Biomedical subjects

Seppo Ylä-Herttuala

Publications and source records attributed to Seppo Ylä-Herttuala.

At least 19 recordsLinked to original sources

PubMed2007

Type I interferon response against viral and non-viral gene transfer in human tumor and primary cell lines.

BACKGROUND: Type I interferon (IFN-alpha/beta) response is one of the major host defence mechanisms against viruses. Some recent reports suggest that IFNs may interfere with the efficacy of both non-viral and virus-vector-mediated therapeutic gene transfer. METHODS: The type I IFN response upon different gene transfer methods in human tumor and primary cell lines was studied by analysing IFN-beta mRNA expression, secretion of type I IFNs and accumulation of IFN-alpha/beta-induced MxA protein (myxovirus resistance protein A). RESULTS: Infection with avirulent Semliki Forest virus A7[74] induced MxA protein accumulation and increased the IFN-beta mRNA level, whereas none of the studied virus vectors (adenovirus, CRAd, lentivirus or AAV) induced IFN response. However, plasmid DNA induced the accumulation of MxA protein when transfected with several commercial transfection reagents. RNA transfection appeared to be an efficient inducer of type I IFN response: replicating alphaviral RNA, eukaryotic total RNA, or mRNA all induced both MxA protein accumulation and IFN-beta expression. siRNA transfection failed to induce MxA response. CONCLUSIONS: The non-viral gene transfer methods have gained more interest in recent years due to their better safety profiles when compared to their viral counterparts. However, the efficiency of non-viral gene transfer is well below those reached by viral vector systems. The type I interferon response induced by non-viral methods may in part contribute to this inefficiency, while most currently used viral gene transfer vectors fail to induce or are able to suppress type I IFN response.

Animals↗

PubMed2006

Short and long-term effects of hVEGF-A(165) in Cre-activated transgenic mice.

We have generated a transgenic mouse where hVEGF-A(165) expression has been silenced with loxP-STOP fragment, and we used this model to study the effects of hVEGF-A(165) over-expression in mice after systemic adenovirus mediated Cre-gene transfer. Unlike previous conventional transgenic models, this model leads to the expression of hVEGF-A(165) in only a low number of cells in the target tissues in adult mice. Levels of hVEGF-A(165) expression were moderate and morphological changes were found mainly in the liver, showing typical signs of active angiogenesis. Most mice were healthy without any major consequences up to 18 months after the activation of hVEGF-A(165) expression. However, one mouse with a high plasma hVEGF-A(165) level died spontaneously because of bleeding into abdominal cavity and having liver hemangioma, haemorrhagic paratubarian cystic lesions and spleen peliosis. Also, two mice developed malignant tumors (hepatocellular carcinoma and lung adenocarcinoma), which were not seen in control mice. We conclude that long-term uncontrolled hVEGF-A(165) expression in only a limited number of target cells in adult mice can be associated with pathological changes, including possible formation of malignant tumors and uncontrolled bleeding in target tissues. These findings have implications for the design of long-term clinical trials using hVEGF-A(165) gene and protein.

Adenoviridae↗

PubMed2006

VEGF-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, NF-kappaB, and RAGE in atherosclerotic lesions of diabetic Watanabe heritable hyperlipidemic rabbits.

