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1.
Pharmacotherapy ; 40(9): 978-983, 2020 09.
Article in English | MEDLINE | ID: mdl-32677113

ABSTRACT

Hydroxychloroquine combined with azithromycin has been investigated for activity against coronavirus disease 2019 (COVID-19), but concerns about adverse cardiovascular (CV) effects have been raised. This study evaluated claims data to determine if risks for CV events were increased with hydroxychloroquine alone or combined with azithromycin. We identified data from 43,752 enrollees that qualified for analysis. The number of CV events increased by 25 (95% confidence interval [CI]: 8, 42, p=0.005) per 1000 people per year of treatment with hydroxychloroquine alone compared with pretreatment levels and by 201 (95% CI: 145, 256, p<0.001) events per 1000 people per year when individuals took hydroxychloroquine and azithromycin. These rates translate to an additional 0.34 (95% CI: 0.11, 0.58) CV events per 1000 patients placed on a 5-day treatment with hydroxychloroquine monotherapy and 2.75 (95% CI: 1.99, 3.51) per 1000 patients on a 5-day treatment with both hydroxychloroquine and azithromycin. The rate of adverse events increased with age following exposure to hydroxychloroquine alone and combined with azithromycin. For females aged 60 to 79 years prescribed hydroxychloroquine, the rate of adverse CV events was 0.92 per 1000 patients on 5 days of therapy, but it increased to 4.78 per 1000 patients when azithromycin was added. The rate of adverse CV events did not differ significantly from zero for patients 60 years of age or younger. These data suggest that hydroxychloroquine with or without azithromycin is likely safe in individuals under 60 years of age if they do not have additional CV risks. However, the combination of hydroxychloroquine and azithromycin should be used with extreme caution in older patients.


Subject(s)
Azithromycin/adverse effects , COVID-19 Drug Treatment , Cardiotoxicity/etiology , Hydroxychloroquine/adverse effects , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Azithromycin/administration & dosage , Cardiotoxicity/epidemiology , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Child , Child, Preschool , Databases, Factual , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/administration & dosage , Infant , Infant, Newborn , Male , Middle Aged , Risk Factors , Sex Factors , Young Adult
2.
Thromb Haemost ; 114(3): 603-13, 2015 Aug 31.
Article in English | MEDLINE | ID: mdl-26063414

ABSTRACT

Cleaved high-molecular-weight kininogen (HKa) or its peptide domain 5 (D5) alone exert anti-adhesive properties in vitro related to impeding integrin-mediated cellular interactions. However, the anti-adhesive effects of HKa in vivo remain elusive. In this study, we investigated the effects of HKa on leukocyte recruitment and neointima formation following wire-induced injury of the femoral artery in C57BL/6 mice. Local application of HKa significantly reduced the accumulation of monocytes and also reduced neointimal lesion size 14 days after injury. Moreover, C57BL/6 mice transplanted with bone marrow from transgenic mice expressing enhanced green fluorescence protein (eGFP) showed a significantly reduced accumulation of eGFP+-cells at the arterial injury site and decreased neointimal lesion size after local application of HKa or the polypeptide D5 alone. A differentiation of accumulating eGFP+-cells into highly specific smooth muscle cells (SMC) was not detected in any group. In contrast, application of HKa significantly reduced the proliferation of locally derived neointimal cells. In vitro, HKa and D5 potently inhibited the adhesion of SMC to vitronectin, thus impairing their proliferation, migration, and survival rates. In conclusion, application of HKa or D5 decreases the inflammatory response to vascular injury and exerts direct effects on SMC by impeding the binding of integrins to extracellular matrix components. Therefore, HKa and D5 may hold promise as novel therapeutic substances to prevent neointima formation.


Subject(s)
Kininogen, High-Molecular-Weight/pharmacology , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Neointima , Peptide Fragments/pharmacology , Vascular System Injuries/prevention & control , Animals , Bone Marrow Transplantation , Cell Proliferation/drug effects , Chemotaxis, Leukocyte/drug effects , Disease Models, Animal , Femoral Artery/drug effects , Femoral Artery/injuries , Femoral Artery/metabolism , Femoral Artery/pathology , Genes, Reporter , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , Humans , Integrins/metabolism , Kininogen, High-Molecular-Weight/genetics , Kininogen, High-Molecular-Weight/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Muscle, Smooth, Vascular/injuries , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Peptide Fragments/genetics , Peptide Fragments/metabolism , Protein Structure, Tertiary , Time Factors , U937 Cells , Vascular System Injuries/metabolism , Vascular System Injuries/pathology , Vitronectin/metabolism
3.
Nat Med ; 20(11): 1289-300, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25344740

ABSTRACT

Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.


