-
[show abstract]
[hide abstract]
ABSTRACT: Multiple populations of stem cells have been indicated to potentially participate in regeneration of injured organs. Especially, embryonic stem cells (ESC) and recently inducible pluripotent stem cells (iPS) receive a marked attention from scientists and clinicians for regenerative medicine because of their high proliferative and differentiation capacities. Despite that ESC and iPS cells are expected to give rise into multiple regenerative applications when their side effects are overcame during appropriate preparation procedures, in fact their most recent application of human ESC may, however, reside in their use as a tool in drug development and disease modeling. This review focuses on the applications of stem cells in pharmaceutical biotechnology. We discuss possible relevance of pluripotent cell stem populations in developing physiological models for any human tissue cell type useful for pharmacological, metabolic and toxicity evaluation necessary in the earliest steps of drug development. The present models applied for preclinical drug testing consist of primary cells or immortalized cell lines that show limitations in terms of accessibility or relevance to their in vivo counterparts. The availability of renewable human cells with functional similarities to their in vivo counterparts is the first landmark for a new generation of cell-based assays. We discuss the approaches for using stem cells as valuable physiological targets of drug activity which may increase the strength of target validation and efficacy potentially resulting in introducing new safer remedies into clinical trials and the marketplace. Moreover, we discuss the possible applications of stem cells for elucidating mechanisms of disease pathogenesis. The knowledge about the mechanisms governing the development and progression of multitude disorders which would come from the cellular models established based on stem cells, may give rise to new therapeutical strategies for such diseases. All together, the applications of various cell types derived from patient specific pluripotent stem cells may lead to targeted drug and cellular therapies for certain individuals.
Current pharmaceutical biotechnology 09/2011; 12(11):1760-73. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Nrf2 transcription factor plays a crucial role in protection of cells against oxidative stress. Under normal conditions Nrf2 is sequestered in cytoplasm by a cytoskeletal protein, Keapl. Situation is changed under stressful conditions,when electrophiles and/or reactiveoxygen species (ROS) cause dissociation of Nrf2 from Keap1. As a consequence, Nrf2 is translocated to the nucleus, that leads to activation of cytoprotective genes involved in electrophile conjugation, excretion of xenobiotics, ROS scavenging and stabilization of cellular redox potential. Amongst xenobiotics, there are many mutagenic and cancerogenic factors. Phase I and II enzymes are responsible for inactivation and removal of such compounds. It has been shown that induction of phase II enzymes confers protection upon insult by reactive metabolites of cancerogens or ROS. Since Nrf2 is an inductor of those enzymes it can be considered as a potential target for cancer chemoprevention. Similarly, in case of neurodegenerative disorders, which pathogenesis is connected to oxidative stress, Nrf2 may be important for therapeutical and preventive strategies
Postepy biochemii 01/2010; 56(2):147-55.
-
[show abstract]
[hide abstract]
ABSTRACT: Studies on the mechanisms of adaptation to adverse hypoxic conditions led to the discovery of hypoxia inducible factors, HIF-1 and HIF-2. These factors regulate the expression of many genes which allow cells to adapt to changes in oxygen concentration and counteract the effects of oxidative stress developing in hypoxia. Regulation of HIF activity is dependent on the prolyl hydroxylases activity and results in its degradation under normoxic conditions by the ubiquitin-dependent proteasome pathway. Recent studies indicate a specific role of reactive oxygenspecies (ROS) generated by the mitochondrial respiratory chain in regulation of HIF stability. ROS affect also the level of nitric oxide (NO), leading to a reduction in its concentration by forming reactive nitrogen species (RNS), which may cause the increase in oxidative and nitrosative stress. Regulation of HIF activity by ROS, NO and RNS is currently the subject of many studies and seems to be a mechanism dependent on conditions (e.g., normoxia/hypoxia), or concentrations of individual stimulators (e.g. NO donor used).
Postepy biochemii 01/2010; 56(2):156-64.
