This Is MS Multiple Sclerosis Knowledge & Support Community

1: Thromb Haemost. 2006 Apr;95(4):708-14. Links
Interleukin-4 differentially regulates osteoprotegerin expression and induces calcification in vascular smooth muscle cells.Hofbauer LC, Schrader J, Niebergall U, Viereck V, Burchert A, Hörsch D, Preissner KT, Schoppet M.
Division of Gastroenterology and Endocrinology, Department of Internal Medicine, Philipps-University, Baldingerstrasse, D-35033 Marburg, Germany. hofbauer@post.med.uni-marburg.de

Vascular calcification is characterized by cellular transdifferentiation and expression of bone-related matrix proteins that result in the presence of bone-like structures in the vascular wall. Interleukin (IL)-4, a pleiotropic cytokine, and osteoprotegerin (OPG), an essential regulator of osteoclast biology, have both been linked to vascular disease. Here, we assessed the role of IL-4 and OPG in vascular calcification in vitro. IL-4 induced OPG mRNA levels and protein secretion by 5-fold in a dose- and time-dependent fashion in human coronary artery smooth muscle cells (CASMC). Activation of the transcription factor STAT6 preceded IL-4-induced OPG expression, and blockade of IL-4-induced STAT6 activation by the phospholipase C inhibitor D609 decreased OPG expression. Long-term exposure of IL-4 for 4 weeks resulted in transformation of CASMC towards an osteoblastic phenotype, based on the expression of the transcription factor Cbfa1 and increased mineral deposition. Notably, calcification of CASMC was inhibited by gene silencing of Cbfa1. During osteogenic transformation, IL-4 down-regulated OPG production in CASMC. IL-4 has differential effects in CASMC: While short-term exposure enhances OPG production through a STAT6-dependent mechanism, long-term exposure causes Cbfa1-dependent osteogenic transformation and a decreased production of OPG, an inhibitor of bone resorption.

PMID: 16601843 [PubMed - indexed for MEDLINE]

1: Mult Scler. 2006 Oct;12(5):541-50. Links
Interferon-beta modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients.Weinstock-Guttman B, Hong J, Santos R, Tamaño-Blanco M, Badgett D, Patrick K, Baier M, Feichter J, Gallagher E, Garg N, Ramanathan M.
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA.

PURPOSE: Multiple sclerosis (MS) patients have a high risk of low bone density. The purpose of this study was to examine the molecular mechanisms potentially capable of modulating bone homeostasis in response to interferon-beta-1a (IFN-beta-1a) treatment and the focus was the bone-modulating system comprised of receptor activator of nuclear factor-kappaB (RANK), its ligand RANKL and its decoy receptor, osteoprotegerin (OPG). METHODS: In this open-label pharmacodynamic study, peripheral blood was obtained from relapsing-remitting MS patients just prior to and at multiple time points after intramuscular injection of 30 microg IFN-beta-1a. Samples were analysed for RANKL, tumour necrosis factor related apoptosis-inducing ligand (TRAIL), OPG and macrophage inflammatory protein-1 alpha/beta expression. Osteoclast precursor differentiation from peripheral blood cells of MS patients in the presence of exogenously added IFN-beta-1a was also assessed. Additionally, the changes in plasma levels of osteocalcin and the C-telopeptides after 1 year of treatment were measured as surrogate markers of bone formation and degradation, respectively. RESULTS: IFN-beta-1a treatment modulated RANKL and OPG in a selective, time-dependent manner. The levels of OPG protein decreased 25% at the 8-h time point, then increased 43% at the 24-h time point. The levels of free RANKL reached a maximum at the 8-h time point. Increases in the levels of macrophage inflammatory protein-1beta (MIP-1beta), a chemokine that increases osteolysis, were observed. The levels of the bone formation marker, osteocalcin, were lower in MS patients compared to controls and increased after one year of treatment. Ex vivo treatment of peripheral blood lymphocytes with IFN-beta resulted in a marked reduction of osteoclast-like cells in the presence of RANKL and macrophage colony stimulating factor. CONCLUSIONS: IFN-beta treatment induces complex, specific and time-dependent changes in multiple proteins and mRNAs related to bone homeostasis in MS patients.

PMID: 17086898 [PubMed - indexed for MEDLINE]

Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme (EC 3.4.21.69) that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. It should not be confused with C peptide or c-reactive protein or protein kinase C.

The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits both anti-inflammatory and anti-apoptotic activities. Its actions are related to development of thrombosis and ischemic stroke. The protein C pathway of the coagulation of the blood involves the influences of lipids and lipoproteins and the study of the strong epidemiologic association between hyperlipidemia and hypercoagulability.[1]

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b.

The best characterized function of Protein S is its role in the anti coagulation pathway, it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity.

Protein S can bind to negatively charged phospholipids via the carboxylated GLA domain. This property allows Protein S to function in the removal of cells which are undergoing apoptosis. Apoptosis is a form of cell death that is used by the body to remove unwanted or damaged cells from tissues. Cells which are apoptotic (ie. in the process of apoptosis) no longer actively manage the distribution of phospholipids in their outer membrane and hence begin to display negatively charged phospholipids, such as phosphatidyl serine, on the cell surface. In healthy cells, an ATP (Adenosine triphosphate)-dependent enzyme removes these from the outer leaflet of the cell membrane. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S can bind to the negatively charged phospholipids and function as a bridging molecule between the apoptotic cell and the phagocyte. The bridging property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring.

gibbledygook wrote:I have been taking a vitamin k supplement from life extension for the last 4 nights. I have noticed a much improved night bladder and reduced spasms in the last 3 nights. However in the morning and today there is somewhat greater stiffness in my bad leg. This seems to improve with a bit more salvia and after my new chinese tea which contains both ginkgo, salvia, ginseng, astragalus and angelica sinensis. I'm not sure whether to continue with the vitamin k. It seems to have both good and bad effects. Most interesting!

interestingly although a lot of vitamin k's effects are on coagulation, it also is necessary for anti-coagulation since Protein C is dependent on vitamin K:

Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme (EC 3.4.21.69) that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. It should not be confused with C peptide or c-reactive protein or protein kinase C.

