Biomedical subjects

Franz Weidinger

Publications and source records attributed to Franz Weidinger.

16 recordsLinked to original sources

PubMed2026

Impact of renal dysfunction on immediate versus staged revascularization of non-culprit lesions in patients with ST segment elevation myocardial infarction: a pre-specified subgroup analysis of the randomized MULTISTARS AMI trial.

BACKGROUND: Renal dysfunction might affect outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD) undergoing percutaneous coronary intervention (PCI). METHODS: In MULTISTARS AMI, patients with STEMI and MVD were randomized to immediate or staged PCI of non-culprit lesions. In this pre-specified analysis, patients were stratified according to the presence of renal dysfunction at baseline, defined at an estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73 m2. Patients with an eGFR < 30 ml/min/1.73 m2 were excluded from the trial. The primary endpoint was a composite of death, non-fatal myocardial infarction, stroke, unplanned revascularization, or hospitalization for heart failure at 1 year. RESULTS: In MULTISTARS AMI, 108 (13%) of 832 patients had renal dysfunction. The primary endpoint occurred more frequently in patients with renal dysfunction (19.4% vs. 11.2%, unadjusted HR 1.82, 95% CI 1.13-2.94), primarily driven by higher rates of death. Among patients with renal dysfunction, the rates of the primary end point were 14.5% and 24.5% in the immediate and staged PCI groups (unadjusted HR 0.55, 95% CI 0.23-1.33). There was no interaction between renal dysfunction and the randomized treatment assignment with respect to the primary end point (adjusted HR 1.30, 95% CI 0.8-2.20, pint 0.82). The occurrence of acute renal insufficiency was statistically similar in patients with renal dysfunction who underwent immediate and staged PCI (10.9% vs. 18.9%, unadjusted HR 0.61, 95% CI 0.22-1.72, pint 0.09). Renal dysfunction at baseline emerged as a strong risk factor for the development of acute renal insufficiency (adjusted HR 5.0, 95% CI 2.30-10.70, p < 0.01). CONCLUSIONS: Outcomes with immediate compared to staged multivessel PCI did not appear significantly altered by the presence of renal dysfunction at baseline. (Supported by Boston Scientific; MULTISTARS AMI ClinicalTrials.gov number, NCT03135275).

Humans↗

PubMed2005

Transient impairment of flow-mediated vasodilation in patients with metabolic syndrome at moderate altitude (1,700 m).

BACKGROUND: The influence of moderate altitude on the cardiovascular system in patients with metabolic syndrome has not been investigated sufficiently, yet. The aim of this study was to assess the effect of acute and mid-term exposure to moderate altitude (1,700 m) on endothelial function in patients with metabolic syndrome. METHODS: Flow-mediated (FMD) and nitroglycerin-mediated vasodilation (NMD) were assessed in 18 patients with coronary risk factors on 5 occasions: (1) at location A (576 m), (2) on the first day at moderate altitude (location B, 1,700 m), (3) after 3 weeks at moderate altitude, (4) and (5) again at location A (6 and 16 weeks after the stay at moderate altitude, respectively). In addition, markers of lipid metabolism, serum erythropoietin and endothelin were measured. RESULTS: FMD on the first day at moderate altitude was similar compared to baseline FMD at location A (7.0 +/- 3.3 vs. 7.4 +/- 4.6%; NS). A 3-week stay at moderate altitude was associated with a significant reduction in FMD (7.4 +/- 4.6 vs. 3.8 +/- 2.5%; p < 0.05) despite a decrease in baseline diameter (4.5 +/- 0.3 vs. 4.3 +/- 0.4 mm; p < 0.05). Six weeks after returning to location A, FMD was still reduced compared to baseline (4.3 +/- 2.8%; p < 0.05) and after further 16 weeks, FMD returned to baseline values (5.5 +/- 3.5%). However, metabolic parameters improved significantly. In contrast, NMD and endothelin levels remained unchanged. CONCLUSION: In patients with metabolic syndrome, a sojourn of 3 weeks at moderate altitude leads to a prolonged, but reversible impairment of FMD. The discrepancy to improvement of other cardiovascular and metabolic parameters requires further investigation.