-
[show abstract]
[hide abstract]
ABSTRACT: Taurine chloramine (TauCl) and Taurine bromamine (TauBr), products of the neutrophil myeloperoxidase halide system, exert anti-inflammatory properties. They inhibit the production of a variety of inflammatory mediators, such as prostaglandin E2 (PGE2), nitric oxide (NO) and proinflammatory cytokines. Heme oxygenase-1 (HO-1), a stress inducible enzyme, degrades heme to biliverdin, free iron and carbon monoxide (CO), which are involved in the anti-inflammatory and antioxidant actions of HO-1. Recently we have demonstrated that taurine haloamines induce the expression of HO-1 in inflammatory cells. In this study we examined whether HO-1 participates in taurine haloamines-mediated suppression of proinflammatory cytokine production. We have shown that TauCl/TauBr and CO inhibit the production of TNF-alpha, IL-12 and IL-6, in a similar dose-dependent manner. However, the suppressor activity of TauCl was not altered in HO-1 deficient mice. Therefore, HO-1 and TauCl may independently regulate the production of proinflammatory cytokines. We suggest that TauCl and TauBr provide a link between the two antioxidant systems: the cysteine pathway and the heme oxygenase system.
Advances in experimental medicine and biology 02/2009; 643:439-50. · 1.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The incidence of inflammatory bowel diseases (Crohn’s
disease and ulcerative colitis) is increasing constantly through
out the world. Many aspects of their pathogenesis are still not
clear, although it is known that genetic predispositions (e.g.
certain gene mutations) as well as environmental factors are
involved in the onset of the disease. Heme oxygenase-1
(HO-1) catalyses the enzymatic breakdown of heme into
the biliverdin, which is subsequently transformed into
bilirubin, ferrous ion and carbon monoxide. It has been shown
to control some of the inflammatory reactions. The results
of many studies suggest its dysregulated expression in
the inflamed tissue. Experiments on animal models show that
induction of HO-1 expression may have the beneficial effects
on the course of disease and can significantly decrease its
complications.
Przegląd Gastroenterologiczny. 01/2009; 4(6):283-287.
-
[show abstract]
[hide abstract]
ABSTRACT: Angiogenesis is indispensable for the growth of solid tumors and angiogenic factors are also involved in the progression of hematological malignancies. Targeting the formation of blood vessels is therefore regarded as a promising strategy in cancer therapy. Interestingly, besides demonstration of some beneficial effects of novel anti-angiogenic compounds, recent data on the activity of already available drugs point to their potential application in anti-angiogenic therapy. Among these are the statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Statins are very efficient in the treatment of hypercholesterolemia in cardiovascular disorders; however, their effects are pleiotropic and some are not directly related to the inhibition of cholesterol synthesis. Some reports particularly highlight the pro-angiogenic effects of statins, which are caused by low, nanomolar concentrations and are regarded as beneficial for the treatment of cardiovascular diseases. On the other hand, the anti-angiogenic activities, observed at micromolar concentrations of statins, may be of special significance for cancer therapy. Those effects are caused by the inhibition of both proliferation and migration and induction of apoptosis in endothelial cells. Moreover, the statin-mediated inhibition of vascular endothelial growth factor synthesis, the major angiogenic mediator, may contribute to the attenuation of angiogenesis. It has been suggested that the anti-cancer effect of statins can be potentially exploited for the cancer therapy. However, several clinical trials aimed at the inhibition of tumor growth by treatment with very high doses of statins did not provide conclusive data. Herein, the reasons for those outcomes are discussed and the rationale for further studies is presented.
Current Cancer Drug Targets 01/2006; 5(8):579-94. · 4.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hydrogen peroxide is an important mediator of intracellular signaling, which potently enhances the expression of heme oxygenase-1 (HO-1) and upregulates synthesis of vascular endothelial growth factor (VEGF). The purpose of the present study was to explore the involvement of HO-1 in regulation of H(2)O(2)-mediated induction of VEGF synthesis. We provide genetic evidence that basal and H(2)O(2)-induced VEGF synthesis is partially dependent on HO-1. Inhibition of HO-1 activity by tin protoporphyrin (SnPPIX) resulted in downregulation of VEGF synthesis in murine fibroblasts and human keratinocytes. The relationship between HO-1 and VEGF was corroborated by using cells derived from HO-1 knockout mice, which demonstrated lower basal and H(2)O(2)-induced production of VEGF. Additionally, knock out of HO-1 gene impaired induction of VEGF by hemin, lysophosphatidylcholine, and prostaglandin-J(2). Our results provide confirmation for the involvement of HO-1 in regulation of angiogenesis.