The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits both anti-inflammatory and anti-apoptotic activities. Its actions are related to development of thrombosis and ischemic stroke. The protein C pathway of the coagulation of the blood involves the influences of lipids and lipoproteins and the study of the strong epidemiologic association between hyperlipidemia and hypercoagulability.[1]

And protein S:

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b.

The best characterized function of Protein S is its role in the anti coagulation pathway, it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity.

Protein S can bind to negatively charged phospholipids via the carboxylated GLA domain. This property allows Protein S to function in the removal of cells which are undergoing apoptosis. Apoptosis is a form of cell death that is used by the body to remove unwanted or damaged cells from tissues. Cells which are apoptotic (ie. in the process of apoptosis) no longer actively manage the distribution of phospholipids in their outer membrane and hence begin to display negatively charged phospholipids, such as phosphatidyl serine, on the cell surface. In healthy cells, an ATP (Adenosine triphosphate)-dependent enzyme removes these from the outer leaflet of the cell membrane. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S can bind to the negatively charged phospholipids and function as a bridging molecule between the apoptotic cell and the phagocyte. The bridging property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring.

1: Cell Mol Life Sci. 2002 Nov;59(11):2004-12. Links
Cyclin D3 and p53 mediate sulforaphane-induced cell cycle delay and apoptosis in non-transformed human T lymphocytes.Fimognari C, Nüsse M, Berti F, Iori R, Cantelli-Forti G, Hrelia P.
Department of Pharmacology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.

Despite experimental evidence that sulforaphane can exert chemopreventive effects, whether these effects are specific for neoplastic cells is not known. Following our previous demonstration that sulforaphane induces cell cycle arrest and apoptosis in human T lymphoblastoid Jurkat leukemia cells and increases p53 and bax protein expression, we tested sulforaphane on non-transformed phytohemagglutinin-stimulated human lymphocytes. Here, we demonstrate that sulforaphane arrested cell cycle progression in G, phase, through a decrease in the protein expression of cyclin D3. Moreover, sulforaphane induced apoptosis (and also necrosis), mediated by an increase in the expression of p53. These findings suggest that sulforaphane is a growth modulator for T cells. Our in vitro evidence that sulforaphane is active and even cytotoxic in normal as well as transformed lymphocytes raises important questions regarding its suitability for cancer chemoprevention.

PMID: 12530531 [PubMed - indexed for MEDLINE]

1: Intern Med J. 2005 Jul;35(7):419-26. Links
New therapeutic target in inflammatory disease: macrophage migration inhibitory factor.Morand EF.
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Melbourne, Victoria, Australia. eric.morand@med.monash.edu.au

The cytokine macrophage migration inhibitory factor (MIF) participates in fundamental events in innate and adaptive immunity. The profile of activities of MIF in vivo and in vitro is strongly suggestive of a role for MIF in the pathogenesis of many inflammatory diseases, including rheumatoid arthritis (RA), and hence antagonism of MIF is suggested as a potential therapeutic strategy in inflammatory disease. The best developed case for therapeutic antagonism of MIF is in RA. In RA, MIF is abundantly expressed in serum and synovial tissue. MIF induces synovial expression of key pro-inflammatory genes, regulates the function of endothelial cells and leucocytes, and is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumour suppressor protein p53. In animal models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. A similar case has been made, for example using MIF-deficient mice, in models of atheroma, colitis, multiple sclerosis and other inflammatory diseases. The relationship with p53 also means MIF may be important in the link between inflammatory disease and cancer, such as is seen in RA or colitis. MIF also has a unique relationship with glucocorticoids, in that despite antagonizing their effects, the expression of MIF is in fact induced by glucocorticoids. Thus, MIF functions as a physiological counter-regulator of the anti-inflammatory effects of glucocorticoids. This may be entrained by selective activation of mitogen-activated protein kinases rather than nuclear factor kappa B. Therapeutic MIF antagonism may therefore provide a specific means of 'steroid sparing'. Exploitation of antibody, soluble receptor or small molecule technologies may soon lead to the ability to test in the clinic the importance of MIF in human inflammatory diseases.

PMID: 15958113 [PubMed - indexed for MEDLINE]

1: J Biol Chem. 2008 Nov 21;283(47):32669-79. Epub 2008 Sep 24. Links
Direct interaction between NM23-H1 and macrophage migration inhibitory factor (MIF) is critical for alleviation of MIF-mediated suppression of p53 activity.Jung H, Seong HA, Ha H.
Department of Biochemistry, Biotechnology Research Institute, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea.

Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine that is involved in host immune and inflammatory responses, as well as tumorigenesis. However, the regulatory mechanism of MIF function is unclear. Here we report that the NM23-H1 interacts with MIF in cells, as demonstrated by cotransfection and coimmunoprecipitation experiments. Analysis of cysteine (Cys) to serine (Ser) substitution mutants of NM23-H1 (C4S, C109S, and C145S) and MIF (C57S, C60S, and C81S) revealed that Cys(145) of NM23-H1 and Cys(60) of MIF are responsible for complex formation. NM23-H1-MIF complexes were dependent on reducing conditions, such as the presence of dithiothreitol or beta-mercaptoethanol, but not H(2)O(2). NM23-H1 alleviated the MIF-mediated suppression of p53-induced apoptosis and cell cycle arrest by promoting the dissociation of MIF from MIF-p53 complexes. In addition, NM23-H1 significantly inhibited the MIF-induced proliferation of quiescent NIH 3T3 cells through a direct interaction with MIF, and decreased the MIF-induced activation of phosphatidylinositol 3-kinase/PDK1 and p44/p42 extracellular signal-regulated (ERK) mitogen-activated protein kinase. The results of the current study suggest that the NM23-H1 functions as a negative regulator of MIF.