Adult↗

PubMed2005

Chronic heart failure is associated with vascular remodeling of the brachial artery.

AIMS: Endothelial dysfunction has been shown to correlate with severity of congestive heart failure (CHF) and recent data suggest morphological changes of peripheral vasculature to be associated with the syndrome. We therefore investigated the hypothesis that vascular remodeling is associated with functional changes in peripheral conduit arteries and with systemic overexpression of ET-1 in patients suffering from CHF. METHODS AND RESULTS: 57 consecutive patients referred to the Innsbruck Heart Failure and Transplantation Program (EF=23+/-7%) and 16 matched controls (EF=60+/-5%) were studied. Flow-mediated vasodilation (FMD), nitroglycerin-mediated vasodilation (NMD), wall thickness (WT), and incremental elastic modulus (Einc) were assessed by high-resolution ultrasound of the brachial artery. FMD (P=0.004) and NMD (P=0.02) were significantly higher in controls as compared to moderate and severe CHF patients. In contrast, brachial artery-wall thickness (BA-WT) was increased in severe CHF patients (P=0.038). BA-WT was significantly correlated with both FMD (r=-0.28; P=0.049) and NMD (r=-0.38; P=0.003), and with the Einc (r=0.45, P=0.001). Lumen diameter was not different among groups. In patients with BA-WT>0.31 mm, bigET-1 was higher compared to BA-WT<0.31 mm (P<0.05). CONCLUSION: CHF is associated with remodeling of the brachial artery, which is characterized by morphological, mechanical and functional changes of the vessel wall. Endothelin-1 may play a role in the vascular remodeling process.

Adult↗

PubMed2004

Endothelial function in a large community.

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Cardiovascular Diseases↗

PubMed2004

Adventitial response to intravascular brachytherapy in a rabbit model of restenosis.

BACKGROUND: The incidence of late major adverse cardiac events (MACE) after coronary brachytherapy is higher than in controls. Because expansive remodeling has been shown to correlate with poor clinical outcome after vascular interventions, we studied adventitial changes after intravascular irradiation in a rabbit model. METHODS: Twenty normolipidemic rabbits underwent balloon injury in both external iliac arteries. One artery was assigned for subsequent irradiation with a 90Y source (15 Gy or 30 Gy at 0.5 mm in the vessel wall). After four weeks morphometric measurements were made and cell density and collagen amount determined. Staining for Ki67 identified proliferating cells; apoptotic cells were identified by TUNEL staining. Proliferative and apoptotic indices were calculated as the number of respective positive cells/total cell count x100. RESULTS: The neointimal area decreased to 0.27 +/- 0.3 mm2 after irradiation compared with 0.55 +/- 0.2 mm2 in controls (p=0.007), whereas adventitial area increased from 0.62 +/- 0.3 mm2 to 0.87 +/- 0.3 mm2 (p=0.02). Irradiation reduced both the proliferative (0.95 +/- 2.6 vs. 3.73 +/- 4.7, p=0.026) and apoptotic (0.006 +/- 0.02 vs. 0.107 +/- 0.2, p=0.03) indices in the neointima, but not in the other arterial-wall layers. Collagen amount and arterial remodeling did not differ between the groups. There was no difference between 15 and 30 Gy in any of the parameters, although adventitial thickening was more pronounced in the high-dose group. CONCLUSIONS: In normolipidemic rabbits, intravascular beta-irradiation after balloon angioplasty is associated with an increase in neoadventitia and a reduction of neointima. It is conceivable that this phenomenon may contribute to the increased incidence of late MACE after vascular brachytherapy.

Angioplasty, Balloon↗

PubMed2004

C-reactive protein plasma levels but not factor VII activity predict clinical outcome in patients undergoing elective coronary intervention.

