Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs
Curator and Author: Aviva Lev-Ari, PhD, RN
Classification of Fast Acting Therapies for Patients at High Risk for Macrovascular events
Macrovascular Disease – Therapeutic Potential of cEPCs
The two leading therapy classes are:
- Cell-based Therapies for angiogenesis and myocardial regeneration
- Intracoronary Delivery of Autologous Bone Marrow originating cells to restore Ischemic Tissue
The European Meeting on Vascular Medicine and Biology is a biannual international conference. The 3rd European Meeting on Vascular Medicine and Biology, took place in September 2005 and the next conference will be in 2007. All abstract presentations are published in Supplement 2, JOURNAL OF VASCULAR RESEARCH, Volume 42, 2005.
One abstract is of special interest to the line of research which focus on endogenous augmentation of cEPCs and to reduction of CVD risk by endogenous induction of regression of atherosclerotic plaques. It was selected by being judged to have the highest potential for commercialization and the potential to replace several therapeutic agents with higher efficacy.
P119 IgG1 antibodies against oxLDL epitopes induce regression of advanced atherosclerotic plaques in LDLR-/- APOBEC mice.
A. Schiopu1, B. Jansson2, P.K. Shah3, R. Carlsson3, J. Nilsson1, G. Nordin Fredrikson1Department of Medicine, Malmö University Hospital, Lund University, Malmö, SE; 2 BioInvent International AB, Lund, SE; 3 Atherosclerosis Research Center, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, US.
Objective: The purpose of our study was to assess the effects of recombinant human IgG1 antibodies against specific oxLDL epitopes on advanced atherosclerotic lesions in mice.
Methods: We have tested 2 recombinant human IgG1 antibodies directed to malondialdehyde (MDA)-modified ApoB-100 peptide sequences. Three weekly 1 mg antibody doses were injected intraperitoneally starting at 25 weeks in LDLR-/-Apobec mice, which were then sacrificed at 29 weeks of age. IgG1 antibodies directed against fluorescein isothiocyanate, which do not bind to either native or oxidized LDL, and a
baseline group sacrificed at 25 weeks of age, to asses plaque status before immunization, were used as controls.
Results: Both antibodies induced a significant regression of already present atherosclerotic plaques in the descending aorta as compared to baseline. This effect was not present in the isotype control group. The changes did not depend on alterations in weight, cholesterol or triacylglycerol content in mice plasma.
Conclusions: The present study suggests that antibody treatment has the ability to reduce the extent of already present, advanced atherosclerotic lesions. Passive immunization with antibodies directed against oxLDL epitopes might constitute a future fast acting therapy for patients at high risk for acute cardiovascular events.
Twenty Research Frontiers in Vascular Medicine of Human Endothelium
Research Frontiers in Vascular Biology and Vascular Disease
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International Research Projects |
Stem Cell biology | Embryonic stem cells in cardiovascularrepairEarly differentiation of human endothelial progenitor cellsVessels transmigration of stem cells depends on activation of the endothelium.
Interaction of embryonal endothelial progenitor cells with platelets Role of smooth muscle cell progenitors on atherosclerotic plaque development and stability.
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Ischemia and Reperfusion | Connexin 43 and myocardial ischemia/reperfusioninjuryEndothelialreperfusion injuryA possible role for hypoxia-inducible factor 1• in protection against reperfusion injury
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Genetic Basis of Vascular Disease | Cardiovascular genomics and oxidative stressNox1 mediates basic fibroblast growth factor induced vascular smooth muscle cell migrationReactive oxygen species upregulate NOX4, but not NOX2, in endothelial cells
Induction of prolyl hydroxylase 2 by nitric oxide interferes with the hypoxia induced feedback loop of HIF-1• regulation Protein disulfide isomerase is a central regulator of NADPH oxidase activity
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Inflammation | Inflammatory mediatorsofvascularInflammationIsoprostanes inhibit in vitro migration and tube formation of endothelial cells via the thromboxane A2 receptor.
Heme oxygenase-1-dependent and -independent regulation of angiogenic and inflammatory genes expression in human microvascular endothelial cells
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Tissue Engineering | Engineered heart tissueEndothelial tissue engineeringBlood vessel growth and remodeling in in-vivo tissue engineering
The effects of cyclic strain on the cytoskeleton of vascular smooth muscle cells
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Atherosclerosis Imaging Experimental | In vivo imaging ofatherosclerosisHoming ofCD34+ progenitor cells to sites ofangiogenic tube formation using real-time video microscopy.Relation between lipoprotein(a) and fibrinogen and serial intravascular ultrasound plaque progression in left main stems
Cardiovascular Development Controlled by Fluid Shear Stress. A Functionomic Approach. Dynamics in microvascular alterations in UCP/DTA mice in vivo – from metabolic syndrome to diabetes mellitus type 2 |
Vascular Cell Signaling | TGF-beta in endothelial cell functionandvascular developmentVEGF signaling
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Atherosclerosis (Clinical / In Vivo) | Pathophysiology of cigarette smoking-inducedatherosclerosisThe homeostatic benefits of plaque ruptureEarly coronary atherogenesis as a
consequence of chronic in-vivo proteasome inhibition.