PMID: 18815136 [PubMed - indexed for MEDLINE]

1: Curr Opin Investig Drugs. 2001 Jun;2(6):778-82.Links
Macrophage migration inhibitory factor as a target molecule in multiple sclerosis.Nishihira J, Ogata A.
Central Research Institute, Hokkaido University Graduate School of Medicine, Sapporo, Japan. j_nishi@med.hokudai.ac.jp

Various therapeutic approaches to multiple sclerosis (MS) have been presented, but no specific and effective method has so far been established. In recent years, macrophage migration inhibitory factor (MIF) has been re-evaluated as a pluripotent cytokine involved in a broad spectrum of inflammation and immune responses. During the course of MIF study, increased levels of MIF were observed in the cerebrospinal fluids of patients with MS in parallel with exacerbation of clinical symptoms, and a number of lymphocytes strongly expressing MIF infiltrate into the pathogenic lesions. It is expected that regulation of the action of MIF by an anti-MIF antibody or small molecule inhibitors would be an effective therapeutic method for this demyelinating disease.

1: J Neurol Sci. 2000 Oct 1;179(S 1-2):127-31. Links
Macrophage migration inhibitory factor in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis and neuro-Behçet's disease.Niino M, Ogata A, Kikuchi S, Tashiro K, Nishihira J.
Department of Neurology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, 060-8638, Sapporo, Japan. niino@med.hokudai.ac.jp

Macrophage migration inhibitory factor (MIF) is becoming increasingly recognized as an important regulator of immune and inflammatory responses. It is released by activated T lymphocytes and macrophages and up-regulates the proinflammatory activity of these cells. MIF is required for antigen- and mitogen-driven T cell activation, and stimulates macrophages to release cytokines and nitric oxide. On the basis of the recent suggestion that pharmacological modulation of MIF production and neutralization of its activity may have important implications for treatment of a variety of autoimmune or inflammatory conditions, we determined the level of MIF in the cerebrospinal fluid (CSF) of patients with conventional-form multiple sclerosis (C-MS) and optic-spinal form multiple sclerosis (OpS-MS), and neuro-Behçet's disease (NBD). As control, the CSF of patients with non-inflammatory neurological diseases (NIND) was used. The concentration of MIF in CSF samples was significantly elevated in relapsed cases of C-MS (4.13+/-1.07 ng/ml) (mean+/-S.D.) compared with control samples (2.38+/-0.60 ng/ml) (P<0.0001), whereas MIF in the CSF of C-MS patients in remission was not elevated (2.65+/-0.67 ng/ml). The concentration of MIF in the CSF of OpS-MS patients in relapse (5.53+/-1.74 ng/ml) was higher than that of patients with C-MS in relapse (P<0.05). In NBD patients, the concentration of MIF in CSF was significantly elevated (7.47+/-5.61 ng/ml) compared with control samples (P<0.01) and correlated well with cell count in these samples (r=0.910, P<0.005). These results suggest that MIF may play a pivotal role in immune-mediated diseases of the central nervous system, and that MIF may be useful in the study of differences between C-MS and OpS-MS.

PMID: 11054496 [PubMed - indexed for MEDLINE]

1: J Neurochem. 2003 May;85(3):635-44. Links
Oligodendrocyte injury in multiple sclerosis: a role for p53.Wosik K, Antel J, Kuhlmann T, Brück W, Massie B, Nalbantoglu J.
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.

PMID: 12694389 [PubMed - indexed for MEDLINE]

1: J Hypertens. 2001 Oct;19(10):1819-25. Links
The impaired glutathione system and its up-regulation by sulforaphane in vascular smooth muscle cells from spontaneously hypertensive rats.Wu L, Juurlink BH.
Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.

The glutathione (GSH) system plays an important role in reducing oxidative stress, the increase of which has been linked to the pathogenesis of hypertension. The aims of this study were to investigate: (1) whether the GSH system was impaired in aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHR), and (2) whether this system could be up-regulated by the phase-2 enzyme inducers, sulforaphane and t-butylhydroquinone (t-BHQ). Basal levels of cellular GSH, GSH-reductase and GSH-peroxidase were significantly lower in SMCs from SHR than from normotensive Wistar-Kyoto (WKY) rats. Heme oxygenase-1 (HO-1) was significantly higher in SHR SMCs, which correlated with the higher oxidative stress experienced by these cells. No differences were observed in the basal activity of GSH-S-transferase nor in the ability to synthesize GSH between SMCs from these two strains. Sulforaphane (0.05-1 micromol/l) and t-BHQ (10-100 micromol/l) induced significant and concentration-dependent increases in cellular GSH levels, HO-1 protein content and activities of GSH-reductase and GSH-peroxidase in SMCs from both rat strains. Upregulation of phase 2 enzymes correlated with a decrease in oxidative stress experienced by the SMCs, particularly with SHR. We conclude that SHR SMCs experience greater oxidative stress than WKY SMCs and that malfunction of the GSH system contributes to the enhanced oxidative stress in SHR SMCs.

PMID: 11593102 [PubMed - indexed for MEDLINE]

1: J Vasc Surg. 2008 Oct;48(4):960-4. Epub 2008 Jul 17. Links
Lower extremity arterial inflow is adversely affected in patients with venous disease.Paolini DJ, Comerota AJ, Jones LS.
Jobst Vascular Center, Section of Vascular Surgery, Toledo, Ohio.