BACKGROUND: Both vascular inflammation as determined by C-reactive protein (CRP) and extrinsic coagulation as measured by factor VII activity (F VII) may predict clinical restenosis rate in patients with stable angina pectoris undergoing elective percutaneous coronary intervention (PCI). HYPOTHESIS: The primary objective of this study was to investigate the associations between baseline CRP levels, F VII activity, and restenosis rate after elective PCI in a 6-month follow-up period. METHODS: This prospective study included 81 patients aged > or = 19 years undergoing PCI for angiographically significant (> or = 70%) stenosis, with or without stenting, and 49 controls. Factor VII activity and CRP were measured in samples collected at angiography and 16-24 h post procedure after overnight fast. Successful PCI was defined as final diameter of < 50% with TIMI 3 flow and no complication within 1 h. After 6 months all patients who had undergone PCI were evaluated via a standardized questionnaire. Clinical restenosis was defined as the occurrence of a major adverse coronary events (MACE), within the follow-up period. RESULTS: Diagnostic angiography led to a significant increase in CRP levels after 16-20 h in patients with discrete CAD (n = 22) but not in patients without any signs of coronary atherosclerosis (n = 27). During a 6-month follow-up after PCI, 17 of 81 (21%) patients developed MACE. Tertiles of CRP levels independently predicted clinical restenosis, as it developed in 33.3% of patients with the highest CRP levels (0.7-4.8 mg/dl), in 16.6% of patients with second tertile CRP levels (0.23-0.69 mg/dl), and in 7.4% of patients with lowest tertile CRP levels (0.0-0.22 mg/dl). There was a significant difference in the restenosis rate between patients from the first and the third tertiles (p = 0.018). Successful PCI was associated with a significant decrease of mean CRP levels after 6 months, whereas PCI in patients suffering from MACE led to no change in CRP levels. There was no association between factor VII activity and clinical outcome after PCI, and F VII activity did not change over a 6-month period. CONCLUSIONS: In patients with stable angina pectoris undergoing elective PCI, increased preprocedural and 6-month follow-up CRP plasma levels are associated with clinical restenosis. Factor VII plasma activity lacks such correlations.

Adult↗

PubMed2004

Association between plasmin activation system and intravascular ultrasound signs of plaque instability in patients with unstable angina and non-st-segment elevation myocardial infarction.

BACKGROUND: The association between intravascular ultrasound (IVUS) signs of plaque instability and plasma levels of biomarkers was determined in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). METHODS: Fifty-two patients underwent coronary angiography and IVUS 8 +/- 5 hours after the onset of chest pain. IVUS analysis included plaque morphology, disruption, thrombi and eccentricity, lumen, external elastic membrane, and plaque plus media areas of culprit lesion and reference segments and arterial remodeling. Plasma levels of the thrombin activation system (thrombin-antithrombin complex [TAT], tissue factor pathway inhibitor [TFPI], and prothrombin fragments 1+2 [F1+2]) and plasmin activation system (tissue and urokinase-type plasminogen activator [t-PA and u-PA], plasminogen activator inhibitor-1 [PAI-1], and D-dimer) were measured with enzyme-linked immunosorbent assay kits before angiography. RESULTS: Elevated levels of TAT (7.2 +/- 6.0 microg/L), F1+2 (1.8 +/- 1.0 nmol/L), TFPI (179.1 +/- 131.0 ng/mL), PAI-1 (95.4 +/- 54.6 ng/mL), t-PA (10.6 +/- 8.8 ng/mL), and u-PA (2.6 +/- 0.9 ng/mL) were found in patients with UA/NSTEMI. The serum levels of D-dimer (40.0 +/- 39.5 ng/mL) remained in reference range. Expansive and constrictive remodeling were found in 18 (35%) and 12 (23%) patients, respectively. Expansive remodeling of the culprit lesion was associated with significantly higher plasma levels of PAI-1 (121.6 +/- 55.0 vs 87.7 +/- 61.5 and 77.4 +/- 42.8 ng/ml, P =.039), and u-PA (3.0 +/- 1.2 vs 2.2 +/- 0.5 and 2.5 +/- 0.7 ng/mL, P =.026) as compared with constrictive and neutral remodeling. Increased plasma levels of u-PA were associated with plaque rupture (3.0 +/- 0.7 vs 2.5 +/- 0.9 ng/mL, P =.062). Plasma levels of PAI-1 and u-PA correlated positively with plaque plus media (P =.0297 and P =.0093) and external elastic membrane areas (P =.010 and P =.0002). CONCLUSIONS: Elevated levels of biomarkers of plasmin activation system are associated with signs of plaque instability of culprit lesion in UA/NSTEMI and might therefore serve as non-invasive determinants of the population that is at high risk for subsequent adverse events.