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Renin-Angiotensin System | ACE inhibitorsstimulate endothelialCOX-2expression by aJNK-dependent ACE signalling pathway.A new ACE on the table: ACE2 expression in human atherosclerosis
Role of the ACE gene in renal and vascular complications of diabetes mellitus, experimental study in the mouse. Bone marrow molecular alterations after myocardial infarction: impact on endothelial progenitor cells and modulation by ACE inhibition or statin treatment. Anti-inflammatory properties of Ramiprilat: reduction of monocyte adhesion to angiotensin II-stimulated endothelium is associated with AT1 downregulation. Activation of phospholipase D by angiotensin II in HUVECS and HMVECS |
Pathogenesis of Atherosclerosis | Metalloproteinases in vascular pathologywhat we know and what we don’t know. |
Stem Cell Therapy | Functional assessment of circulatingcellsHuman fetal vascular progenitor cellsaccelerate the healing of ischemic diabetic ulcers
Peri-infarct gene transfer of human tissue kallikrein gene prevents left ventricle dysfunction by stimulating angiogenesis/arteriogenesis and cardiac stem cell activation and by inhibiting cardiomyocyte apoptosis.
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Genomics / Proteomics in Vascular Biology | Genomic analysis of animal modelsforatherosclerosis.Differential gene expression analysis of tube forming and non-tube forming microvascular endothelial cells in vitro, separated by differences in morphology
Proteomic and metabolomic analysis of atherosclerotic vessels in ApoE-/- mice Hypoxic angiogenic transcriptome in human keratinocytes and microvascular endothelial cells: macroarray and real-time PCR analysis. Gene expression profiling of human red blood cells.
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Oxidant and Lipid Signaling | Lipid modifications in atherogenesis.Epoxyeicosatrienoic acids in vascularHomeostasis
Oxidized phospholipids as modulators of Inflammation |
Chemokines — Cell-Cell Interactions | Endothelial cell-to-celljunctionsInterplay ofchemokines and platelets invascular cell recruitment
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Vascular Development | Embryonic vesseldeterminationVascular remodeling: differentiation ofarteries, veins and lymph vessels
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Vascular Aneurysms and VascularDegradation | MMP in aneurysmdevelopmentFurin-likeproproteinconvertases regulate membrane type-1 matrixmetalloproteinase in atherosclerosisNon-viral, electroporation mediated gene
transfer of TIMP-1.ATF, a cell-surface directed MMP inhibitor, suppresses intimal hyperplasia in vein grafts more efficiently than TIMP-1 in vivo. EMMPRIN regulates MMP activity in cardiovascular cells. Implications in Acute Myocardial Infarction. NF-kB promotes monocyte adhesion in vessels exposed to high intraluminal pressure |
Diabetes Mellitus and InsulinResistance | The endothelial cellglycocalyx indiabetesVasocrine signaling and insulin resistanceEarly arteriogenic defects in a diabetic
ischemic hindlimb model Diabetes-induced overproduction of reactive oxygen species impairs post-ischemic neovascularization
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Microparticles / Platelets | The significance of membranemicroparticles in vascular pathophysiology andintercellularcommunication.Influences of nuclear receptors on platelet function.
Cellular origin of microparticles in human atherosclerotic plaques Apoptotic microparticles derived from endothelial cells, smooth muscle cells and monocytes induce thrombin generation via different pathways |
Smooth Muscle Cells | Role of epigenetic mechanisms in control of SMC differentiation in development anddiseaseThe cytoskeletal proteinzyxin is amechanosensitive signaltransducer in vascular smooth muscle cells.Leukotriene-induced migration and
proliferation of vascular smooth muscle cells: implications for atherosclerosis and restenosis
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Stem Cells | Transfer of stem cell-derived endothelial cells retardedneointimal lesions in the injured artery.Stimulation ofreendothelialization viarecruitment of endothelial progenitor cells with selective antibodies against progenitor cell surface markers
Caspase-8 activity is essential for endothelial progenitor cell adherence |
The table is a good display of how to view these developments.
Dr. Larry.
This post id the first in a series og four posts all ready.
Upon posting the last one, please go back to your comprehensive integrative post and WEAVE in it concepts from the Four posts.
Thank you for your comment.
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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