BACKGROUND: Lower extremity chronic venous disease is due to venous hypertension resulting from reflux and/or obstruction. Studies of venous valvular function have validated and quantified valve closure times defining normal and abnormal valve function, and investigators have categorized the amount of venous reflux with validated criteria. However, hemodynamics of venous outflow obstruction remains poorly defined. The purpose of this study is to assess whether chronic venous disease alters arterial inflow at rest or during hyperemic limb challenge, and whether there are differences in patients with primary chronic venous insufficiency (1 degrees CVI) versus those with postthrombotic venous disease. METHODS: Twenty-two normal limbs and 32 limbs in patients with chronic venous disease (C-3 or greater) were examined between September 2006 and January 2008. Chronic venous disease patients consisted of 22 postthrombotic patients and 10 with 1 degrees CVI. Arterial inflow was measured at rest using venous occlusion plethysmography and after induced arterial inflow using postocclusive reactive hyperemia (PORH). Volume changes were recorded with volume plethysmography. A minimum of 10 minutes elapsed between the resting and PORH measurements of arterial inflow. RESULTS: Resting arterial inflow was greater in patients with 1 degrees CVI when compared to normal patients (2.81 vs 1.26, P = .008) and to patients with postthrombotic venous disease (2.81 vs 1.13, P = .03). There was a 7.3-fold increase in maximal arterial inflow in normal patients during PORH versus a 4.8-fold increase in patients with postthrombotic venous disease (P = .015). Patients with 1 degrees CVI had a marked attenuation of maximal arterial inflow during hyperemic limb challenge, demonstrating only a twofold increase relative to their baseline resting arterial inflow (P = .08). CONCLUSION: Increases in arterial inflow during a hyperemic limb challenge are less robust in patients with postthrombotic venous disease than in normal volunteers. These data suggest that the pain of venous claudication may in part be due to a diminished arterial inflow response.

PMID: 18639424 [PubMed - indexed for MEDLINE]

1: Nippon Jinzo Gakkai Shi. 1990 Jul;32(7):823-8.Links
[Paradoxical response of blood pressure to salt loading in renovascular hypertension][Article in Japanese]


Aoi W, Koide Y, Sakamoto R, Ueda Y, Yamachika S, Daikoku S, Seto S, Hashiba K.
Department of Internal Medicine, Japanese Red Cross Nagasaki Atomic Bomb Hospital, Japan.

We studied the effect of high salt intake on blood pressure in two cases with renovascular hypertension. They had hypertension with hyperreninemia and marked difference in plasma renin activity between both renal veins. Blood pressure significantly decreased after single oral administration of captopril. Renal arteriogram revealed significant stenosis in the main artery to the left (case 1) and right (case 2) kidney. Blood pressure response was evaluated after seven (case 1) and five (case 2) days of low salt and seven days (both cases) of high salt intake. Mean blood pressure in two patients was significantly decreased (case 1; 118 +/- 5.5 to 108 +/- 6.1 mmHg and case 2; 150 +/- 3.8 to 138 +/- 3.1 mmHg). Plasma renin activity was also decreased (case 1; 6.25 to 0.77 ng/ml/hr and case 2; 22.8 to 6.3 ng/ml/hr). In case 2, blood pressure elevated markedly during low salt intake, compared with blood pressure level during normal salt intake. The results suggest that excessive salt intake in patients with unilateral renovascular hypertension produces blood pressure reduction because of suppression of renin-angiotensin system. We concluded that in patients with unilateral renovascular hypertension dietary sodium depletion may be harmful, whereas salt supplement may have a beneficial effect.

PMID: 2273599 [PubMed - indexed for MEDLINE

1: Pharmacology. 2008;82(1):67-73. Epub 2008 May 14. Links
Disodium disuccinate astaxanthin prevents carotid artery rethrombosis and ex vivo platelet activation.Lauver DA, Driscoll EM, Lucchesi BR.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Mich 48109, USA.

BACKGROUND/AIMS:The disodium disuccinate derivative of astaxanthin (DDA) is a carotenoid antioxidant under development for the treatment of ischemic cardiovascular events. Recent evidence suggests that reactive oxygen species (ROS) play an important role in platelet activation. This study seeks to investigate the effects of a reactive oxygen species quencher, DDA, in a canine model of carotid artery thrombosis. METHODS: After formation of an occlusive carotid thrombus, dogs were administered recombinant tissue plasminogen activator intra-arterially to achieve thrombolysis in the presence of either 0.9% NaCl solution or DDA (10-50 mg/kg i.v. infusion). Ex vivo platelet aggregation and tongue bleeding times were measured before and after drug administration. Residual thrombus mass was analyzed at the end of each experiment. RESULTS:The data indicated a dose- dependent reduction in the incidence of carotid artery rethrombosis. In addition, platelet aggregation and thrombus weights were dose-dependently inhibited by DDA. No change was recorded in tongue bleeding time among the treatment groups. CONCLUSIONS:The data demonstrate that at the doses used in this study, DDA significantly reduced the incidence of secondary thrombosis while maintaining normal hemostasis. The results suggest that upon further study, DDA may one day find utility in revascularization procedures. Copyright 2008 S. Karger AG, Basel.

PMID: 18477858 [PubMed - indexed for MEDLINE]

1: Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1679-85. Links
Inhibition of choroidal neovascularization with an anti-inflammatory carotenoid astaxanthin.Izumi-Nagai K, Nagai N, Ohgami K, Satofuka S, Ozawa Y, Tsubota K, Ohno S, Oike Y, Ishida S.
Laboratory of Retinal Cell Biology, Keio University of Medicne, Tokyo, Japan.

