Biomedical subjects

Uichi Ikeda

Publications and source records attributed to Uichi Ikeda.

At least 19 recordsLinked to original sources

PubMed2006

Circulating endothelial progenitor cells in congestive heart failure.

BACKGROUND: Endothelial progenitor cells (EPCs) circulate in the adult peripheral blood and contribute to neovascularization. EPCs are considered to be included in CD34 positive mononuclear cells (CD34+ MNCs). Kinetics of circulating EPCs in congestive heart failure (CHF) has not been fully investigated. METHODS: We determined the numbers of white blood cells (WBCs), plasma brain natriuretic peptide (BNP), serum erythropoietin, vascular endothelial growth factor (VEGF) and thrombomodulin levels in 16 mild CHF patients (NYHA I, II), 10 severe CHF patients with acute exacerbation (NYHA III, IV), and 22 control subjects. The number of CD34+ MNCs in peripheral blood was quantified by flow cytometry. RESULTS: The ratio of CD34+ MNCs:10(3) WBCs in mild CHF patients was higher than that in control subjects (P<0.05). Interestingly, the ratio of CD34+ MNCs:10(3) WBCs in severe CHF patients at admission was significantly lower than that in control subjects (P<0.005) or in mild CHF patients (P<0.05). Levels of BNP and erythropoietin in severe CHF patients were significantly higher than those in mild CHF patients. However, VEGF and thrombomodulin levels were not different between mild and severe CHF patients. In addition, the ratio of CD34+ MNCs:10(3) WBCs in severe CHF patients increased in proportion to the amelioration of CHF during hospitalization, and this increase correlated with the decrease in BNP level. CONCLUSIONS: The ratio of CD34+ MNCs:10(3) WBCs was decreased in severe CHF. These findings suggest that impaired EPC recruitment might be involved in the pathophysiology of severe CHF.

Aged↗

PubMed2006

M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1-CXCR4 system.

OBJECTIVE: Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice. METHODS AND RESULTS: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF [500 microg/(kg x day)] or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34+/Flk-1+) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4+ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation. CONCLUSIONS: These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1-CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases.

Animals↗

PubMed2006

Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction.

Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34+/Flk-1+ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI.

Animals↗

PubMed2006

Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH.

Animals↗

PubMed2006

Development of liver regenerative therapy using glycoside-modified bone marrow cells.

Several recent studies have reported that bone marrow cells (BMCs) have the ability to generate functional hepatocytes. However, the efficiency at which BMC transplantation generates functional hepatocytes is rather low. We assumed that if BMCs accumulated directly in liver, the functional BMC-derived hepatocytes should increase efficiently. We tried to increase the accumulation of BMCs directly in liver through the interaction between hepatic asialoglycoprotein receptor and desialylated BMCs. Desialylated BMCs were produced with treatment of neuraminidase. Desialylated BMCs that expressed green fluorescent protein (GFP) were injected into Long Evans Cinnamon (LEC) rats, a human Wilson's disease model, intravenously. At 3 and 5 months after transplantation, GFP-expressing hepatocyte nodules appeared in the liver of these BMC-transplanted LEC rats. These findings suggest that the functional BMC-derived hepatocytes can be generated by the direct accumulation of BMCs and that this strategy is new BMC therapy for liver regeneration.

Animals↗

PubMed2006

Collagen synthesis is required for ascorbic acid-enhanced differentiation of mouse embryonic stem cells into cardiomyocytes.

Ascorbic acid has been reported to promote the differentiation of embryonic stem (ES) cells into cardiomyocytes; however, the specific functions of ascorbic acid have not been defined. A stable form of ascorbic acid, namely, l-ascorbic acid 2-phosphate (A2-P), significantly enhanced cardiac differentiation; this was assessed by spontaneous beating of cardiomyocytes and expression of cardiac-specific markers obtained from mouse ES cells. This effect of ascorbic acid was observed only when A2-P was present during the early phase of differentiation. Treatment with two types of collagen synthesis inhibitors, l-2-azetidine carboxylic acid and cis-4-hydroxy-d-proline, significantly inhibited the A2-P-enhanced cardiac differentiation, whereas treatment with the antioxidant N-acetyl cysteine showed no effect. These findings demonstrated that ascorbic acid enhances differentiation of ES cells into cardiomyocytes through collagen synthesis and suggest its potential in the modification of cardiac differentiation of ES cells.

