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Biomedical subjects

Kenji Kangawa

Publications and source records attributed to Kenji Kangawa.

At least 127 records · Page 7Linked to original sources
PubMed2004

Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis, and renal damage.

BACKGROUND: Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function. The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice. METHODS AND RESULTS: Mice heterozygous for an AM-null mutation (AM+/-) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-beta, collagen type I, brain natriuretic peptide, and c-fos. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AM+/- mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK) activation, as did cardiac myocytes from neonates treated acutely with Ang II. Again the effect was more pronounced in AM+/- mice, which showed increases in cardiac myocyte size, protein synthesis, and fibroblast proliferation. ERK activation was suppressed by protein kinase C inhibition to a greater degree in AM+/- myocytes. In addition, treatment of cardiac myocytes with recombinant AM suppressed Ang II-induced ERK activation via a protein kinase A-dependent pathway. CONCLUSIONS: Endogenous AM exerts a protective effect against stress-induced cardiac hypertrophy via protein kinase C- and protein kinase A-dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.

Adrenomedullin↗
PubMed2004

Inhibitory effect of C-type natriuretic peptide (CNP) on cultured cardiac myocyte hypertrophy: interference between CNP and endothelin-1 signaling pathways.

C-type natriuretic peptide (CNP) is known to play a role in the local regulation of vascular tone. We recently found that CNP is also produced by cardiac ventricular cells. However, its local effect on myocyte hypertrophy remains to be elucidated. The present study investigated the effects of CNP on cultured cardiac myocyte hypertrophy and the interaction between CNP and endothelin-1 (ET-1) signaling pathways. CNP attenuated basal and ET-1-augumented protein synthesis, atrial natriuretic peptide secretion, hypertrophy-related gene expression, GATA-4 and MEF-2 DNA binding activities, Ca(2+)/calmodulin-dependent kinase II activity, and ERK phosphorylation. CNP also inhibited ET-1-induced increase in intracellular Ca(2+) concentration. These effects of CNP were mimicked by a cGMP analog, 8-bromo cGMP. However, the inhibitory effects of CNP on the hypertrophic response of myocytes were significantly diminished at high concentrations of ET-1. Although CNP increased intracellular cGMP levels in myocytes, ET-1 suppressed CNP-induced cellular cGMP accumulation. A protein kinase C activator and Ca(2+) ionophore mimicked this suppressive effect of ET-1. We further examined the effect of CNP on the paracrine action of ET-1 secreted from cardiac nonmyocytes. CNP and 8-bromo cGMP significantly inhibited ET-1 secretion from nonmyocytes. Although nonmyocyte-conditioned medium increased the protein synthesis in myocytes through endogenous ET-1 action, this increase was significantly attenuated by pretreatment of nonmyocytes with CNP and 8-bromo cGMP. These findings demonstrate that CNP inhibits ET-1-induced cardiac myocyte hypertrophy via a cGMP-dependent mechanism, and conversely, ET-1 inhibits CNP signaling by a protein kinase C- and Ca(2+)-dependent mechanism, suggesting mutual interference between CNP and ET-1 signaling pathways.

Animals↗
PubMed2004

Ventricular nonmyocytes inhibit doxorubicin-induced myocyte apoptosis: involvement of endogenous endothelin-1 as a paracrine factor.

A cross-talk between cardiac myocytes and nonmyocytes via humoral factors plays an important role in the development of cardiac growth. However, it remains to be elucidated whether humoral factors produced from nonmyocytes have a protective effect on acute myocardial injury. The present in vitro study investigated the antiapoptotic effect of nonmyocytes on doxorubicin (DOX)-induced myocyte apoptosis and its molecular mechanism. Myocyte-nonmyocyte coculture and treatment with nonmyocyte-conditioned media significantly attenuated DOX-induced myocyte apoptosis. Treatment with nonmyocyte-conditioned media stimulated the phosphorylation of ERK, Akt, and cAMP response element-binding protein (CREB) in myocytes. Nonmyocyte-conditioned media also increased protein levels of Bcl-2 but not Bcl-xL and decreased caspase-3 activation induced by DOX. MAPK kinase-specific inhibitor PD98059, phosphatidylinositol-3 kinase-Akt inhibitor LY294002, and CREB antisense oligonucleotide significantly blocked the antiapoptotic effect of nonmyocyte-conditioned media. A considerable amount of endothelin (ET)-1 production was detected in nonmyocytes but not in myocytes. Exogenous ET-1 mimicked nonmyocyte-conditioned media-mediated ERK and CREB phosphorylation and Bcl-2 protein increase but not Akt phosphorylation. In addition, ET-A receptor antagonists BQ123 and BQ485 partially blocked nonmyocyte-conditioned media-mediated antiapoptotic effect, ERK and CREB phosphorylation, and Bcl-2 protein increase. Nonmyocyte-conditioned media and exogenous ET-1 unchanged protein levels of manganese superoxide dismutase and oxidative stress-related product levels augmented by DOX. The present findings demonstrate that cardiac nonmyocytes inhibit DOX-induced myocyte apoptosis, at least in part, via ET-1 secretion-mediated CREB activation independent of the decrease in oxidative stress.