PURPOSE: Astaxanthin (AST) is a carotenoid found in marine animals and vegetables. The purpose of the present study was to investigate the effect of AST on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms. METHODS: Laser photocoagulation was used to induce CNV in C57BL/6J mice. Mice were pretreated with intraperitoneal injections of AST daily for 3 days before photocoagulation, and treatments were continued daily until the end of the study. CNV response was analyzed by volumetric measurements 1 week after laser injury. Retinal pigment epithelium-choroid levels of IkappaB-alpha, intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2 were examined by Western blotting or ELISA. AST was applied to capillary endothelial (b-End3) cells, macrophages, and RPE cells to analyze the activation of NF-kappaB and the expression of inflammatory molecules. RESULTS: The index of CNV volume was significantly suppressed by treatment with AST compared with that in vehicle-treated animals. AST treatment led to significant inhibition of macrophage infiltration into CNV and of the in vivo and in vitro expression of inflammation-related molecules, including VEGF, IL-6, ICAM-1, MCP-1, VEGFR-1, and VEGFR-2. Importantly, AST suppressed the activation of the NF-kappaB pathway, including IkappaB-alpha degradation and p65 nuclear translocation. CONCLUSIONS: AST treatment, together with inflammatory processes including NF-kappaB activation, subsequent upregulation of inflammatory molecules, and macrophage infiltration, led to significant suppression of CNV development. The present study suggests the possibility of AST supplementation as a therapeutic strategy to suppress CNV associated with AMD.

PMID: 18385091 [PubMed - indexed for MEDLINE]

1: Biol Pharm Bull. 2006 Apr;29(4):684-8. Links
Antihypertensive potential and mechanism of action of astaxanthin: III. Antioxidant and histopathological effects in spontaneously hypertensive rats.Hussein G, Goto H, Oda S, Sankawa U, Matsumoto K, Watanabe H.
International Research Center for Traditional Medicine, Toyama Prefecture, Japan. ghazihussein@hotmail.com

We investigated the effects of a dietary astaxanthin (ASX-O) on oxidative parameters in spontaneously hypertensive rats (SHR), by determination of the level of nitric oxide (NO) end products nitrite/nitrate (NO2-/NO3-) and lipid peroxidation in ASX-O-treated SHR. Oral administration of the ASX-O significantly reduced the plasma level of NO2-/NO3- compared to the control vehicle (p<0.05). The lipid peroxidation level, however, was reduced in both ASX-O- and olive oil-treated groups. We also analyzed the post-treatment effects of ASX-O on the vascular tissues by examining the changes in the aorta and coronary arteries and arterioles. The dietary ASX-O showed significant reduction in the elastin bands in the rat aorta (p<0.05). It also significantly decreased the [wall : lumen] aerial ratio of the coronary arteries. These results suggest that ASX-O can modulate the oxidative condition and may improve vascular elastin and arterial wall thickness in hypertension.

PMID: 16595899 [PubMed - indexed for MEDLINE]

1: Histol Histopathol. 2008 Feb;23(2):179-86. Links
Down-regulation of lysyl oxydase-like in aging and venous insufficiency.Pascual G, Mendieta C, Mecham RP, Sommer P, Bellón JM, Buján J.
Department of Medical Specialities, Networking Research Center on Biomaterials and Nanomedicine (CIBER-BBN), Alcalá de Henares, Madrid, Spain.

BACKGROUND: Elastin expression is higher in tissues where elastic fibres are essential for the correct maintenance of function such as blood vessels. Elastin expression usually diminishes with age, however, it may be re-expressed in response to injury or repair processes. Some authors attribute the characteristic loss of elasticity of the varicose vein to a drop in the population of smooth muscle cells in the media layer. A reduction in elastin has been observed in chronic venous insufficiency, but little is known about some of the factors involved in elastin synthesis such as lysyl oxidases. The aim of this study was to examine the in vivo expression of the elastin precursor, tropoelastin (TE), and lysyl oxidase-like 1 (LOXL1), a cross-linking enzyme responsible for elastin polymer deposition. The effects of age on these expression patterns were also evaluated. METHODS: Saphenous vein segments were obtained during surgery from organ donors (controls, n=20) and subjects with venous insufficiency (varicose veins, n=20). Both these groups were subdivided according to subject age into <50 years (n=10) and >or=50 years (n=10). Control and varicose vein tissue specimens were immunolabelled using anti-tropoelastin and anti-LOXL1 antibodies and also subjected to Western blot analysis. RESULTS: Our results indicate that the levels of these markers of elastin synthesis (LOXL/tropoelastin) in the vein wall diminish in a significant way (p<0.05) with the age factor. Excluding the age factor, LOXL1 was significantly decreased in the varicose condition (p<0.05). In the younger pathological population they showed an inverse relationship (LOXL decreased, tropoelastin increased). CONCLUSIONS: The already established reduction in elastin in the varicose condition may be related, at least in part, to the decreased LOXL1 levels observed here. These events could reduce spontaneous reticulation of elastin and the partial loss of tissue elasticity in this group of patients.

PMID: 17999374 [PubMed - indexed for MEDLINE]

1: Eur J Vasc Endovasc Surg. 1999 Oct;18(4):349-54. Links
Venous morphology predicts class of chronic venous insufficiency.Jones GT, Solomon C, Moaveni A, van Rij AM, Thomson IA, Galvin I.
Department of Surgery, Otago Medical School, Dunedin, New Zealand.

OBJECTIVES: this study aimed to determine specific morphological differences in long saphenous veins from patients with various grades of chronic venous insufficiency. DESIGN: comparable veins from a control group were compared with patients with either primary varicose veins or those with associated skin changes including venous ulcers. MATERIALS: below-knee segments of saphenous vein were examined from a total of 64 patients. METHODS: veins were examined for elastic-tissue disruption and endothelial-cell changes and comparisons made between clinical groups. RESULTS: elastic-tissue disruption, as measured by fragmentation of the elastic lamina and the percentage of the intimal-medial boundary containing elastin, increased with increasing severity of venous disease. Moreover, endothelial cells became more densely packed, as measured by endothelial cell and endothelial-cell nuclei density, with increasing severity of disease. Other measures such as the density of multinucleated "giant" endothelial cells and the number of nuclei per "giant" cell did not correlate with venous disease, however. CONCLUSIONS: this study demonstrates that several morphological characteristics of superficial saphenous veins correlate with severity of venous disease. In particular, the alterations to the structure of elastic tissue within these veins appears indicative of the progressive nature of chronic venous insufficiency. Copyright 1999 Harcourt Publishers Ltd.

