL on adipogenesis. To this end, human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes as well as stromal-vascular cells isolated from human white adipose tissue were used as model systems...
October 13, 2016: Cell Death & Disease
Ayala Gover-Proaktor, Galit Granot, Saar Shapira, Oshrat Raz, Oren Pasvolsky, Arnon Nagler, Dorit L Lev, Aida Inbal, Ido Lubin, Pia Raanani, Avi Leader
Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. With the advent of highly efficacious therapy, the focus has shifted toward managing TKI adverse effects, such as vascular adverse events (VAEs). We used an in vitro angiogenesis model to investigate the TKI-associated VAEs. Our data show that imatinib, nilotinib, and ponatinib reduce human umbilical vein endothelial cells (HUVECs) viability. Pharmacological concentrations of ponatinib induced apoptosis, reduced migration, inhibited tube formation of HUVECs, and had a negative effect on endothelial progenitor cell (EPC) function...
October 12, 2016: Leukemia & Lymphoma
Maik Gollasch
Excess visceral adipose tissue is associated with increased risk of high blood pressure, lipid disorders, type 2 diabetes, and cardiovascular disease. Adipose tissue is an endocrine organ with multiple humoral and metabolic roles in regulating whole-body physiology. However, perivascular adipose tissue (PVAT) also plays a functional role in regulating the contractile state of the underlying smooth muscle cell layer. Work during the past decade has shown that this adipose-vascular coupling is achieved by production of numerous substances released from PVAT...
October 10, 2016: Annual Review of Pharmacology and Toxicology
Giuseppe Tarantini, Francesco Saia, Piera Capranzano, Bernardo Cortese, Marco Mojoli, Giacomo Boccuzzi, Andrea Cuculo, Salvatore Geraci, Alessio Mattesini, Jacopo Oreglia, Francesco Summaria, Luca Testa, Sergio Berti, Giovanni Esposito, Alessio La Manna, Ugo Limbruno, Alfredo Marchese, Ciro Mauro, Fabio Tarantino, Alessandro Salvi, Gennaro Santoro, Ferdinando Varbella, Roberto Violini, Giuseppe Musumeci
Drug-eluting stents (DES) are the current gold standard for percutaneous treatment of coronary artery disease. However, DES are associated with a non-negligible risk of long-term adverse events related to persistence of foreign material in the coronary artery wall. In addition, DES implantation causes permanent caging of the native vessel, thus impairing normal vasomotricity and the possibility of using non-invasive coronary imaging or preforming subsequent bypass surgery. On the contrary, coronary bioresorbable stents (BRS) may provide temporary mechanical support to coronary wall without compromising the subsequent recovery of normal vascular physiology, and have the potential to prevent late adverse events related to permanent elements...
October 2016: Giornale Italiano di Cardiologia
Davide Capodanno, Dominick J Angiolillo
Daily administration of low-dose of aspirin has proven to be beneficial in preventing recurrent cardiovascular events. However, the role of aspirin for primary prevention in patients with no overt cardiovascular disease is more controversial. In fact, in lower risk patients, the modest benefit in reducing serious vascular events can be offset by the increased risk of bleeding, including intracranial and gastrointestinal hemorrhage. Diabetes mellitus (DM) has been associated with a substantially increased risk of both first and recurrent atherothrombotic events, which makes aspirin therapy of potential value in these subjects...
October 11, 2016: Circulation
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