Aged↗

PubMed2003

Plasma distribution of apoA-IV in patients with coronary artery disease and healthy controls.

Recent studies showed lower apolipoprotein A-IV (apoA-IV) plasma concentrations in patients with coronary artery disease (CAD). The actual distribution of the antiatherogenic apoA-IV in human plasma, however, is discussed controversially and it was never investigated in CAD patients. We therefore developed a gentle technique to separate the various apoA-IV-containing plasma fractions. Using a combination of precipitation of all lipoproteins with 40% phosphotungstic acid and 4 M MgCl2, as well as immunoprecipitation of all apoA-I-containing particles with an anti-apoA-I antibody, we obtained three fractions of apoA-IV: lipid-free apoA-IV (about 4% of total apoA-IV), apoA-IV associated with apoA-I (LpA-I:A-IV, 12%), and apoA-I-unbound but lipoprotein-containing apoA-IV (LpA-IV, 84%). We compared these three apoA-IV fractions between 52 patients with a history of CAD and 52 age- and sex-matched healthy controls. Patients had significantly lower apoA-IV levels when compared to controls (10.28 +/- 3.67 mg/dl vs. 11.85 +/- 2.82 mg/dl, P = 0.029), but no major differences for the three plasma apoA-IV fractions. We conclude that our gentle separation method reveals a different distribution of apoA-IV than in many earlier studies. No major differences exist in the apoA-IV plasma distribution pattern between CAD patients and controls. Therefore, the antiatherogenic effect of apoA-IV has to be explained by other functional properties of apoA-IV (e.g., the antioxidative characteristics).

Adult↗

PubMed2003

HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells.

OBJECTIVE: Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. METHODS AND RESULTS: Simvastatin, atorvastatin, and lovastatin (0.1 to 10 micro mol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-kappaB or AP-1-dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IkappaB-alpha protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1alpha. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells. CONCLUSIONS: HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-kappaB, AP-1, and hypoxia-inducible factor-1alpha. These findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases.

Atorvastatin↗

PubMed2003

Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells.

OBJECTIVES: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Atorvastatin↗

PubMed2002

Morphologic rather than functional or mechanical sonographic parameters of the brachial artery are related to angiographically evident coronary atherosclerosis.

OBJECTIVES: The purpose of this study was to determine the relationship among coronary atherosclerosis and functional, morphologic, and mechanical parameters assessed noninvasively within the brachial artery (BA). BACKGROUND: Flow-mediated vasodilation (FMD) of the BA, intima-media thickness (IMT) of the carotid artery, and distensibility of the aorta have been correlated with the presence of coronary artery disease (CAD). METHODS: The BA was examined with high-resolution ultrasound (13 MHz) in 117 male patients, in whom coronary angiography was performed. Coronary artery disease (> or =30% diameter stenosis in > or =1 major branch) was found in 84 patients, and 33 patients had smooth coronary arteries (non-CAD). Wall cross-sectional area (WCSA) was calculated from resting diameter and IMT. RESULTS: The BA-WCSA (5.3 +/- 1.5 mm(2) vs. 4.4 +/- 1.4 mm(2), p = 0.002) and IMT (0.37 +/- 0.07 mm vs. 0.31 +/- 0.07 mm, p < 0.001) were significantly greater in patients with CAD compared with non-CAD patients. Flow-mediated vasodilation and distensibility were similar among groups. Using logistic regression analyses adjusting for age, positive family history, hypertension, hypercholesterolemia, smoking, FMD, and distensibility, only WCSA (p < 0.01) and IMT (p < 0.001) correlated independently with the presence of CAD. CONCLUSIONS: Morphologic but not functional and mechanical parameters of the BA are associated with the presence of CAD. Among BA sonographic parameters, IMT and WCSA seem to be the most accurate ones for the estimation of coronary atherosclerotic risk.

Adult↗

PubMed2002

Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease.