Plaque angiogenesis may be associated with the development of unstable and vulnerable plaques. Vascular endothelial growth factors (VEGFs) are potent angiogenic factors that can affect plaque neovascularization. Our objective was to determine the effect of diabetes on atherosclerosis and on the expression of angiogenesis-related genes in atherosclerotic lesions. Alloxan was used to induce diabetes in male Watanabe heritable hyperlipidemic (WHHL) rabbits that were sacrificed 2 and 6 months after the induction of diabetes. Nondiabetic WHHL rabbits served as controls. Blood glucose (Glc), serum-free fatty acids (FFA), and serum triglyceride levels were significantly higher in diabetic rabbits. Accelerated atherogenesis was observed in the diabetic WHHL rabbits together with increased intramyocellular lipids (IMCL), as determined by 1H-NMR spectroscopy. Atherosclerotic lesions in the diabetic rabbits had an increased content of macrophages and showed significant increases in immunostainings for vascular endothelial growth factor (VEGF)-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, RAGE, and NF-kappaB. VEGF-A165 and VEGFR-2 mRNA levels were significantly increased in aortas of the diabetic rabbits, where a trend toward increased plaque vascularization was also observed. These results suggest that diabetes accelerates atherogenesis, up-regulates VEGF-A, VEGF-D, and VEGF receptor-2 expression, and increases NF-kappaB, RAGE, and inflammatory responses in atherosclerotic lesions in WHHL rabbits.

Alloxan↗

PubMed2006

Non-specific binding of [18F]FDG to calcifications in atherosclerotic plaques: experimental study of mouse and human arteries.

PURPOSE: [(18)F]FDG has been used as an inflammation marker and shown to accumulate in inflammatory atherosclerotic plaques. The aim of this study was to investigate the uptake and location of [(18)F]FDG in atherosclerotic plaque compartments. METHODS: The biodistribution of intravenously administered [(18)F]FDG was analysed in atherosclerotic LDLR/ApoB48 mice (n=11) and control mice (n=9). Digital autoradiography was used to detect the ex vivo distribution in frozen aortic sections. In vitro binding of [(18)F]FDG in human atherosclerotic arteries was also examined. RESULTS: The uptake of [(18)F]FDG was significantly higher in the aorta of atherosclerotic mice as compared with the control mice. Autoradiography of excised arteries showed higher [(18)F]FDG uptake in the plaques than in the healthy vessel wall (mean ratio +/-SD 2.7+/-1.1). The uptake of [(18)F]FDG in the necrotic, calcified sites of the advanced atherosclerotic lesions was 6.2+/-3.2 times higher than that in the healthy vessel wall. The in vitro studies of human arterial sections showed marked binding of [(18)F]FDG to the calcifications but not to other structures of the artery wall. CONCLUSION: In agreement with previous studies, we observed [(18)F]FDG uptake in atherosclerotic plaques. However, prominent non-specific binding to calcified structures was found. This finding warrants further studies to clarify the significance of this non-specific binding in human plaques in vivo.

Animals↗

PubMed2006

Biology of vascular endothelial growth factors.

Angiogenesis is the process by which new blood vessels are formed from existing vessels. The vascular endothelial growth factors (VEGFs) are considered as key molecules in the process of angiogenesis. The VEGF family currently includes VEGF-A, -B, -C, -D, -E, -F and placenta growth factor (PlGF), that bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. VEGF-C and VEGF-D also play a crucial role in the process of lymphangiogenesis. Here, we review the biology of VEGFs and evaluate their role in pathological angiogenesis and lymphangiogenesis.

Arthritis, Rheumatoid↗

PubMed2006

Adventitial VEGF165 gene transfer prevents lumen loss through induction of positive arterial remodeling after PTCA in porcine coronary arteries.

Negative arterial remodeling still plays an important role in the pathogenesis of coronary restenosis even in the era of interventional stenting (e.g. arterial narrowing occurs proximal and distal of a stented segment). Previous studies suggest that increased angiogenesis and inhibited regression of injury-induced adventitial microvessels prevents negative remodeling. We have examined the effect of local vascular endothelial growth factor (VEGF(165)) gene transfer on adventitial microvessel angiogenesis/regression and arterial remodeling after coronary angioplasty. Twenty pigs underwent angioplasty, each one in two major coronary arteries, followed by plasmid liposome gene transfer with either VEGF(165) or control gene LacZ (50 microg DNA with 50 microg of Lipofectine) into the (peri)adventitial space using a needle injection catheter. Arteries were examined at days 1, 7, 14, and 28. Local delivery of VEGF(165) gene into the outer compartments of balloon-injured porcine coronary arteries reduced lumen area loss due to distinct positive remodeling (arterial enlargement). Prevention of adventitial microvessel regression, enhanced adventitial elastin accumulation, reduced adventitial myofibroblast numbers, and a pronounced adventitial inflammatory response considered as a part of arterial healing seem to be the main VEGF-mediated mechanisms indicating the therapeutic potential of VEGF for restenosis prevention.