Subject(s)
Forkhead Transcription Factors/metabolism , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Signal Transduction , Adult , Animals , Apoptosis/drug effects , Apoptosis/genetics , Bone Morphogenetic Proteins/metabolism , Bromodeoxyuridine/metabolism , Cell Proliferation/drug effects , Cytokines/metabolism , Female , Forkhead Transcription Factors/genetics , Gene Deletion , Gene Expression Regulation/drug effects , Humans , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/physiopathology , Intercellular Signaling Peptides and Proteins/metabolism , Lung/blood supply , Lung/pathology , Lung/physiopathology , Male , Mice , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Paclitaxel/pharmacology , Pulmonary Artery/pathology , Quinolones/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Signal Transduction/drug effects , Signal Transduction/genetics , Small Molecule Libraries/pharmacology , Vascular Remodeling/drug effects , Vascular Remodeling/genetics
4.
Cardiovasc Res ; 103(4): 564-72, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25020912

ABSTRACT

AIMS: MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice. METHODS AND RESULTS: MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1. CONCLUSION: Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.


Subject(s)
Endothelial Cells/metabolism , MicroRNAs/genetics , Neointima/genetics , Neovascularization, Pathologic/genetics , Vascular System Injuries/genetics , Animals , Cells, Cultured , Endothelium, Vascular/metabolism , Humans , Mice , RNA Interference/physiology
5.
PLoS One ; 8(3): e55445, 2013.
Article in English | MEDLINE | ID: mdl-23533567

ABSTRACT

BACKGROUND: The phosphatase PTEN represents an important physiological inhibitor of phosphatidylinositol-3 kinase (PI3-K)/protein kinase B (Akt) signalling, however, the functional role of PTEN in the initial phase of angioplasty-induced vascular injury remains elusive. In the present study we sought to determine PTEN's effect on vascular smooth muscle cell (VSMC) apoptosis following acute injury in vivo and in vitro. METHODS AND RESULTS: Immunohistochemistry indicated a faint basal expression and equal distribution of PTEN in uninjured rat carotid arteries. 12 h following balloon-injury, PTEN expression was strongly increased in apoptotic (TUNEL+) VSMC. In vitro, stimulation with serum or different growth factors or subjecting VSMC to cyclic stretch had no effect on PTEN expression, whereas stimulation with H2O2 robustly increased PTEN expression in a time- and dose-dependent manner. To evaluate the functional role of PTEN expression, human VSMC were transduced with WT-PTEN. Overexpression of PTEN increased the number of apoptotic VSMC (19.8%±4.4 vs. 5.6%±2.3; P<0.001) as determined by TUNEL assay. In contrast, siRNA-mediated knock-down of PTEN attenuated the basal as well as H2O2-induced apoptosis of VSMC. Mechanistically, overexpression of PTEN prevented serum-induced Akt-phosphorylation, whereas siRNA-mediated knock down of PTEN augmented Akt-activation. Moreover, co-transfection of PTEN and a constitutive active Akt mutant prevented PTEN-dependent augmentation of VSMC apoptosis, indicating, that PTEN regulates VSMC apoptosis by inhibition of Akt phosphorylation/activation. CONCLUSION: By interfering with the PI3-K/Akt-dependent survival signalling, the oxidative stress-induced up regulation of PTEN in VSMC of injured arteries augments the sensitivity of VSMC to apoptotic stimuli in the early phase following vascular injury, augmenting the initial injury and cell loss of the injured vessel wall. Thus, these data add to our understanding of PTEN's role during vascular remodelling.