PMID: 10550272 [PubMed - indexed for MEDLINE]

1: Biol Pharm Bull. 2005 Jun;28(6):967-71. Links
Antihypertensive potential and mechanism of action of astaxanthin: II. Vascular reactivity and hemorheology in spontaneously hypertensive rats.Hussein G, Goto H, Oda S, Iguchi T, Sankawa U, Matsumoto K, Watanabe H.
International Research Center for Traditional Medicine, Toyama Prefecture, Japan. ghazihussein@hotmail.com

The current study was designed to determine the effects of a dietary astaxanthin (ASX-O) on vascular reactivity in spontaneously hypertensive rats (SHR), in order to verify its antihypertensive action mechanism. We evaluated contractions induced by phenylephrine (Phe), angiotensin II (Ang II) and the xanthine/xanthine oxidase (Xan/XOD) system, and relaxations induced by sodium nitroprusside (SNP) as well as endothelium-dependent relaxations mediated by acetylcholine (ACh) in thoracic aorta of the SHR, with and without ASX-O intervention. We also investigated the effects of ASX-O on blood rheology using a microchannel array system. In this study, ASX-O showed a significant modulatory effect on nitric oxide (NO)-induced vasorelaxation by the NO-donor SNP (p<0.05). However, it did not show significant effects in restoring the impaired endothelium-dependent relaxation to ACh in the SHR. On the other hand, the constrictive effects by Phe, Ang II and Xan/XOD were ameliorated by ASX-O (p<0.05). ASX-O also demonstrated significant hemorheological effect by decreasing the microchannel transit time of whole blood. In conclusion, the results suggest that ASX-O may act in modulating the blood fluidity in hypertension, and that the antihypertensive effects of ASX-O may be exerted through mechanisms including normalization of the sensitivity of the adrenoceptor sympathetic pathway, particularly [alpha]-adrenoceptors, and by restoration of the vascular tone through attenuation of the Ang II- and reactive oxygen species (ROS)-induced vasoconstriction.

PMID: 15930728 [PubMed - indexed for MEDLINE]

1: Mol Carcinog. 2005 Jun;43(2):75-85. Links
Transcriptional regulation of connexin 43 expression by retinoids and carotenoids: similarities and differences.Vine AL, Leung YM, Bertram JS.
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA.

Gap junctions, connexons, are formed by assembly of trans-membrane connexin proteins and have multiple functions including the coordination of cell responses. Most human tumors are deficient in gap junctional communication (GJC) and restoration of GJC by forced expression of connexins reduces indices of neoplasia. Expression of connexin 43 (Cx43), the most widely-expressed connexin family member, is upregulated by cancer-preventive retinoids and carotenoids in normal and preneoplastic cells; an action considered of mechanistic significance. However, the molecular mechanism for upregulated expression is poorly understood. The retinoic acid receptor antagonist Ro 41-5253 was capable of suppressing retinoid-induction Cx43 luciferase reporter construct in F9 cells, but did not suppress reporter activity induced by the non-pro-vitamin A carotenoids astaxanthin or lycopene, indicating that retinoids have separate mechanisms of gene activation than non-pro-vitamin A carotenoids. Neither class of compound required protein synthesis for induction of Cx43 mRNA, nor was the 5.0 h half-life of Cx43 mRNA altered, indicating direct transcriptional activation. The responsive region was found within -158 bp and +209 bp of the transcription start site; this contains a Sp1/Sp3 GC-box to which Sp1 and Sp3 were bound, as revealed by electrophoretic mobility shift assays (EMSA), but no retinoic acid response element (RARE). Site directed mutagenesis of this GC-box resulted in increased basal levels of transcription and loss of responsiveness to a synthetic retinoid. In this construct astaxanthin and lycopene produced marginally, but not significantly higher, reporter activity than the control.

PMID: 15754312 [PubMed - indexed for MEDLINE]

1: J Neurosci Res. 2005 Jun 15;80(6):798-808. Links
Connexin43, the major gap junction protein of astrocytes, is down-regulated in inflamed white matter in an animal model of multiple sclerosis.Brand-Schieber E, Werner P, Iacobas DA, Iacobas S, Beelitz M, Lowery SL, Spray DC, Scemes E.
Department of Neurology, Albert Einstein College Medicine, Bronx, NY 10461, USA. ebrand@aecom.yu.edu

Both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), its animal model, involve inflammatory attack on central nervous system (CNS) white matter, leading to demyelination and axonal damage. Changes in astrocytic morphology and function are also prominent features of MS and EAE. Resting astrocytes form a network that is interconnected through gap junctions, composed mainly of connexin43 (Cx43) protein. Although astrocytic gap junctional connectivity is known to be altered in many CNS pathologies, little is known about Cx43 expression in inflammatory demyelinating disease. Therefore, we evaluated the expression of Cx43 in spinal cords of EAE mice compared with healthy controls. Lumbar ventral white matter areas were heavily infiltrated with CD11beta-immunoreactive monocytes, and within these infiltrated regions loss of Cx43 immunoreactivity was evident. These regions also showed axonal dystrophy, demonstrated by the abnormally dephosphorylated heavy-chain neurofilament proteins. Astrocytes in these Cx43-depleted lesions were strongly glial fibrillary acidic protein reactive. Significant loss (38%) of Cx43 protein in EAE mouse at the lumbar portion of spinal cords was confirmed by Western blot analysis. Decreased Cx43 transcript level was also observed on cDNA microarray analysis. In addition to changes in Cx43 expression, numerous other genes were altered, including those encoding adhesion and extracellular matrix proteins. Our data support the notion that, in addition to damage of myelinating glia, altered astrocyte connectivity is a prominent feature of inflammatory demyelination. Copyright 2005 Wiley-Liss, Inc.