Angioplasty, Balloon, Coronary↗

PubMed2006

Stable RNA interference: comparison of U6 and H1 promoters in endothelial cells and in mouse brain.

BACKGROUND: RNA interference (RNAi) is a post-transcriptional RNA degradation process, which has become a very useful tool in gene function studies and gene therapy applications. Long-term cellular expression of small interfering RNA (siRNA) molecules required for many gene therapy applications can be achieved by lentiviral vectors (LVs). The two most commonly used promoters to drive the short hairpin RNA (shRNA) expression are the human U6 small nuclear promoter (U6) and the human H1 promoter (H1). METHODS: We investigated whether there is any significant difference between the efficiencies of U6 and H1 in LV-mediated RNAi using green fluorescent protein (GFP) as a target gene by flow cytometry and real-time reverse-transcription polymerase chain reaction (RT-PCR) in endothelial cells. Also, we compared the efficiencies of U6 and H1 in the GFP transgenic mouse brain after stereotactic LV injection. RESULTS: We show that the U6 promoter is more efficient than H1 in GFP silencing in vitro, leading to 80% GFP knockdown at an average of one integrated vector genome per target cell genome. The silencing is persistent for several months. In addition, the U6 promoter is superior to H1 in vivo and leads to stable GFP knockdown in mouse brain for at least 9 months. CONCLUSIONS: These results show that LV-mediated RNAi is a powerful gene-silencing method for the long-term inhibition of gene expression in vitro and in vivo.

Animals↗

PubMed2006

Targeted magnetic resonance imaging of Scavidin-receptor in human umbilical vein endothelial cells in vitro.

Current therapeutic approaches to treat cancer are often hampered by the lack of specificity of the drugs used for therapy. Scavidin, a novel fusion protein expressed on cell membranes, could be utilized for targeting of therapeutic molecules. Scavidin exploits the high binding affinity between avidin and biotin and is capable of mediating endocytosis of a bound ligand. In the current study we evaluated the efficiency of biotinylated ultrasmall superparamagnetic iron oxide (USPIO) particles in Scavidin-expressing human umbilical vein endothelial cell (HUVEC) cultures in vitro as a novel receptor-targeted magnetic resonance imaging contrast agent. Biotinylated USPIO (bUSPIO) were targeted to Scavidin adenovirus-transduced HUVECs in vitro. Scavidin expressing cells were capable of binding and mediating endocytosis of the bUSPIO in vitro, which led to a significant decrease in T2 relaxation times, and a loss of signal intensity in comparison to controls. The findings were confirmed with Prussian blue staining for iron and detection of Scavidin by bound biotinylated horseradish peroxidase. Our data shows that biotinylated ligands target specifically to Scavidin-expressing HUVEC in vitro. The utilization of Scavidin gene transfer ex vivo thus constitutes a platform for potential ligand delivery via cell therapy and time-independent imaging of biologic processes.

Adenoviridae↗

PubMed2006

Extracellular superoxide dismutase with vaccinia virus anti-inflammatory protein 35K or tissue inhibitor of metalloproteinase-1: Combination gene therapy in the treatment of vein graft stenosis in rabbits.