Biochemical and Biophysical Research Communications 02/2005; 326(3):670-6. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In the majority of potential applications gene therapy will require an effective transfer of a transgene in vivo resulting in high-level and long-term transgene expression, all in the absence of significant toxicity or inflammatory responses. The most efficient vehicles for delivery of foreign genes to the target tissues are modified adenoviruses. Adenoviral vectors of the first generation, despite the high infection efficacy, have an essential drawback: they induce strong immune response, which leads to short term expression of the transgene, and limits their usefulness in clinical trials. In contrast, helper-dependent adenoviral vectors (HdAd) lacking all viral coding sequences display only minimal immunogenicity and negligible side-effects, allowing for long-term transgene expression. Thus, HdAd vehicles have become the carrier of choice for adenoviral vector-mediated experimental gene therapy, effectively used in animal models for delivery of transgenes into the liver, skeletal muscle, myocardium or brain. Strong and long-lasting expression of therapeutic genes has allowed for successful treatment of dyslipidemias, muscular dystrophy, obesity, hemophilia, and diabetes. Additionally, the large cloning capacity of HdAd, up to 37 kb, facilitates the use of physiologically regulated, endogenous promoters, instead of artificial viral promoter sequences. This enables also generation of the single vectors expressing multiple genes, which can be potentially useful for treatment of polygenic diseases. In this review we characterize the basic features of HdAd vectors and describe some of their experimental and potential clinical applications.
Acta biochimica Polonica 02/2005; 52(3):589-99. · 1.49 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 15-Deoxy-delta12,14-Prostaglandin-J2 (15d-PGJ2), an endogenous ligand of PPARgamma transcription factor, modifies expression of many genes involved in inflammation and angiogenesis. Enzyme which contributes to regulation of both these processes is endothelial nitric oxide synthase (eNOS). Our aim was to investigated the effect of 15d-PGJ2 on eNOS in human umbilical vein endothelial cells (HUVEC). We demonstrated that 24 h incubation of HUVEC with 15d-PGJ2 (1-10 microM) does not influence eNOS. On the contrary, the longer exposure (48-72 h) resulted in concentration-dependent inhibition of eNOS mRNA and protein expressions and led to reduction in eNOS enzymatic activity by approximately 50%. This effect was mediated by regulation of the transcription rate from eNOS promoter, what may be associated with inhibition of AP-1 binding capacity. The stability of mRNA was unchanged. Since none of the observed effects could be mimicked by troglitazone, a more potent PPARgamma ligand, we suppose that 15d-PGJ2 diminishes expression of eNOS via PPARgamma-independent mechanisms.
Prostaglandins & other lipid mediators 11/2004; 74(1-4):11-28. · 2.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Angiogenesis occurring during reparative or pathological processes is driven by various inflammatory mediators that influence the synthesis of growth factors. It has been recognized recently that reactive oxygen species (ROS) and nitric oxide (NO) are important modulators of the synthesis and activity of vascular endothelial growth factor (VEGF), a major angiogenic molecule. Moreover, heme oxygenase-1 (HO-1), a ubiquitous stress-inducible enzyme that is induced by ROS and NO, was recently discovered to be involved in angiogenesis. Genetic overexpression of HO-1 enhanced VEGF synthesis and augmented formation of vascular capillaries, improving the blood flow in ischemic tissues. In addition, by-products of HO-1 exert numerous effects that can also influence angiogenesis in both positive and negative ways. Therefore, the antiinflammatory effects of HO-1 can attenuate the excess formation of blood vessels in inflammatory angiogenesis. In this review, the recent data on the role of HO-1 in angiogenesis are critically discussed. It is suggested that further studies using potent and specific augmentation of HO-1 gene expression by viral vectors, as well as targeted, specific inhibition of HO-1 expression, are required to elucidate fully the complex role of this enzymatic pathway in angiogenesis.
Antioxidants and Redox Signaling 11/2004; 6(5):858-66. · 8.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Synthesis of vascular endothelial growth factor (VEGF), the major angiogenic molecule, is induced by nitric oxide (NO) in various cell types, including vascular smooth muscle cells (VSMC). Therefore, compounds which inhibit NO generation can also influence VEGF synthesis. Here we investigated the effect of increased glucose concentration (25 mM vs. 5.5 mM) on cytokine-induced VEGF synthesis in rat VSMC. The cells growing in the medium containing 5.5 mM glucose and exposed to IL-1-beta, TNF-alpha and IFN-gamma induced expression of an inducible isoform of nitric oxide synthase (NOS II). This is followed by generation of NO and the concomitant expression of VEGF gene and release of VEGF protein. In contrast, 25 mM glucose impaired induction of NOS II expression and thus NO synthesis was lower than in 5.5 mM glucose. Consequently, the VEGF promoter activation was attenuated, resulting in decreased mRNA synthesis and lower production of VEGF protein. The results indicate that abnormally high concentrations of glucose can impair generation of NO and the NO-dependent VEGF synthesis. This may play a role in the development and progression of vascular dysfunctions in cardiovascular diseases.