Animals↗

PubMed2006

Granulocyte colony-stimulating factor (G-CSF) accelerates reendothelialization and reduces neointimal formation after vascular injury in mice.

OBJECTIVE: Neointimal formation following percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularization. Since reendothelialization is one of the determinant factors for the development of neointimal formation, we examined the effects of granulocyte colony-stimulating factor (G-CSF) on reendothelialization and neointimal formation after vascular injury in mice. METHODS AND RESULTS: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. G-CSF pretreatment significantly accelerated reendothelialization and decreased neointimal formation following vascular injury; however, this inhibitory effect of G-CSF was diminished when G-CSF was started following the injury. Flow cytometry analysis revealed that G-CSF treatment increased the number of endothelial progenitor cells (EPCs: CD34+/Flk-1+) in the peripheral circulation. Vascular injury was also produced in 2 types of mice whose bone marrow was replaced with that of enhanced green fluorescent protein- and Tie2/LacZ-transgenic mice. In the reendothelialized artery of these mice, few bone marrow-derived EPCs were detected. Furthermore, G-CSF treatment reduced the serum level of interleukin (IL)-6. CONCLUSION: G-CSF treatment accelerated reendothelialization and decreased neointimal formation following vascular injury, although there was little contribution of bone marrow-derived EPCs to the reendothelialization of the artery. These results suggest that G-CSF pretreatment has a therapeutic potential for prevention of restenosis following PCI.

Angioplasty, Balloon, Coronary↗

PubMed2006

Efficacy of mycophenolic acid combined with KRP-203, a novel immunomodulator, in a rat heart transplantation model.

BACKGROUND: To explore a more effective and less toxic immunosuppressive strategy in organ transplantation, we recently developed the novel sphingosine-1-phosphate receptor agonist KRP-203. This study examined the efficacy of KRP-203 combined with mycophenolic acid (MPA), an active metabolite of mycophenolate mofetil, in rat heart allografts. METHODS: Heterotopic heart transplantation was performed in a rat combination of DA (MHC haplotype: RT1(a)) to Lewis (RT1). The recipients were divided into 12 groups (n = 5-7): Syngeneic (Lewis to Lewis), Vehicle, KRP-203 (0.3 and 1 mg/kg), MPA (10 and 20 mg/kg), 10 mg/kg MPA with KRP-203 (0.03, 0.3, 1, and 3 mg/kg), and 20 mg/kg MPA with KRP-203 (0.3 and 1 mg/kg). MPA, KRP-203, and vehicle were given orally. RESULTS: The mean days of survival were 5.8 (vehicle), 7 and 7.9 (0.3 and 1 mg/kg KRP-203, respectively), 12.7 and >54.4 (10 and 20 mg/kg MPA), >39.6 and >30.5 (10 mg/kg MPA with 1 and 3 mg/kg KRP-203), >100 and >87.8 (20 mg/kg MPA with 0.3 and 1 mg/kg KRP-203). Histologic and immunohistochemical analysis revealed that diffuse mononuclear cell infiltration (macrophages and T cells), hemorrhage, myocardial necrosis and fibrosis, and expression of endothelin-1, transforming growth factor-beta1, monocyte chemoattractant protein-1, interleukin-8, and E-selectin were markedly diminished in the allografts treated with MPA combined with KRP-203. Pharmacokinetic experiments indicated no interaction between MPA and KRP-203, and both combination regimens were well tolerated. CONCLUSIONS: Combination therapy of MPA with KRP-203 has a therapeutic potential as a novel immunosuppressant strategy in clinical transplantation.

Animals↗

PubMed2006

Temporary inferior vena cava filter for deep vein thrombosis and acute pulmonary thromboembolism: effectiveness and indication.