Bypass graft surgery is limited by stenosis of vein grafts. Neointimal formation in vein graft stenosis is affected by oxidative stress, acute inflammatory response, and proliferation. Gene therapy offers a novel treatment strategy for vein graft stenosis because gene transfer can be done ex vivo during the graft operation. In this study we used adenovirus-mediated ex vivo gene transfer of extracellular superoxide dismutase (EC-SOD) alone or in combination with tissue inhibitor of metalloproteinase-1 (TIMP-1) or vaccinia virus antiinflammatory protein 35K to prevent vein graft stenosis in a jugular vein graft model in normocholesterolemic New Zealand White rabbits. Vein grafts were analyzed 14 and 28 days after the gene transfer, using histological methods. It was found that at the 2-week time point EC-SOD + 35K and EC-SOD + TIMP-1 combinations delivered by gene transfer were the most efficient treatments in decreasing neointimal formation. At the 4-week time point the effect was seen only in the EC-SOD + TIMP-1 combination group. The combination of antiinflammatory proteins (EC-SOD + 35K) was the most effective in reducing macrophage accumulation, which was still significant at the 4-week time point, but this did not prevent vein graft thickening. In conclusion, oxidative, inflammatory, and proliferative processes are important for neointimal formation in vein graft stenosis. In the rabbit model of vein graft disease, combination gene therapy with antioxidative, antiinflammatory, and antiproliferative genes was effective in decreasing neointimal formation. This may be because two different genes may more efficiently affect different pathogenetic pathways at the early stage of the disease process than gene transfer approaches based on single genes.

Animals↗

PubMed2006

Dietary (n-3) fatty acids reduce plasma F2-isoprostanes but not prostaglandin F2alpha in healthy humans.

(n-3) Fatty acids are unsaturated and are therefore easily subject to oxidization; however, they have several beneficial health effects, which include protection against cardiovascular diseases. The aim of this study was to investigate whether (n-3) fatty acids, with a controlled fat quality in the background diet, affect nonenzymatic and enzymatic lipid peroxidation and antioxidant status in humans. A total of 162 men and women in a multicenter study (The KANWU study) were randomly assigned to a diet containing a high proportion of saturated fatty acids or monounsaturated fatty acids (MUFA) for 3 mo. Within each diet group, there was a second random assignment to supplementation with fish-oil capsules [3.6 g (n-3) fatty acids/d] or placebo. Biomarkers of nonenzymatic and enzymatic lipid peroxidation in vivo were determined by measuring 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) and prostaglandin F(2alpha) (PGF(2alpha)) concentrations in plasma at baseline and after 3 mo. Antioxidant status was determined by measuring plasma antioxidant capacity with an enhanced chemiluminescence assay. The plasma 8-iso-PGF(2alpha) concentration was significantly decreased after 3 mo of supplementation with (n-3) fatty acids (P = 0.015), whereas the PGF(2alpha) concentration was not affected. The antioxidant status was not affected by supplementation of (n-3) fatty acids, but was improved by the background diet with a high proportion of MUFA. We conclude that supplementation with (n-3) fatty acids decreases nonenzymatic free radical-catalyzed isoprostane formation, but does not affect cyclooxygenase-mediated prostaglandin formation.

Administration, Oral↗

PubMed2006

Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation.

Lymphatic vessel plasticity and stability are of considerable importance when attempting to treat diseases associated with the lymphatic vasculature. Development of lymphatic vessels during embryogenesis is dependent on vascular endothelial growth factor (VEGF)-C but not VEGF-D. Using a recombinant adenovirus encoding a soluble form of their receptor VEGFR-3 (AdVEGFR-3-Ig), we studied lymphatic vessel dependency on VEGF-C and VEGF-D induced VEGFR-3 signaling in postnatal and adult mice. Transduction with AdVEGFR-3-Ig led to regression of lymphatic capillaries and medium-sized lymphatic vessels in mice under 2 weeks of age without affecting collecting lymphatic vessels or the blood vasculature. No effect was observed after this period. The lymphatic capillaries of neonatal mice also regressed partially in response to recombinant VEGFR-3-Ig or blocking antibodies against VEGFR-3, but not to adenovirus-encoded VEGFR-2-Ig. Despite sustained inhibitory VEGFR-3-Ig levels, lymphatic vessel regrowth was observed at 4 weeks of age. Interestingly, whereas transgenic expression of VEGF-C in the skin induced lymphatic hyperplasia even during embryogenesis, similar expression of VEGF-D resulted in lymphangiogenesis predominantly after birth. These results indicate considerable plasticity of lymphatic vessels during the early postnatal period but not thereafter, suggesting that anti-lymphangiogenic therapy can be safely applied in adults.

