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Biomedical subjects

U Ikeda

Publications and source records attributed to U Ikeda.

At least 19 recordsLinked to original sources
PubMed2004

Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice.

Inflammation is a major contributor to atherosclerosis by its effects on arterial wall biology and lipoprotein metabolism. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that may modulate the atherosclerotic disease process. We investigated the effects of adeno-associated virus (AAV) vector-mediated gene transfer of IL-10 on atherogenesis in apolipoprotein E (ApoE)-deficient mice. A murine myoblast cell line, C2C12, transduced with AAV encoding murine IL-10 (AAV2-mIL10) secreted substantial amounts of IL-10 into conditioned medium. The production of monocyte chemoattractant protein-1 (MCP-1) by the murine macrophage cell line, J774, was significantly inhibited by conditioned medium from AAV2-mIL10-transduced C2C12 cells. ApoE-deficient mice were injected with AAV5-mIL10 into their anterior tibial muscle at 8 weeks of age. The expression of MCP-1 in the vascular wall of the ascending aorta and serum MCP-1 concentration were decreased in AAV5-mIL10-transduced mice compared with AAV5-LacZ-transduced mice. Oil red-O staining of the ascending aorta revealed that IL-10 gene transfer resulted in a 31% reduction in plaque surface area. Serum cholesterol concentrations were also significantly reduced in AAV5-mIL10-transduced mice. To understand the cholesterol-lowering mechanism of IL-10, we measured the cellular cholesterol level in HepG2 cells, resulting in its significant decrease by the addition of IL-10 in a dose-dependent manner. Furthermore, IL-10 suppressed HMG-CoA reductase expression in the HepG2 cells. These observations suggest that intramuscular injection of AAV5-mIL10 into ApoE-deficient mice inhibits atherogenesis through anti-inflammatory and cholesterol-lowering effects.

Adenoviridae↗
PubMed2003

Increased urinary 15-F2t-isoprostane concentrations in patients with non-ischaemic congestive heart failure: a marker of oxidative stress.

OBJECTIVE: To investigate a novel marker of oxidative stress in patients with congestive heart failure (CHF). PATIENTS: 15 patients with mild CHF, 15 patients with severe CHF with acute exacerbation, and 15 control subjects. MAIN OUTCOME MEASURES: Measurement of urinary 15-F2t-isoprostane, plasma brain natriuretic peptide (BNP), serum interleukin 6 (IL-6), and serum thrombomodulin concentrations. In patients with severe CHF, samples were taken at admission and 4, 7, and 14 days after admission. RESULTS: Urinary 15-F2t-isoprostane, plasma BNP, and serum IL-6 concentrations in patients with severe CHF were significantly higher than those in control subjects or in patients with mild CHF. However, concentrations of serum thrombomodulin, a marker of endothelial damage, were not different between patients with CHF and control subjects. In addition, urinary 15-F2t-isoprostane, plasma BNP, and serum IL-6 concentrations in patients with severe CHF gradually decreased in proportion to the severity of CHF during hospitalisation. Interestingly, urinary 15-F2t-isoprostane concentrations significantly correlated with plasma BNP concentrations and serum IL-6 concentrations, but not with serum thrombomodulin concentrations. CONCLUSIONS: Urinary 15-F2t-isoprostane concentrations increased in proportion to the severity of CHF in patients. This may be caused by increased 15-F2t-isoprostane production. These findings suggest that urinary 15-F2t-isoprostane may be a marker of morbidity as well as oxidative stress in patients with CHF.