Subject(s)
PTEN Phosphohydrolase/metabolism , Angioplasty, Balloon , Animals , Apoptosis/physiology , Carotid Artery, Common/cytology , Carotid Artery, Common/metabolism , Cell Proliferation , Cells, Cultured , Humans , Immunohistochemistry , In Vitro Techniques , Male , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Rats
6.
Basic Res Cardiol ; 107(3): 261, 2012 May.
Article in English | MEDLINE | ID: mdl-22418922

ABSTRACT

Dedifferentiation, migration, and proliferation of resident vascular smooth muscle cells (SMCs) are key components of neointima formation after vascular injury. Activation of signal transducer and activator of transcription-3 (STAT3) is suggested to be critically involved in this process, but the complex regulation of STAT3-dependent genes and the functional significance of inhibiting this pathway during the development of vascular proliferative diseases remain elusive. In this study, we demonstrate that STAT3 was activated in neointimal lesions following wire-induced injury in mice. Phosphorylation of STAT3 induced trans-activation of cyclin D1 and survivin in SMCs in vitro and in neointimal cells in vivo, thus promoting proliferation and migration of SMCs as well as reducing apoptotic cell death. WP1066, a highly potent inhibitor of STAT3 signaling, abrogated phosphorylation of STAT3 and dose-dependently inhibited the functional effects of activated STAT3 in stimulated SMCs. The local application of WP1066 via a thermosensitive pluronic F-127 gel around the dilated arteries significantly inhibited proliferation of neointimal cells and decreased the neointimal lesion size at 3 weeks after injury. Even though WP1066 application attenuated the injury-induced up-regulation of the chemokine RANTES at 6 h after injury, there was no significant effect on the accumulation of circulating cells at 1 week after injury. In conclusion, these data identify STAT3 as a key molecule for the proliferative response of SMC and neointima formation. Moreover, inhibition of STAT3 by the potent and specific compound WP1066 might represent a novel and attractive approach for the local treatment of vascular proliferative diseases.


Subject(s)
Cardiovascular Agents/pharmacology , Cell Proliferation/drug effects , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Neointima/prevention & control , Pyridines/pharmacology , STAT3 Transcription Factor/antagonists & inhibitors , Tyrphostins/pharmacology , Animals , Apoptosis/drug effects , Binding Sites , Cell Movement/drug effects , Cells, Cultured , Chemokine CCL5/metabolism , Cyclin D1/metabolism , Disease Models, Animal , Humans , Inhibitor of Apoptosis Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Neointima/metabolism , Neointima/pathology , Phosphorylation , Promoter Regions, Genetic , Repressor Proteins/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Survivin , Time Factors
7.
Lab Invest ; 89(2): 152-63, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19079320

ABSTRACT

Placental vascular development begins very early in pregnancy and is characterized by construction of a primitive vascular network in a low-oxygen environment. In vitro three-component assays of this process are scarce. In this study, a complex three-dimensional spheroid model for in vitro studies of placental vasculogenesis with regard to cell-cell interactions between cytotrophoblasts (CTs), villous stromal cells and endothelial precursor cells was established. Microscopic and immunohistochemical analyses of the spheroids showed structural and differentiation patterns resembling the structure and differentiation of early placental chorionic villous tissue (in regard to the expression of multiple markers cytokeratin-7, vimentin, CD34, CD31). The authenticity of this model to in vivo events allowed investigation of placental vascular development and trophoblast invasion under physiological and pathological conditions. Particularly enhanced spheroidal expression of SDF-1alpha and its receptor CXCR4, the major chemokine system in embryonic vasculogenesis, in a low-oxygen environment was detected. In addition, our model confirmed previously described invasive phenotype of trophoblasts through collagen under low- (physiologic), but not high- (pathologic) oxygen concentrations. Therefore, the three-dimensional spheroid model consisting of major placental cell types proved to be an appropriate system to investigate early placental vessel development under both physiological and pathological conditions.


Subject(s)
Neovascularization, Physiologic/physiology , Placenta/blood supply , Spheroids, Cellular/cytology , Trophoblasts/cytology , Adult , Biomarkers/metabolism , Chemokine CXCL12/metabolism , Chorionic Villi/growth & development , Chorionic Villi/metabolism , Dose-Response Relationship, Drug , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Female , Humans , In Vitro Techniques , Oxygen/administration & dosage , Oxygen/metabolism , Placentation/physiology , Pregnancy , Receptors, CXCR4/metabolism , Spheroids, Cellular/metabolism , Trophoblasts/physiology , Umbilical Veins/cytology , Young Adult
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