Adenoviridae↗

PubMed2006

An update on angiogenic gene therapy: vascular endothelial growth factor and other directions.

Therapeutic angiogenesis is a promising new concept for the treatment of tissue ischemia and other related medical conditions or processes, such as wound healing. Members of the vascular endothelial growth factor (VEGF) family are among the most powerful modulators of vascular growth; they regulate vascular growth and maintenance during embryogenesis and in adults. Despite progress in basic research and preclinical animal studies of therapeutic angiogenesis, significant problems still exist in translating experimental findings into beneficial clinical approaches. This review summarizes these problems and highlights recent findings in the field of therapeutic angiogenesis using VEGF and other factors, with special reference to potential clinical applications. Also, in order to better optimize vectors, doses and treatment approaches, it is proposed that the analysis of new parameters is introduced. These parameters consist of: i) spreading throughout and reaching appropriate cells in the target tissue, ii) transfection efficiency, iii) expression strength, and iv) duration of expression. It is envisaged that this 'STED' analysis will aid the clinical development of gene therapy.

Adenoviridae↗

PubMed2005

Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis.

BACKGROUND: For clinically relevant proangiogenic therapy, it would be essential that the growth of the whole vascular tree is promoted. Vascular endothelial growth factor (VEGF) is well known to induce angiogenesis, but its capability to promote growth of larger vessels is controversial. We hypothesized that blood flow remodels vascular growth during VEGF gene therapy and may contribute to the growth of large vessels. METHODS AND RESULTS: Adenoviral (Ad) VEGF or LacZ control gene transfer was performed in rabbit hindlimb semimembranous muscles with or without ligation of the profound femoral artery (PFA). Contrast-enhanced ultrasound and dynamic susceptibility contrast MRI demonstrated dramatic 23- to 27-fold increases in perfusion index and a strong decrease in peripheral resistance 6 days after AdVEGF gene transfer in normal muscles. Enlargement by 20-fold, increased pericyte coverage, and decreased alkaline phosphatase and dipeptidyl peptidase IV activities suggested the transformation of capillaries toward an arterial phenotype. Increase in muscle perfusion was attenuated, and blood vessel growth was more variable, showing more sprouting angiogenesis and formation of blood lacunae after AdVEGF gene transfer in muscles with ligated PFA than in normal muscles. Three-dimensional ultrasound reconstructions and histology showed that the whole vascular tree, including large arteries and veins, was enlarged manifold by AdVEGF. Blood flow was normalized and enlarged collaterals persisted in operated limbs 14 days after AdVEGF treatment. CONCLUSIONS: This study shows that (1) blood flow modulates vessel growth during VEGF gene therapy and (2) VEGF overexpression promotes growth of arteries and veins and induces capillary arterialization leading to supraphysiological blood flow in target muscles.

Adenoviridae↗

PubMed2005

Vascular endothelial growth factor C-induced collateral formation in a model of myocardial ischemia.