Aged↗
PubMed2001

Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARgamma mRNA is present in cardiac myocytes; however, whether PPARgamma affects cardiac hypertrophy remains unknown. METHODS AND RESULTS: We investigated the effects of PPARgamma activators on cardiac hypertrophy in neonatal rat cardiac myocytes. Cyclic 4% biaxial mechanical strain caused enlargement of cardiac myocytes (1.3-fold versus control, P<0.0001), but the PPARgamma activators troglitazone and 15-deoxy-Delta(12-14)-prostaglandin J(2) (15d-PGJ(2)) (10 micromol/L) inhibited this effect (troglitazone, -72%, P<0.0005; 15d-PGJ(2), -88%, P<0.0002). Total cell protein was increased by mechanical strain (control, 164.3 microgram/dish; strain, 265.5, P<0.0002), and this effect was inhibited by troglitazone and 15d-PGJ(2) (troglitazone, -61%, P<0.005; 15d-PGJ(2), -72%, P<0.001). [(3)H]Leucine uptake was also increased by mechanical strain (1.9-fold versus control, P<0.002), and this increase was inhibited by troglitazone and 15d-PGJ(2) (troglitazone, -52% at 10 micromol/L, P<0.01; 15d-PGJ(2), -70% at 10 micromol/L, P<0.005). An increase in [(3)H]leucine uptake induced by angiotensin II or phenylephrine was significantly inhibited by troglitazone and 15d-PGJ(2). Mechanical strain induced mRNA expression for brain natriuretic peptide, but PPARgamma activators inhibited this induction. Furthermore, PPARgamma activators inhibited mechanically induced activation of nuclear factor (NF)-kappaB. Pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, inhibited strain-induced [(3)H]leucine uptake (-50% at 100 micromol/L, P<0.05). CONCLUSIONS: These results demonstrate that PPARgamma activators inhibit cardiac hypertrophy in cardiac myocytes and suggest that PPARgamma activators may regulate cardiomyocyte hypertrophy at least partially through the NF-kappaB pathway.

Angiotensin II↗
PubMed2001

Interleukin-6 and acute coronary syndrome.

The designation of atherosclerosis as a chronic inflammatory process represents an exciting and logical paradigm shift for cardiologists. Plasma concentrations of interleukin-6 (IL-6) and its hepatic by-product C-reactive protein (CRP) appear to reflect the intensity of occult plaque inflammation and by inference may determine vulnerability to rupture. Indeed, circulating IL-6 levels are elevated in patients with acute myocardial infarction (AMI), and also in patients with unstable, but not with stable angina. Coronary sinus IL-6 concentrations are also increased after percutaneous coronary intervention (PCI), and late restenosis correlates with an increase in IL-6 concentration after the procedure, indicating that IL-6 expression may be not only related to instability of atheromatous plaques, but also to the formation of restenotic lesions after PCI. These observations suggest the advantage of screening for circulating IL-6 concentration and the use of anti-inflammatory treatment for those thought be at high risk to reduce the risk of future AMI.

Angina Pectoris↗
PubMed2001

Macrophage migration inhibitory factor as a redox-sensitive cytokine in cardiac myocytes.

OBJECTIVE: Macrophage migration inhibitory factor (MIF), which plays a pivotal role in the control of inflammatory responses, was first characterized as a T-cell cytokine, but later was also found as a pituitary peptide released in response to infection and stress. However, MIF's role and expression in the myocardium has never been reported. The goal of this study is to examine MIF in the myocardium. METHODS AND RESULTS: MIF protein and mRNA levels were assayed using enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Increased MIF concentrations were detected in the sera of patients with acute myocardial infarction (AMI). In cultured rat cardiac myocytes, significant amounts of MIF were produced in response to hypoxia and hydrogen peroxide (H(2)O(2)), but not to angiotensin II, endothelin-1, interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNFalpha). H(2)O(2)-induced MIF production increased in a time- and dose-dependent manner and was completely abolished in the presence of catalase. H(2)O(2) also induced MIF mRNA expression. The H(2)O(2)-induced MIF production was completely inhibited by the protein kinase C (PKC) inhibitor GF109203X, partially inhibited by the tyrosine kinase inhibitor herbimycin A, and uninhibited by calcium chelation or phorbol ester-sensitive PKC down-regulation. This suggests that H(2)O(2)-induced MIF production is mediated by an atypical PKC isoform. DNA microarray analysis revealed that 52 genes were preferentially expressed in response to MIF. Of these, the MIF-induced expression of both glutathione S-transferase (GST) and lipopolysaccharide-induced CXC chemokine (LIX) mRNAs was confirmed using RT-PCR analysis. CONCLUSION: The present results suggest that MIF is expressed by the myocardium in response to redox stress and may play a role in the pathogenesis of myocardial ischemia.

Analysis of Variance↗
PubMed2001

Interaction between monocytes and vascular endothelial cells induces adrenomedullin production.