Apoptosis↗
PubMed2004

Adrenomedullin gene transfer induces therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia: benefits of a novel nonviral vector, gelatin.

BACKGROUND: Earlier studies have shown that adrenomedullin (AM), a potent vasodilator peptide, has a variety of cardiovascular effects. However, whether AM has angiogenic potential remains unknown. This study investigated whether AM gene transfer induces therapeutic angiogenesis in chronic hind limb ischemia. METHODS AND RESULTS: Ischemia was induced in the hind limb of 21 Japanese White rabbits. Positively charged biodegradable gelatin was used to produce ionically linked DNA-gelatin complexes that could delay DNA degradation. Human AM DNA (naked AM group), AM DNA-gelatin complex (AM-gelatin group), or gelatin alone (control group) was injected into the ischemic thigh muscles. Four weeks after gene transfer, significant improvements in collateral formation and hind limb perfusion were observed in the naked AM group and AM-gelatin group compared with the control group (calf blood pressure ratio: 0.60+/-0.02, 0.72+/-0.03, 0.42+/-0.06, respectively). Interestingly, hind limb perfusion and capillary density of ischemic muscles were highest in the AM-gelatin group, which revealed the highest content of AM in the muscles among the three groups. As a result, necrosis of lower hind limb and thigh muscles was minimal in the AM-gelatin group. CONCLUSIONS: AM gene transfer induced therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia. Furthermore, the use of biodegradable gelatin as a nonviral vector augmented AM expression and thereby enhanced the therapeutic effects of AM gene transfer. Thus, gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of peripheral vascular diseases.

Adrenomedullin↗
PubMed2004

Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Adrenomedullin (AM) is a potent pulmonary vasodilator peptide. However, whether intratracheal delivery of aerosolized AM has beneficial effects in patients with idiopathic pulmonary arterial hypertension remains unknown. Accordingly, we investigated the effects of AM inhalation on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. METHODS AND RESULTS: Acute hemodynamic responses to inhalation of aerosolized AM (10 microg/kg body wt) were examined in 11 patients with idiopathic pulmonary arterial hypertension during cardiac catheterization. Cardiopulmonary exercise testing was performed immediately after inhalation of aerosolized AM or placebo. The work rate was increased by 15 W/min until the symptom-limited maximum, with breath-by-breath gas analysis. Inhalation of AM produced a 13% decrease in mean pulmonary arterial pressure (54+/-3 to 47+/-3 mm Hg, P<0.05) and a 22% decrease in pulmonary vascular resistance (12.6+/-1.5 to 9.8+/-1.3 Wood units, P<0.05). However, neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly increased peak oxygen consumption during exercise (peak o(2), 14.6+/-0.6 to 15.7+/-0.6 mL. kg(-1). min(-1), P<0.05) and the ratio of change in oxygen uptake to that in work rate (Deltao(2)/DeltaW ratio, 6.3+/-0.4 to 7.0+/-0.5 mL. min(-1). W(-1), P<0.05). These parameters remained unchanged during placebo inhalation. CONCLUSIONS: Inhalation of AM may have beneficial effects on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.

Administration, Inhalation↗
PubMed2004

Clinical endocrinology and metabolism. Ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach.

Recent identification of novel appetite-regulating hormones has revealed the complex interactions of these humoral factors in the regulation of feeding behavior in mammals. One of these hormones, ghrelin, a natural ligand of the orphan receptor GHS-R, purified from stomach, is able to stimulate growth hormone release from pituitary cells. Ghrelin is a 28 amino acid peptide containing an n-octanoylated serine 3 residue that is essential for its activity. Ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, the region known to control food intake. As an orexigenic peptide, ghrelin is therefore an endogenous regulator of feeding behavior from the peripheral tissues to the central nervous system.

Amino Acid Sequence↗
PubMed2004

Different secretion patterns of two molecular forms of cardiac adrenomedullin in pressure- and volume-overloaded human heart failure.