Life Sciences 11/2004; 75(21):2573-86. · 2.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Nitric oxide (NO) and reactive oxygen species (ROS) are emerging as important regulators of angiogenesis. NO enhances VEGF synthesis in several cell types and is required for execution of VEGF angiogenic effect in endothelial cells. Similarly, hydrogen peroxide induces VEGF synthesis and recent studies indicate the involvement of ROS in signaling downstream of VEGF stimulation. VEGF synthesis can not only be enhanced by gene transfer of VEGF but also by overexpression of NO synthase genes. Here, we examined the possibility of augmentation of VEGF production by gene transfer of copper/zinc superoxide dismutase (CuZnSOD, SOD1). Overexpression of human SOD1 in mouse NIH 3T3 fibroblasts increased SOD activity, enhanced intracellular generation of H2O2 and significantly stimulated VEGF production as determined by increase in VEGF promoter activity, VEGF mRNA expression and VEGF protein synthesis. The stimulatory effect on VEGF synthesis induced by SOD1 gene transfer was reverted by overexpression of human catalase. The effect of H2O2 produced by engineered cells is mediated by activation of hypoxia-inducible factor response element (HRE) as well as Sp1 recognition site of VEGF promoter. This data suggest the feasibility of stimulation of angiogenesis by overexpression of SOD1.
Molecular and Cellular Biochemistry 10/2004; 264(1-2):169-81. · 2.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We compared effects of vascular endothelial growth factor-121 (VEGF121) and vascular endothelial growth factor-165 (VEGF165) on generation of NO in HUVEC and the involvement of NO in VEGF121- and VEGF165-induced angiogenesis. VEGF stimulated synthesis of NO within seconds, reaching peak concentrations of 450 +/- 25 and 180 +/- 15 nmol/l for VEGF121, and VEGF165, respectively. The VEGF121 increased NO production for about 40 s while VEGF165-stimulated NO release lasted only for about 20 s. Accordingly, cGMP elevation was stronger in VEGF121- than in VEGF165-treated cells. The VEGF121 was a very weak mitogen but strong chemoattractant for HUVEC, whereas VEGF165 potently induced both cell proliferation and migration. NO appeared to be involved in the endothelial migration and morphogenesis but not in the proliferation. NO was also a permissive molecule for VEGF121- but not for VEGF165-induced capillary sprouting in spheroid culture. In conclusion, VEGF121 is a stronger stimulator of endothelial nitric oxide synthase (eNOS) activity, and angiogenic potential of VEGF121 is more reliant on NO contribution.
Growth Factors 04/2004; 22(1):19-28. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The vascular endothelial growth factor (VEGF) is produced in response to hypoxia or inflammatory cytokines. In normoxia VEGF synthesis is upregulated by 15-deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)) via induction of heme oxygenase-1 (HO-1). Here we compared the influence of 15d-PGJ(2) on VEGF expression in human microvascular endothelial cells in normoxia (approximately 20% O(2)) and hypoxia ( approximately 2% O(2)). Regardless of the oxygen concentration, 15d-PGJ(2) inhibited activity of hypoxia inducible factor-1 (HIF-1), the major hypoxic regulator of VEGF. However, in normoxic conditions 15d-PGJ(2) (1-10microM) activated the VEGF promoter and increased synthesis of the VEGF protein. Concomitantly, it strongly induced expression of HO-1. In contrast, in hypoxia, 15d-PGJ(2) decreased VEGF promoter activity and reduced VEGF release by 50%. Inhibition of HO-1 activity additionally attenuated VEGF synthesis in hypoxia. We conclude that induction of HO-1 by 15d-PGJ(2) results in augmentation of VEGF synthesis in normoxia. In hypoxia, however, the stimulatory effect of HO-1 is outweighed by 15d-PGJ(2)-mediated inhibition of the HIF-1 pathway.
Biochemical and Biophysical Research Communications 02/2004; 314(1):31-8. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: HMG-CoA reductase inhibitors (statins) can modulate the formation of new blood vessels, but the reports on their contribution to angiogenesis are contradictory. Therefore, we investigated whether the effect of statins is dependent either on the concentration of the drug or on the cell type.