OBJECTIVES: The aim of this study was to test a possible influence of atorvastatin on the production of vascular endothelial growth factor (VEGF) in patients with coronary artery disease (CAD) and in vitro. BACKGROUND: Vascular endothelial growth factor is suggested to be involved in the growth of atherosclerotic plaque by inducing its neovascularization. Hepatic hydroxymethyl glutaryl-coenzyme A reductase inhibitors (statins) are known to have atheroprotective effects beyond lipid lowering. METHODS: Blood was collected from 14 male hypercholesterolemic patients with angiographically confirmed CAD at baseline and after two months of atorvastatin therapy (20 mg/d) and from eight male control patients. In an ex vivo assay, human coronary artery smooth muscle cells (HCASMC) were incubated with the patient plasma collected before and after atorvastatin therapy. To test the direct effect of atorvastatin on VEGF synthesis in vitro, HCASMC were treated with atorvastatin (1, 3 and 10 microM). The VEGF concentration was measured by enzyme-linked immunosorbent assay. RESULTS: Atorvastatin therapy reduced VEGF plasma levels in CAD patients (from 31.1 +/- 6.1 to 19.0 +/- 3.6 pg/ml; p < 0.05). The VEGF plasma concentration tended to be higher in CAD patients before treatment compared to control patients (31.1 +/- 6.1 vs. 23.4 +/- 3.6 pg/ml; p = NS). Plasma collected before therapy induced significantly more VEGF in HCASMC compared to the plasma collected after treatment and compared to control cells. In vitro, atorvastatin decreased both the basal and the interleukin-1beta-induced VEGF release in HCASMC. CONCLUSIONS: These data suggest that atorvastatin may lower the plasma level of VEGF in CAD patients, which could represent a novel beneficial effect of this and perhaps other statins.

Anticholesteremic Agents↗

PubMed2002

Association of wall thickness of the brachial artery measured with high-resolution ultrasound with risk factors and coronary artery disease.

Intima-media thickness of the carotid and femoral arteries has been associated with coronary atherosclerosis and its clinical sequelae. The brachial artery (BA) is widely used for the assessment of flow-mediated vasodilation. The aim of this study was to examine whether BA wall thickness (WT) is associated with coronary artery disease (CAD) and risk factors. High-resolution ultrasound (13 MHz) examination of the BA was performed in 179 patients undergoing coronary angiography for the evaluation of chest pain. CAD (> or =30% diameter stenosis in > or =1 major branch) was found in 132 patients, whereas 47 patients had smooth coronary arteries. WT of the posterior BA wall (0.4 +/- 0.05 vs 0.35 +/- 0.06 mm, p <0.001) and wall index (WI) (WT/vessel diameter x 100; 16.1 +/- 0.0 vs 13.8 +/- 0.8, p <0.001) were greater in patients with than without CAD. On univariate analysis, WT and WI correlated with age, presence of CAD, systemic hypertension, maximum coronary diameter stenosis, and baseline diameter. On logistic regression analyses adjusting for age, cholesterol levels, systemic hypertension, smoking, and positive family history, WT (p <0.01) and WI (p = 0.02) remained significantly correlated with the presence of CAD. Thus, BA-WT is independently correlated with the presence of CAD. WT may provide a novel noninvasive marker of atherosclerosis that can be assessed together with flow-mediated vasodilation to yield functional and morphologic information in the same vessel.

Adult↗

PubMed2002

Short- and long-term changes of flow-mediated vasodilation in patients under statin therapy.

BACKGROUND: Flow-mediated vasodilation (FMD) of the brachial artery (BA) has been shown to improve in response to lipid-lowering therapy and other therapeutic interventions, usually within 1 to 2 months. Whether FMD remains improved under therapy in the longer term is unknown. HYPOTHESIS: The aim of this study was to examine the short- and long-term changes of FMD under statin therapy. METHODS: Flow-mediated vasodilation and nitroglycerin-mediated vasodilation (NMD) of the BA were measured with high-resolution ultrasound (13 MHz) at baseline and at 4 and 10 months in 18 consecutively recruited patients with coronary artery disease (CAD), in whom statin therapy was newly established. RESULTS: The decrease of total plasma cholesterol levels after 4 and 10 months of statin therapy (243 +/- 31 vs. 186 +/- 30 vs. 191 +/- 40 mg/dl; p < 0.001) was accompanied by an increase in FMD from 4.4 +/- 3.8% at baseline to 9.6 +/- 2.7% at 4 months and to 9.5 +/- 2.6% at 10 months (p < 0.001). Nitroglycerin-mediated vasodilation showed a trend toward improvement after 4 months (14.6 +/- 7.5 vs. 19.1 +/- 3.6 vs. 19.4 +/- 5.6%; NS). The FMD/NMD ratio also rose significantly after 4 months and remained improved after 10 months of statin therapy (0.31 +/- 0.25 vs. 0.52 +/- 0.16 vs. 0.50 +/- 0.14; p < 0.01). CONCLUSION: Statin therapy is associated with sustained improvement of endothelial function up to 10 months. These data support the utility of FMD for the assessment of vascular function in response to lipid-lowering therapy or other therapeutic interventions in long-term studies.