PMID: 15898103 [PubMed - indexed for MEDLINE]

1: Angiology. 2003 Jul-Aug;54 Suppl 1:S13-8. Links
Chronic venous insufficiency: dysregulation of collagen synthesis.Sansilvestri-Morel P, Rupin A, Badier-Commander C, Fabiani JN, Verbeuren TJ.
Division of Angiology, Servier Research Institute, Suresnes, France.

Varicose vein disease is a common condition. Its pathology is not well characterized. A disorganization of smooth muscle cells and extracellular matrix components in the venous wall have been described. The objective of this paper is to offer an explanation for the abnormal distensibility of varicose veins. The content of hydroxyproline was quantified in control and varicose human saphenous veins. The synthesis of collagen types I, III, and V was quantified in cultured venous smooth muscle cells and dermal fibroblasts of control subjects and patients with varicose veins. The proportion of collagen type III in the heterofibrils composed by collagen types I, III, and V was calculated. The level of hydroxyproline was increased in varicose veins, suggesting an increased content of collagen. This augmentation of collagen in diseased tissues appears to be correlated with an increase of collagen type I since the collagen I mRNA was overexpressed in varicose veins, whereas collagen type III mRNA was not altered. The quantification of collagen synthesis in cultured cells shows that proportion of collagen type III was significantly decreased in cultured smooth muscle cells and dermal fibroblasts derived from patients with varicose veins. The results indicate a deficiency in collagen type III in patients with varicose veins. Since collagen type III is involved in tissue elasticity, these results offer an explanation for the abnormal distensibility of varicose veins. Moreover, this defect seems to be generalized in different tissues and argues in favor of a genetic alteration of remodeling in these patients.

PMID: 12934753 [PubMed - indexed for MEDLINE]

1: Ann Pharm Fr. 2003 Jul;61(4):234-42. Links
[Cytochromes P450, vascular tone varicosis][Article in French]


Bertrand C, Batt AM.
Centre du Médicament, INSERM U525, 30 rue Lionnois, F54000 Nancy.

Chronic venous insufficiency is a complex pathology that is characterised by various symptoms such as venous hypertension, endothelium dysfunction, vascular wall remodelling due to smooth muscle cell hypertrophy and inflammation resulting from the release of pro-inflammatory cytokines from invading leucocytes. Age, hormonal excess, multiparity, sedentariness and prolonged heat exposure represent the main risk factors among many others including hypoxia and shear stress which also influence varicose pathology. Some members of the large cytochrome P450 (CYP) family that are involved in the biotransformation of steroids and arachidonic acid have been shown to be expressed in various cell types (endothelial cells, smooth muscle cells, macrophages) of cardiovascular tissues. The vascular metabolites produced by CYPs are important factors in the regulation of the vascular tone. Most CYPs are markedly expressed in all the cell types of varicose veins in relation to the overall vascular remodelling associated with smooth muscle hypertrophy and periendothelial leucocyte infiltration. Because CYPs produce various vasoactive arachidonic acid metabolites, their increased expression could play a role in the impairement of the vascular tone which is characteristic of varicose veins. Furthermore, polymorphisms, particularly the CYP3A5 polymorphism, may promote changes in the level of expression of CYPs and thus may influence varicose vein formation or functions. This suggests that CYP modulators could be potentially active drugs to treat chronic venous insufficiency symptoms and control its evolution.

PMID: 12843956 [PubMed - indexed for MEDLINE]

1: Curr Drug Metab. 2004 Jun;5(3):225-34. Links
Cytochrome P450 in neurological disease.Liu M, Hurn PD, Alkayed NJ.
Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Advances in a multitude of disciplines support an emerging role for cytochrome P450 enzymes and their metabolic substrates and end-products in the pathogenesis and treatment of central nervous system disorders, including acute cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such as Alzheimer's and Parkinson's disease, as well as epilepsy, multiple sclerosis and psychiatric disorders, including anxiety and depression. The neural tissue contains its own unique set of P450 genes that are regulated in a manner that is distinct from their molecular regulation in peripheral tissue. Furthermore, brain P450s catalyze the formation of important brain signaling molecules, such as neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics and environmental neurotoxins. These unique characteristics allow this family of proteins and their metabolites to perform such vital functions in brain as neurotrophic support, neuroprotection, control of cerebral blood flow, temperature control, neuropeptide release, maintenance of brain cholesterol homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter levels and other functions important in brain physiology, development and disease.

PMID: 15180492 [PubMed - indexed for MEDLINE]

1: Clin Exp Pharmacol Physiol. 2004 May-Jun;31(5-6):295-301. Links
Cytochromes P450 are differently expressed in normal and varicose human saphenous veins: linkage with varicosis.Bertrand-Thiebault C, Ferrari L, Boutherin-Falson O, Kockx M, Desquand-Billiald S, Fichelle JM, Nottin R, Renaud JF, Batt AM, Visvikis S.
INSERM U525, 30 rue Lionnois, F-54000 Nancy, France.

The expression of cytochrome P450 (CYP) enzymes and cyclo-oxygenases (COX) was investigated in human saphenous veins by reverse transcription-polymerase chain reaction analysis. Non-varicose veins were obtained from patients undergoing aortocoronary bypass grafting, whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins. In non-varicose veins, CYP1B1, CYP2C, CYP2E1 and CYP4A11 were detected, whereas CYP2J2, CYP3A5, COX-1 and COX-2 were detected almost exclusively in varicose veins. CYP4F2 was not detectable. Except for CYP4A11, the levels of individual CYP mRNA were higher in varicose veins than in control veins. Smooth muscle cell volume, determined by a colour image-analysis system, was increased approximately 1.5-fold in varicose veins. Because CYPs and COXs produce various vasoactive compounds, increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology. Then, CYP or COX modulators may be potentially active in the treatment of chronic venous insufficiency.