Under basal conditions human vascular smooth muscle cells (HVSMC) and microvascular endothelial cells (HMEC-1) constitutively generate and release vascular endothelial growth factor (VEGF). In contrast, primary macrovascular endothelial cells (HUVEC) produce minute amounts of VEGF. Different statins (atorvastatin, simvastatin and lovastatin, 1-10 micromol/l) significantly reduced basal and cytokine-, nitric oxide- or lysophosphatidylcholine (LPC)-induced VEGF synthesis in HMEC-1 and HVSMC. Interestingly, at the same concentrations statins upregulated VEGF generation in HUVEC. Furthermore, statins exerted dual, concentration-dependent influence on angiogenic activities of HUVEC as determined by tube formation assay. At low concentrations (0.03-1 micromol/l) the pro-angiogenic activity of statins is prevalent, whereas at higher concentrations statins inhibit angiogenesis, despite increasing VEGF synthesis.
Our data show that statins exert concentration- and cell type-dependent effects on angiogenic activity of endothelial cells and on VEGF synthesis. The data are of relevance for elucidating the differential activity of statins on angiogenesis in cardiovascular diseases and cancer.
Atherosclerosis 11/2003; 170(2):229-36. · 3.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The activity of heme oxygenase enzymes (HOs) is responsible for the endogenous source of carbon monoxide (CO). Their activities can be inhibited by tin protoporphyrin-IX (SnPPIX). Recent data indicate the involvement of HOs in the regulation of angiogenesis. Here, we investigated the role of the HO pathway in the production and angiogenic activity of vascular endothelial growth factor (VEGF) in endothelial cells treated with SnPPIX, or cultured in the presence of a CO-releasing molecule (CO-RM). Addition of CO-RM or induction of HO-1 by hemin resulted in a threefold elevation in CO production in culture medium (up to 20.3 microg/L) and was associated with a 30% increase in VEGF synthesis. Much higher levels of CO (up to 60 microg/L) and a further increase in VEGF production (by 277%) were measured in cells treated with prostaglandin-J(2), a potent activator of HO-1. SnPPIX prevented the induction of CO generation and inhibited VEGF synthesis. Moreover, SnPPIX reduced the VEGF-elicited angiogenic activities of endothelial cells by decreasing their proliferation (by 26%), migration (by 46%), formation of tubes on Matrigel (by 48%), and outgrowth of capillaries from endothelial spheroids (by 30%). In contrast, overexpression of HO-1 or incubation of cells with CO-RM led to an increase in capillary sprouting. Thus, HO activity up-regulates VEGF production and augments the capability of endothelial cells to respond to exogenous stimulation.
Antioxidants and Redox Signaling 05/2003; 5(2):155-62. · 8.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Vascular endothelial growth factor (VEGF) is the major molecule governing angiogenesis, defined as the growth of blood vessels from vascular structure. There is abundant evidence that nitric oxide (NO) is an effector molecule mediating the activity of VEGF. By binding to its receptors, VEGF initiates the signaling cascades leading to NO production and angiogenic activation of endothelial cells. Recent data show that NO induces VEGF synthesis in numerous cell types, including vascular smooth muscle cells, macrophages, keratinocytes, and tumor cells. NO enhances VEGF production by augmenting its expression through activation of Akt kinase, followed by induction of several transcription factors, of which stabilization of hypoxia-inducible factor (HIF-1) is the critical step. With respect to its effect on VEGF expression, NO mimics hypoxia, the classical activator of HIF-1 and VEGF synthesis. The effect of NO on VEGF production is also mediated by heme oxygenase, an enzyme generating carbon monoxide, which appears to stimulate VEGF release. In this review, we attempt to elucidate the molecular mechanisms underlying the effects of NO on VEGF synthesis. We also discuss some discrepant data and suggest explanations for various aspects of the NO-VEGF relationship.