BACKGROUND: Besides being a known lymphangiogenic activator, vascular endothelial growth factor (VEGF)-C may express angiogenic potential by proteolytic cleavage and activation of endothelial cells. We assessed myocardial collateral formation and functional changes after adenovirus-mediated VEGF-C gene transfer in an ischemic porcine model. METHODS: Fifteen Landrace piglets underwent Ameroid-induced gradual occlusion of the left circumflex artery (LCx) and consequent progressive myocardial ischemia. Three weeks after Ameroid placement, the animals underwent gated 99mTc SPECT during rest and stress, in vivo angiography and 18FDG PET. Pigs were randomized to intramyocardial injections of adenoviruses encoding vascular endothelial growth factor (VEGF-C; n = 7) or control beta-galactosidase (LacZ; n = 5). Four weeks later, the examinations were repeated and histology was analyzed. RESULTS: Angiography showed significant progression of LCx stenosis in both groups during the treatment period. Left ventricular wall thickening (LVWT) at the LCx area in gated 99mTc SPECT remained unchanged in the VEGF-C group, indicating that VEGF-C prevented progression of myocardial ischemia, whereas LVWT deteriorated in the LacZ group (p = 0.042). Semi-quantitative assessment of 18FDG PET suggests more reduction in ischemia in the adVEGF-C group than in controls (p = 0.052). Angiography showed significant clustering of collaterals in the adVEGF-C gene transfer area compared that in LacZ (p = 0.004). von Willebrand factor staining revealed a significantly (p = 0.03) greater number of microvessels in the adVEGF-C-treated myocardium. CONCLUSIONS: This appears to be the first large-animal study in which, during progressive ischemia, functional and metabolic benefits of intramyocardial VEGF-C gene transfer were apparent. VEGF-C-induced collateral formation occurred at the site of gene transfer. The angiogenic potency of VEGF-C deserves further study as a therapeutic option.

Adenoviridae↗

PubMed2005

Autoantibodies against oxidized LDL are associated with severe chest pain attacks in patients with coronary heart disease.

Autoantibodies against oxidized low-density lipoprotein (oxLDL) predict the progression of atherosclerosis. Several studies have shown that oxLDL is present in atherosclerotic lesions and that several factors present in active atherosclerotic plaques can oxidatively modify LDL. Oxidation of LDL induces production of autoantibodies against oxLDL (oxLDLab) that can be measured using an EIA test. Our aim was to see whether oxLDLab are associated with severe chest pain attacks in coronary heart disease (CHD) patients. Patients having two- or three-vessel CHD, as assessed by coronary angiography, and their siblings were recruited into the study (n = 568, mean age 55.8 years, range 29.3-83.2 years). Nondiabetic patients having a history of severe chest pain attacks had significantly higher oxLDLab levels (0.611 +/- 0.56) than those who did not have a history of severe chest pain attacks (0.487 +/- 0.40) (p = 0.027), even though age, cholesterol level, body mass index, and blood pressure were similar in both groups. However, no difference was found in oxLDLab levels in diabetic patients with or without a history of severe chest pain attacks. Increased levels of oxLDL autoantibodies are associated with severe chest pain attacks in nondiabetic patients with CHD.

Adult↗

PubMed2005

Gene transfers of vascular endothelial growth factor-A, vascular endothelial growth factor-B, vascular endothelial growth factor-C, and vascular endothelial growth factor-D have no effects on atherosclerosis in hypercholesterolemic low-density lipoprotein-receptor/apolipoprotein B48-deficient mice.