Although the temporary inferior vena cava filter (IVC-F) is being used increasingly for protection against pulmonary thromboembolism (PTE), indications for its use are not established. Our strategy for the prevention of PTE is: (1) contraindication or failure of anticoagulation: permanent IVC-F; (2) for patients with residual proximal deep vein thrombosis (a) who have permanent risk factor: permanent IVC-F; (b) who have transient risk factor: temporary IVC-F; (3) others: no IVC-F. Temporary IVC-F was also implanted in deep vein thrombosis (DVT) patients without PTE who were preoperation or had floating thrombus. We investigated the outcome of patients given a temporary IVC-F versus those given a permanent IVC-F to clarify the efficacy and our strategy for implantation of a temporary IVC-F. Subjects were 12 men and 38 women with acute PTE and/or floating DVT admitted to our hospital between April 1999 and April 2002. Patient age was 25-91 years (mean 63 years). Eighteen patients were given a permanent IVC-F (group A) and 32 patients were given a temporary IVC-F (group B) as primary treatment, according to our criteria. There were no major complications in either group. Mortality after implantation of the IVC-F was 35% (6/17) in group A and 16% (4/25) in group B, with no significant difference (P = 0.14). Pulmonary thromboembolism recurred in 18% (3/17) of group A patients but in no group B patients (P = 0.10). All recurrences resulted in death. The 14 patients in group B who were not given a permanent IVC-F after removal of the temporary IVC-F survived. The temporary IVC-F can be used safely in patients with venous thromboembolism and is efficacious in preventing recurrence of PTE. Prognosis after removal of the temporary IVC-F is excellent.

Aged↗

PubMed2006

Therapeutic angiogenesis by bone marrow implantation for critical hand ischemia in patients with peripheral arterial disease: a pilot study.

OBJECTIVE: Implantation of bone marrow mononuclear cells (BM-MNCs), including endothelial progenitor cells, into ischemic lower limbs has been shown to improve symptoms in patients with peripheral arterial diseases (PAD). This study investigated whether BM-MNC implantation (BMI) is also effective for the ischemic hands of these patients. METHODS: Seven PAD patients with hand ischemia were enrolled: six patients had thromboangiitis obliterans and one had collagen disease. All seven had symptoms involving either resting pain or non-healing ischemic ulcers of the hand. Approximately 600 mL of MNCs were separated from BM and concentrated to a final volume of 40-50 mL, which were injected into ischemic hands. Ischemic status was evaluated by measuring the digital/brachial pressure index (DBI), visual analog pain scale, and the healing of ulcers before and 6 months after BMI. RESULTS: The mean number of implanted MNCs, CD34-positive cells, and CD34,133-positive cells was 3.67 +/- 0.53 x 10(9), 4.94 +/- 2.45 x 10(7), and 2.52 +/- 1.57 x 10(7), respectively. Mean DBI in those patients was 0.15 +/- 0.30 before BMI and significantly increased to 0.67 +/- 0.19 at 6 months after BMI (p = 0.004). All patients also showed improvement of pain scale and ischemic ulcers. There was no significant correlation between the number of implanted cells and improvement in the degree of DBI or the pain scale. CONCLUSION: Autologous BMI could be a promising and safe method of therapeutic angiogenesis for critical hand ischemia in PAD patients.

Adult↗

PubMed2006

Determination of p-glycoprotein ATPase activity using luciferase.

We investigated whether P-glycoprotein (P-gp) ATPase activity of Caco-2 cell membranes could be estimated by measuring consumption of ATP using luciferin-luciferase reaction, and whether the results would be useful for assessment of the interactions between P-gp and drugs. The vanadate-sensitive ATPase activity of Caco-2 cell membranes was measured rapidly with high sensitivity using luciferin-luciferase reaction. Cyclosporin A, verapamil, digoxin and quinidine stimulated the ATPase activity concentration-dependently with Km values of 5.3, 0.9, 1.2 and 4.1 microM, respectively. These values except for digoxin were comparable with previous reports. The ATPase activity and P-gp mRNA expression in Caco-2 cells were induced by all-trans-retinoic acid, digoxin and levothyroxine, but not dexamethasone or rifampicin. This method was useful to assess interactions with P-gp and drugs, and was used to elucidate the mechanisms of interaction of levothyroxine and digoxin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension.

The phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, has been reported to produce sustained pulmonary vasodilatation in patients with pulmonary hypertension (PH). Recently, vardenafil, a more potent and selective PDE-5 inhibitor than sildenafil, has been approved for the treatment of erectile dysfunction. However, the long-term effects of oral vardenafil in patients with PH are unknown. We studied five consecutive patients with PH; one with primary pulmonary hypertension, two with chronic pulmonary thromboembolism, one with Eisenmenger syndrome (ventricular septal defect) and one with secondary pulmonary hypertension after a ventricular septal defect closure operation. In an acute hemodynamic trial, vardenafil (5 mg) significantly decreased both the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) with an increase in cardiac output. In a chronic hemodynamic trial, the maintenance dose of vardenafil (10 to 15 mg) for 3 months significantly decreased the PVR, but not the SVR, with a 20.7% reduction of the PVR/ SVR ratio. Plasma brain natriuretic peptide (BNP) levels were also significantly decreased after 3 months. This pilot study demonstrates that long-term oral vardenafil therapy may be a safe and effective treatment for patients with PH.