Antioxidants and Redox Signaling 03/2003; 5(1):123-32. · 8.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Heme oxygenase-1 (HO-1), an inducible enzyme degrading heme to biliverdin, iron and carbon monoxide, is involved in regulation of inflammation and angiogenesis. Tin protoporphyrin (SnPPIX) and zinc protoporphyrin (ZnPPIX) are commonly used as competitive inhibitors of HO-1. We aimed to compare the effects of SnPPIX and ZnPPIX on the production of vascular endothelial growth factor (VEGF), activity of inducible nitric oxide synthase (iNOS) and cell viability. All experiments were performed on rat vascular smooth muscle cells and murine RAW264.7 macrophages treated with 3-10 microM protoporphyrins. Some cells were additionally stimulated with IL-1beta or with lipopolysaccharide. After a 24 h incubation period SnPPIX and ZnPPIX significantly reduced the generation of VEGF in vascular smooth muscle cells and RAW264.7, both in resting and stimulated cells. The inhibitory potentials of both protoporphyrins on VEGF synthesis were very similar. In contrast, analysis of iNOS activity revealed that results obtained with different HO-1 inhibitors are discrepant. Generation of nitric oxide by iNOS was significantly increased by SnPPIX but strongly decreased by ZnPPIX. Similar differences were observed when cell viability was compared. SnPPIX improved the cell survival rate, whereas the same doses of ZnPPIX exerted some cytotoxic effects. In summary, SnPPIX and ZnPPIX can be used as HO-1 inhibitors in some experimental models. However, these compounds produce also HO-independent effects, which can make the interpretation of experiments very uncertain. Thus the involvement of the HO-1 pathway should be always confirmed by more specific methods.
Acta biochimica Polonica 02/2003; 50(1):69-79. · 1.49 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-inducible nuclear receptor that functions as a transcription factor involved in lipid metabolism, inflammatory response and angiogenesis. The most potent endogenous PPARgamma activator is 15-deoxy-Delta(12,14)prostaglandin-J(2) (15d-PGJ(2)), whereas synthetic ligands include the oral antidiabetic drugs thiazolidinediones (TZDs). Activation of PPARgamma was reported to decrease the synthesis of matrix metalloproteinases (MMPs) in vascular smooth muscle cells and macrophages. We aimed to investigate the effect of PPARgamma ligands on expression of MMP-1 and urokinase plasminogen activator (uPA) in human microvascular endothelial cells (HMEC-1). We found that treatment of HMEC-1 with 15d-PGJ(2) increased the synthesis of MMP-1 protein up to 168% comparing to untreated cells. TZDs (ciglitazone and troglitazone), more potent activators of PPARgamma in HMEC-1, did not influence MMP-1 production, arguing against the involvement of PPARgamma in this process. Importantly, the stimulatory effect of 15d-PGJ(2) was reversed by the antioxidant N-acetyl-cysteine (NAC), suggesting a contribution of oxidative stress. We demonstrated also that 15d-PGJ(2) did not change the activity of MMP-1 promoter, but increased the stability of MMP-1 mRNA. In contrast, 15d-PGJ(2) very potently inhibited the synthesis of uPA. This effect was in part mimicked by ciglitazone and troglitazone implying an involvement of PPARgamma. Accordingly, NAC did not modify the inhibitory effect of 15d-PGJ(2) on uPA expression. In conclusion, we postulate that 15d-PGJ(2) may differently regulate the synthesis of proteases involved in angiogenesis: it upregulates MMP-1 expression in HMEC-1 through induction of oxidative stress, and inhibits uPA synthesis partly by activation of PPARgamma.
Acta biochimica Polonica 02/2003; 50(3):677-89. · 1.49 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Carbon monoxide (CO) is an odorless, tasteless and colorless gas which is generated by heme oxygenase enzymes (HOs). HOs degrade heme releasing equimolar amounts of CO, iron and biliverdin, which is subsequently reduced to bilirubin. CO shares many properties with nitric oxide (NO), an established cellular messenger. Both CO and NO are involved in neural transmission and modulation of blood vessel function, including their relaxation and inhibition of platelet aggregation. CO, like NO, binds to heme proteins, although CO binds only ferrous (FeII) heme, whereas NO binds both ferrous and ferric (FeIII). CO enhances the activity of guanylate cyclase although it is less potent than NO. In contrast, CO inhibits other heme proteins, such as catalase or cytochrome p450. The effects of CO on gene expression can be thus varied, depending on the cellular microenvironment and the metabolic pathway being influenced. In this review the regulation of gene expression by HO/CO in the cardiovascular system is discussed. Recent data, derived also from our studies, indicate that HO/CO are significant modulators of inflammatory reactions, influencing the underlying processes such as cell proliferation and production of cytokines and growth factors.
Acta biochimica Polonica 02/2003; 50(1):31-47. · 1.49 Impact Factor