BACKGROUND: The role of vascular endothelial growth factors (VEGFs) in large arteries has been proposed to be either vasculoprotective or proatherogenic. Because VEGF family members are used for human therapy, it is important to know whether they could enhance atherogenesis. We tested the effects of the members of the VEGF gene family on atherogenesis in LDL-receptor/apolipoprotein (apo) B48 double-knockout (LDLR/apoB48) mice using systemic adenoviral gene transfer. METHODS AND RESULTS: Six groups of LDLR/apoB48-deficient mice (n=110) were kept 3 months on a Western-type diet. After 6 weeks of diet, mice were injected via tail vein with recombinant adenoviruses expressing VEGF-A, -B, -C, or -D or LacZ (1 x 10(9) PFU) or rhVEGF-A protein (2 microg/kg) and euthanized 6 weeks later. Also, older mice (n=36) were injected after 4 months on the diet and euthanized 6 weeks later (total time on the diet, 22 weeks) to evaluate the effects of gene transfers on the development of more mature lesions. Aortas were analyzed for the presence of macroscopic lesions, cross-sectional lesion areas, neovascularization, and cellular composition of the lesions. All groups had equivalent plasma cholesterol and triglyceride levels. Gene transfers with recombinant adenoviruses or administration of rhVEGF-A protein had no statistically significant effects on en face atherosclerotic lesions in the aorta, cross-sectional lesion area, neovascularization, or cellular composition of the lesions. CONCLUSIONS: This study shows no proatherogenic effects of adenovirus-mediated gene transfers of VEGF-A, -B, -C, or -D in the LDLR/apoB48-deficient hypercholesterolemic mice, in which lipoprotein profile and atherosclerosis closely resemble those in human disease.

Adenoviridae↗

PubMed2005

Stabilized HIF-1alpha is superior to VEGF for angiogenesis in skeletal muscle via adeno-associated virus gene transfer.

Therapeutic angiogenesis provides a potential alternative for the treatment of cardiovascular ischemic diseases. Vascular endothelial growth factor (VEGF) is an important component of the angiogenic response to ischemia. Here we used adeno-associated virus (AAV) gene delivery to skeletal muscle to examine the effects of VEGF vs. a stabilized form of hypoxia-inducible factor-1alpha (HIF-1alpha). The recombinant AAVs were injected into mouse tibialis anterior muscle, and their effects were analyzed by immunohistochemistry and functional assays. These analyses showed that stabilized HIF-1alpha markedly increase capillary sprouting and proliferation, whereas VEGF164 or VEGF120 induced only proliferation of endothelial cells without formation of proper capillary structures. The Evans Blue permeability assay indicated that, unlike VEGF, HIF-1alpha overexpression did not increase vascular leakiness in the transduced muscle. Doppler ultrasound imaging showed that vascular perfusion in the HIF-1alpha treated muscles was significantly enhanced when compared to the controls and not further improved by co-expression of the arteriogenic growth factors angiopoietin-1 or platelet-derived growth factor-B. Our results show that AAV-mediated transduction of a stabilized form of HIF-1alpha can circumvent the problems associated with overexpression of individual angiogenic growth factors. HIF-1alpha should thus offer a potent alternative for pro-angiogenic gene therapy.

Animals↗

PubMed2005

Antibodies against oxidized LDL and cardiolipin and mortality in patients with coronary heart disease.

The association between antibodies against oxidized LDL (oxLDL) and cardiolipin and the risks of death and cardiovascular disease events were evaluated in patients with established coronary heart disease (CHD). The patients (mean age: 61 years, range: 33-74 years) were participants in the EUROASPIRE study; 108 of them had undergone coronary artery bypass surgery, 106 had balloon angioplasty, 101 had a diagnosis of acute myocardial infarction (AMI), and 98 acute myocardial ischemia. Antibodies against oxLDL and cardiolipin were measured and incidence of CHD events and deaths were followed up for 5 years in 284 men and 129 women. During the follow-up 36 patients died and 21 had AMI. After adjustment for cardiovascular disease risk factors the relative risks (RR [95% confidence interval]) of death were 1 (reference), 2.50 (0.97-6.49) and 2.21 (0.85-5.80) in increasing tertile categories of anti-oxLDL antibody titers, respectively (P for trend 0.16). The risks of CHD-death or AMI combined were 1 (reference), 2.61 (1.02-6.65) and 1.06 (0.37-3.03) in increasing tertile categories of anticardiolipin antibody titers, respectively (P for trend 0.03). In conclusion, the results suggest that antibodies against oxLDL and cardiolipin are not major predictors of risks of death and CHD events in patients with established CHD.

Aged↗