Adult↗

PubMed2006

Therapeutic potential of endothelial progenitor cells for cardiovascular diseases.

In the past decade, researchers have defined committed stem or progenitor cells from various tissues, including bone marrow, peripheral blood, brain, liver and reproductive organs, in both adult animals and humans. Recently, endothelial progenitor cells (EPCs) were isolated from peripheral blood mononuclear cells and were shown to be incorporated into foci of neovascularization. This finding that circulating EPCs may home into sites of neovascularization and differentiate into mature endothelial cells in situ is consistent with the concept of 'vasculogenesis' and suggests that vasculogenesis and angiogenesis might constitute complementary mechanisms for postnatal neovascularization. Furthermore, experimental and clinical studies on ischemic cardiovascular diseases suggest a therapeutic potential for EPC transplantation. In this review, we summarize the biological features of EPCs and discuss their therapeutic potential for the treatment of cardiovascular diseases.

Adult↗

PubMed2006

[Anti-platelet drugs (aspirin, ticlopidine, etc)].

Previous clinical trials have shown that anti-platelet drugs, such as aspirin and ticlopidine, are approved for prevention of serious cardiovascular events in special populations who are at increased risk of cardiovascular events. Of these trials, the Antithrombotic Trialists' Collaboration (ATT) meta-analysis includes approximately 200,000 patients: Anti-platelet therapy was associated with a 34% reduction in the risk of nonfatal myocardial infarction, a 25% reduction in the risk of stroke, and a 15% reduction in the risk of vascular death. Also in patients with acute coronary syndrome (acute myocardial infarction and unstable angina), both aspirin and ticlopidine have been shown to prevent serious cardiovascular events.

Angina, Unstable↗

PubMed2005

Changes in cardiac lipid metabolism during sepsis: the essential role of very low-density lipoprotein receptors.

OBJECTIVE: Sepsis accompanies myocardial dysfunction and dynamic alterations of cardiac metabolism. We have recently demonstrated that the very low-density lipoprotein receptor (VLDL-R), which is abundantly expressed in the heart, plays a key role in energy metabolism of the fasting heart. However, little is known about the function and regulation of the VLDL-R during sepsis. In the present study, we explored lipid accumulation and VLDL-R expression in the lipopolysaccharide (LPS)-stimulated heart in vivo and regulation of VLDL-R expression in vitro. METHODS AND RESULTS: Electron microscopy and immunohistochemistry demonstrated that LPS significantly decreased both lipid accumulation and VLDL-R expression in the hearts of fasting mice. Treatment with LPS also downregulated VLDL-R in rat neonatal cardiac myocytes, and this downregulation was completely reversed by interleukin (IL)-1beta receptor antagonist. IL-1beta downregulated the expression of VLDL-R in a time- and dose-dependent manner and markedly reduced the uptake of DiI-labeled beta-VLDL but not DiI-labeled low-density lipoprotein (LDL). Use of specific pharmacologic inhibitors and short interference RNA revealed that Hsp90 was required for IL-1beta to downregulate VLDL-R expression. CONCLUSIONS: These findings suggest that IL-1beta is a principle mediator of changes in cardiac lipid and energy metabolism during sepsis through the downregulation of myocardial VLDL-R expression.

Animals↗

PubMed2005

Cre/loxP-mediated CTLA4IgG gene transfer induces clinically relevant immunosuppression via on-off gene recombination in vivo.