Adult↗

PubMed2002

Effect of prostaglandin-J(2) on VEGF synthesis depends on the induction of heme oxygenase-1.

Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades heme to carbon monoxide, iron ions, and biliverdin. Its expression can be induced by 15-deoxy-Delta(12,14)prostaglandin-J(2) (15d-PGJ(2)), a natural ligand of peroxisome proliferator-activated receptor-gamma transcription factor. In macrophages and vascular smooth muscle cells, 15d-PGJ(2) up-regulates the expression of vascular endothelial growth factor (VEGF), a fundamental regulator of angiogenesis. Here we investigated the involvement of HO-1 in the 15d-PGJ(2)-mediated regulation of VEGF production by human microvascular endothelial cells (HMEC-1). Resting HMEC-1 released approximately 20 pg/ml VEGF protein after 24 h of incubation. Treatment of cells with 15d-PGJ(2) (1-10 microM) significantly and dose-dependently increased the VEGF promoter activity, mRNA expression, and protein secretion. In the same cells, 15d-PGJ(2) potently induced the expression of HO-1 protein that correlated with HO-1 promoter activity. Activation of HO-1 with hemin or ectopic overexpression of HO-1 in HMEC-1 perfectly mimicked the effect of 15d-PGJ(2) and led to increased VEGF production. Importantly, the inhibition of the HO-1 pathway by tin protoporphyrin-IX significantly reduced the stimulatory effect of 15d-PGJ(2) on VEGF synthesis. Thus, we postulate that the up-regulation of VEGF expression in response to 15d-PGJ(2 )in HMEC-1 is mediated by the activation of HO-1.

Animals↗

PubMed2002

Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells.

Hypoxia, cytokines, and nitric oxide (NO) stimulate the generation of vascular endothelial growth factor (VEGF) and induce heme oxygenase-1 (HO-1) expression in vascular tissue. HO-1 degrades heme to carbon monoxide (CO), iron, and biliverdin, the latter being reduced to bilirubin by biliverdin reductase. In the present study, we investigated the role of HO-1 in the modulation of VEGF synthesis in rat vascular smooth muscle cells (VSMC). In VSMC stimulated with cytokines, inhibition of NO production significantly, but not completely, reduced VEGF release. In contrast, inhibition of HO activity by tin protoporphyrin IX (SnPPIX) totally prevented cytokine-induced increase in VEGF, despite an augmented synthesis of intracellular NO. Stimulation of HO-1 activity by hemin enhanced VEGF production; this effect was abrogated by blockade of the HO pathway. Similarly, VEGF synthesis induced by hypoxia was down-regulated by SnPPIX, but not by inhibitors of NO synthase. To elucidate further a direct involvement of HO-1 in the observed effects, we generated transfected cells that overexpressed the HO-1 gene. Notably, these cells synthesized significantly more VEGF protein than cells transfected with a control gene. Among the products of HO-1, biliverdin and bilirubin showed no effect, whereas iron ions inhibited VEGF synthesis. Exposure of cells to 1% CO resulted in a marked accumulation of VEGF (20-fold increase) over the basal level. Our data indicate that HO-1 activity influences the generation of VEGF in VSMC in both normoxic and hypoxic conditions. As CO and iron, respectively the inducer and the inhibitor of VEGF synthesis, are concomitantly produced during the degradation of heme, these data indicate that HO by-products may differentially modulate VEGF production.

Animals↗