Adrenomedullin (AM), a potent vasodilator peptide, has natriuretic effects, and its plasma concentration is elevated in cardiovascular diseases. In the present study, we investigated the induction of AM expression due to interactions between THP-1 cells (human monocytic cell line) and human umbilical cord vein endothelial cells (HUVECs). AM levels in the culture medium were measured by radioimmunoassay. The luciferase vector containing the 5'-flanking region of the human AM gene was transfected into either HUVECs or THP-1 cells. Addition of THP-1 cells to HUVECs for 48 h induced marked increases in AM levels, which were 16-fold higher than those of HUVECs alone. Luciferase vectors containing the 5'-flanking region of human AM gene (pLCF-1534) were transferred into THP-1 cells or HUVECs. Addition of THP-1 cells to pLCF-1534-transfected HUVECs induced an increase in luciferase activity in cell lysates, which was 5-fold higher than that of the transfected HUVECs alone. In contrast, the luciferase activity of lysates from pLCF-1534-transfected THP-1 cells was not affected by coculture with HUVECs. A separate coculture experiment revealed that direct contact of THP-1 cells and HUVECs contributed to enhanced AM production in the cocoulture. Co-incubation of the cell membrane fraction from THP-1 cells augmented AM production by HUVECs. Both anti-interleukin (IL)-1alpha antibody and IL-1 receptor antagonist significantly inhibited AM production in the cocultures. The cell-to-cell interaction between monocytes and HUVECs induces AM production by HUVECs, which may play an important role in the pathogenesis of vascular disorders.

Adrenomedullin↗
PubMed2001

Chemokine expression in coronary circulation after coronary angioplasty as a prognostic factor for restenosis.

Recent studies have clarified the significance of chemokines in cardiovascular diseases, such as development of atherosclerosis, atheromatous plaque rupture and restenosis after coronary angioplasty. We investigated changes in chemokine expression in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA) and their clinical significance. We examined 40 patients with angina pectoris who underwent elective PTCA for isolated stenotic lesions of the left coronary artery. Eight patients received PTCA only, 14 percutaneous transluminal rotational atherectomy and 18 stent implantation. Venous blood samples were obtained from the coronary sinus before, and immediately after as well as 4 and 24 h after PTCA. Plasma levels of interleukin (IL)-8, macrophage-colony stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP)-1 were measured by enzyme-linked immunosorbent assay. Plasma levels of M-CSF in the coronary sinus blood showed significant increases 4 and 24 h after PTCA. On the other hand, plasma MCP-1 levels did not change significantly during a 24-h observation period after PTCA. Immunoreactive IL-8 was not detected in any patients before or after PTCA. A significant positive correlation was found between plasma M-CSF levels 24 h after PTCA and late loss index 6 months after the procedure. Plasma levels of M-CSF 24 h after PTCA were significantly higher in patients with than in those without late restenosis. PTCA induced increases in plasma levels of M-CSF in the coronary circulation. Increased M-CSF expression may be involved in neointima formation at injured vessels through activation of mononuclear phagocytes.

Angioplasty, Balloon, Coronary↗
PubMed2001

Adeno-associated virus-mediated transfer of endothelial nitric oxide synthase gene inhibits protein synthesis of rat ventricular cardiomyocytes.

We investigated whether nitric oxide (NO) synthase gene transfer could attenuate growth of cultured cardiac myocytes. First, we investigated the effects of exogenous NO and cGMP analog on protein synthesis of cultured neonatal rat cardiac myocytes. The NO donor 3-morpholino-sydnonimine-hydrochloride (SIN-1) and 8-bromo-cGMP caused concentration-dependent decreases in phenylephrine-stimulated incorporation of 3H-leucine into cardiac myocytes. We then transferred endothelial constitutive NO synthase (ecNOS) gene into cultured neonatal rat cardiac myocytes using adeno-associated virus (AAV) vectors. ecNOS gene transfer into cardiac myocytes induced 140 kD ecNOS protein expression and significantly increased cGMP contents of myocytes compared with control cells. ecNOS gene transfer inhibited 3H-leucine incorporation into cardiac myocytes in response to phenylephrine, which was significantly recovered in the presence of the NOS inhibitor N(G)-monomethyl-L-arginine acetate. These results indicate that endogenously generated NO by ecNOS gene transfer using AAV vectors inhibits the alpha-adrenergic agonist-induced cardiac protein synthesis at least partially via cGMP production.

Adenoviridae↗