OBJECTIVE: Transfer of the CTLA4IgG gene induces long-term and high levels of CTLA4IgG expression, which can result in generalized immunosuppression. In this study, we utilized Cre/loxP-mediated on-off switch recombination to eliminate transgene expression of CTLA4IgG following acceptance of murine cardiac allografts. METHODS: Fully MHC-mismatched hearts from BALB/c donor mice were transplanted into C3H/He recipient mice. Adenovirus-containing CTLA4IgG flanked between two loxP sites was administered via a recipient tail vein immediately after transplantation. Cre-recombinase gene was subsequently transferred at day 30 posttransplantation. RESULTS: Long-term allograft survival was observed in recipients that received the CTLA4IgG gene. Cre-mediated recombination reduced CTLA4IgG gene expression without any adverse effect on the graft survival. Secondary skin grafts of donor type and of third party were promptly rejected in the recipients that accepted cardiac allografts. In addition, the B cell response against ovalbumin was suppressed during high levels of serum CTLA4IgG, but recovered after Cre-mediated inactivation of CTLA4IgG gene. CONCLUSION: CTLA4IgG gene transfer promoted long-term survival of murine cardiac allografts; however, this was not sufficient to induce tolerance. Cre/loxP-mediated on-off switch recombination was useful to inactivate the CTLA4IgG gene so that recipients' immune responses against neoantigens were restored without an influence on the allograft survival. This system may open novel strategies to orchestrate clinically relevant immunosuppression.

Abatacept↗

PubMed2005

Gene expression profiling of human atrial myocardium with atrial fibrillation by DNA microarray analysis.

BACKGROUND: Atrial fibrillation (AF) is the most frequently encountered arrhythmia in the clinical setting. However, a comprehensive investigation of the molecular mechanism of AF has not been performed. The aim of this study was to clarify transcriptional profiling of genes modulated in the atrium of AF patients using DNA microarray technology. METHODS: We obtained 17 fresh cardiac specimens, right atrial appendages, isolated from 10 patients with normal sinus rhythm and seven chronic AF patients who underwent cardiac surgery. Affymetrix GeneChip (Human Genome U95A) investigating 12,000 human genes was used for each specimen. Quantitative analysis of selected genes was performed by the real-time PCR method. RESULTS: The left atrial diameter in the AF group was greater than that in the sinus rhythm group. We could identify 33 AF-specific genes that were significantly activated (>1.5-fold), compared with the sinus rhythm group, including an ion channel, an antioxidant, an inflammation, three cell growth/cell cycle, three transcription such as nuclear factor-interleukin 6-beta, several cell signaling and several protein genes, and seven expressed sequence tags (ESTs). In contrast, we found 63 sinus rhythm-specific genes, including several cell signaling/communication such as sarcoplasmic reticulum Ca2+-ATPase 2, several cellular respiration and energy production and two antiproliferative or negative regulator of cell growth genes, and 22 ESTs. CONCLUSIONS: The present study demonstrated that about one hundred genes were modulated in the atria of AF patients. These findings suggest that these genes may play critical roles in the initiation or perpetuation of AF and the pathophysiology of atrial remodeling.

Adolescent↗

PubMed2005

Interleukin-1beta attenuates beta-very low-density lipoprotein uptake and its receptor expression in vascular smooth muscle cells.

The very low-density lipoprotein (VLDL) receptor is a member of the low-density lipoprotein (LDL) receptor gene family with distinct tissue distribution and function. VLDL receptors are also expressed in vascular smooth muscle cells (VSMCs) and have been shown to be upregulated in atherosclerotic lesions. In the present study, we examined the effects of interleukin-1beta (IL-1beta) on the uptake of betaVLDL and its receptor expression in rat VSMCs. IL-1beta downregulated expression of the VLDL receptor in a time and dose-dependent manner as shown by Western blotting, Northern blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Treatment with IL-1beta significantly reduced the uptake of beta-VLDL but not LDL in VSMCs. Use of specific pharmacologic inhibitors indicated that the tyrosine kinase inhibitors, herbimycin A and geldanamycin, completely reversed IL-1beta-induced downregulation of the VLDL receptor expression. Another tyrosine kinase inhibitor, genistein, the protein kinase C inhibitors, GF109203X and H7, the mitogen-activated protein (MAP) kinase inhibitors (MEK inhibitor PD098059 for [MEK] and SB203580 for p38-MAP kinase), and the protein kinase A inhibitor, KT5270 all had no effect on receptor expression. In addition, the c-Src specific inhibitor PP2 or adenoviral-mediated gene transfer of kinase inactive (KI)-c-Src failed to reverse IL-1beta-induced downregulation of VLDL receptor expression. These results indicate that IL-1beta attenuates uptake of VLDL through downregulation of its receptor in VSMCs, and that this downregulation is mediated through a benzoquinone ansamycin-dependent but c-Src-independent pathway.

Animals↗