PMID: 15191401 [PubMed - indexed for MEDLINE]

1: Circ Res. 2002 May 17;90(9):1020-7. Links

Comment in:
Circ Res. 2002 May 17;90(9):936-8.
Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids.Sun J, Sui X, Bradbury JA, Zeldin DC, Conte MS, Liao JK.
Vascular Medicine Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02139, USA.

Vascular smooth muscle cell (SMC) migration and proliferation contribute to neointimal hyperplasia and restenosis after vascular injury. The epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess vasodilatory, antiinflammatory, and fibrinolytic properties. To determine whether these compounds also possess antimigratory and antiproliferative properties, we stimulated rat aortic SMCs with either 20% serum or platelet-derived growth factor (PDGF-BB, 20 ng/mL). In a concentration-dependent manner, treatment with EETs, particularly 11,12-EET, inhibited SMC migration through a modified transwell filter by 53% to 60%. EETs, however, have no inhibitory effects on PDGF-stimulated SMC proliferation. Adenoviral-mediated overexpression of the CYP isoform, CYP2J2, in SMCs also inhibited serum- and PDGF-induced SMC migration by 32% and 26%, respectively; both effects of which were reversed by the CYP inhibitors SKF525A or clotrimazole, but not by the K(Ca) channel blocker, charybdotoxin, or the cyclooxygenase inhibitor, diclofenac. The effect of EETs correlated with increases in intracellular cAMP levels. Indeed, forskolin and 8-bromo-cAMP exert similar inhibitory effects on SMC migration as 11,12-EET and the effects of 11,12-EET were blocked by cAMP and protein kinase A (PKA) inhibitors. These findings indicate that EETs possess antimigratory effects on SMCs through the cAMP-PKA pathway and suggest that CYP epoxygenase-derived eicosanoids may play important roles in vascular disease and remodeling.

PMID: 12016269 [PubMed - indexed for MEDLINE]

Forskolin is a labdane diterpene that is produced by the Indian Coleus plant (Coleus forskohlii). Forskolin is commonly used to raise levels of cyclic AMP (cAMP) in the study and research of cell physiology. Forskolin resensitizes cell receptors by activating the enzyme adenylyl cyclase and increasing the intracellular levels of cyclic Adenosine Monophosphate (cyclic AMP or cAMP). Cyclic AMP is an important signal carrier that is necessary for the proper biological response of cells to hormones and other extracellular signals. It is required for cell communication in the hypothalamus/pituitary gland axis and for the feedback control of hormones. It acts by activating protein kinase A.

Potential medical use
Applied with rolipram, forskolin provides a route to inhibition of colon cancer cell growth and survival. [1]
Forskolin is a vasodilator.
To date, there have been more than two clinical studies examining the effectiveness of forskolin as a weight loss aid. Only one has been subject to peer-review and published in a medical journal. This clinical study also observed forskolin's role in significantly increasing lean mass, bone mass, and testosterone in the subjects involved.[2] This research has led to companies marketing forskolin as a Bodybuilding supplement.
Forskolin may be helpful to control the underlying cause of glaucoma. The sometimes successful use of forskolin to reduce intraocular pressure may be due to its unique ability to stimulate adenylate cyclase activity and increase cyclic adenosine monophosphate (cAMP) which regulates and activates critical enzymes required for the cellular energy required to move fluid out of the eye.
Increase skin's natural resistance to burning under UV light (see links below)
Stimulate a tanning response when applied topically.
Reduce urinary tract infections and enhance the ability of antibiotics to kill bacteria that normally survive.
Forskolin can also be used to promote nerve repair by increasing cAMP concentrations. Forskolin can activate or upregulate the proliferation of Schwann cells in culture, together with Fibroblast growth factor or Transforming Growth Factor-Beta.

Various experimental studies are underway in using Forskolin as an adjuvant in treatment for diseases such as Parkinsons and/or nerve damage caused by trauma/accident.

1: Arch Biochem Biophys. 2005 Jan 15;433(2):413-20. Links
Vascular protective effects of cytochrome p450 epoxygenase-derived eicosanoids.Spiecker M, Liao JK.
Department of Medicine II, St. Josef-Hospital, Bochum Gudrunstrasse 56 44791 Bochum, Germany. martin.spiecker@ruhr-uni-bochum.de <martin.spiecker@ruhr-uni-bochum.de>

Cytochrome P450 epoxygenases metabolize arachidonic acid to biologically active eicosanoids. Primary epoxidation products are four regioisomers of cis-epoxyeicosatrienoic acid (EET), 5,6-, 8,9-, 11,12-, and 14,15-EET. One of the predominant epoxygenase isoforms involved in EET formation belongs to the CYP2 gene family. In humans, the P450 epoxygenase, CYP2J2, is expressed in the cardiovascular system, namely the endothelium, vascular smooth muscle, and cardiomyocyte. CYP2J2 possesses vascular protective effects, which include but are not limited to, protection against ischemia-reperfusion injury, suppression of reactive oxygen species following hypoxia-reoxygenation, inhibition of the pro-inflammatory transcription factor, nuclear factor-kappaB (NF-kappaB), attenuation of vascular smooth muscle migration, and enhancement of a fibrinolytic pathway. Although regioisomers of EET elicit these effects to varying degrees, 11,12-EET appears to be the most potent with respect to anti-inflammatory, anti-migratory, and pro-fibrinolytic effects. Thus, CYP2J2 and its derived arachidonic acid metabolites may play important roles in regulating vascular function under normal and pathophysiological conditions.

PMID: 15581597 [PubMed - indexed for MEDLINE]