BACKGROUND: In the final step of production of adrenomedullin (AM), an inactive intermediate form of glycine-extended AM (AM-glycine) is converted to the active mature form of adrenomedullin (AM-mature) by enzymatic amidation. Recent studies have revealed that AM-mature and AM-glycine circulate in human plasma. In this study, we investigated the differences of the concentrations of cardiac AM between pressure-overloaded (PO) heart failure (HF) and volume-overloaded (VO)-HF in humans. METHODS AND RESULTS: We measured AM-mature and AM-glycine by immunoradiometric assays in pericardial fluid and plasma in 38 patients who underwent valve replacement surgery (PO-HF: aortic stenosis, n=14; VO-HF: aortic or mitral regurgitation, n=24). Stable coronary artery disease with normal left ventricular function served as the control (n=24). Plasma AM-mature (VO-HF: +59%, PO-HF: +65%, P<.05) and AM-glycine (VO-HF: +43%, PO-HF: +50%, P<0.05) were similarly higher in the 2 HF groups than in the control group. Interestingly, pericardial fluid AM-mature was markedly higher than that in plasma (control: +789%, VO-HF: +1050%, PO-HF: +1745%, all P<.001). Pericardial fluid AM-mature was higher in VO-HF (+106%, P<.01) than in controls and they were further increased in PO-HF (+243%, P<.05). Pericardial fluid molecular forms of AM correlated with left ventricular systolic pressure, but not with left ventricular end-diastolic volume index in PO-HF. In contrast, they correlated with left ventricular end-diastolic volume index, but not with left ventricular systolic pressure in VO-HF. CONCLUSION: These results suggest that cardiac AM is differently regulated from plasma AM and that cardiac AM production is upregulated in both types of HF in response to each different stimulus.

Adrenomedullin↗
PubMed2004

Upregulation of ghrelin expression in cachectic nude mice bearing human melanoma cells.

Ghrelin is a gastrointestinal peptide that stimulates food intake and growth hormone (GH) secretion. We studied the biosynthesis and secretion of ghrelin in a cancer cachexia mouse model. G361, a human melanoma cell line, was inoculated into nude mice. The body weight was reduced and the plasma concentration of interleukin-1beta (IL-1beta) was markedly higher in tumor-inoculated mice compared with vehicle-treated mice. Furthermore, white adipose tissue (WAT) weight, blood sugar level, and plasma concentrations of leptin and nonesterified fatty acids (NEFA) were significantly lower in tumor-inoculated mice. The plasma concentration of ghrelin increased with the progression of cachexia. The levels of both ghrelin peptide and mRNA in the stomach were also upregulated in tumor-inoculated mice. This study demonstrates that both ghrelin biosynthesis and secretion are stimulated in the long-term negative energy balance of tumor-inoculated cachectic mice. These findings suggest the involvement of ghrelin in the regulation of energy homeostasis in cancer cachexia.

Adipose Tissue↗
PubMed2004

Direct effects of high glucose and insulin on protein synthesis in cultured cardiac myocytes and DNA and collagen synthesis in cardiac fibroblasts.

The present study examined the direct effects of high glucose and insulin on protein synthesis in cardiac myocytes and DNA and collagen synthesis in cardiac fibroblasts. Cultured rat cardiac myocytes and fibroblasts were grown in media containing normal glucose, high glucose, or osmotic control, and incubated with or without insulin. In cardiac myocytes, high glucose had no effect, but insulin increased protein synthesis and atrial natriuretic peptide (ANP) secretion and gene expression. The extracellular signal-regulated protein kinase (ERK)/mitogen-activated protein kinase (MAPK) inhibitor and the protein kinase C (PKC) inhibitor blocked insulin-induced protein synthesis. In cardiac fibroblasts, high glucose and osmotic control media increased DNA synthesis. Collagen synthesis and fibronectin and transforming growth factor-beta1 (TGF-beta1) mRNA expression were stimulated by high glucose, but not by osmotic control. Insulin increased DNA and collagen synthesis in fibroblasts, and the insulin-induced increase in DNA synthesis was blocked by the phosphatidylinositol 3 kinase (PI3K) inhibitor. Our findings suggest that cardiomyocyte protein synthesis is mainly regulated by insulin rather than high glucose and both high glucose and insulin contribute to fibroblast DNA and collagen synthesis. High glucose accelerates fibroblast DNA synthesis and collagen synthesis, and fibronectin and TGF-beta1 mRNA expression, dependent or independent of osmotic stress. Insulin regulates myocyte protein synthesis and fibroblast DNA synthesis through different intracellular mechanisms.

Animals↗
PubMed2004

Regulation of ghrelin secretion during pregnancy and lactation in the rat: possible involvement of hypothalamus.

We investigated the plasma concentration of ghrelin peptide during pregnancy and lactation in rats. Plasma ghrelin levels on days 10 and 15 of pregnancy were significantly lower than those of the non-pregnant rats. Thereafter, the plasma ghrelin levels on day 20 of pregnancy sharply increased to levels comparable with those in non-pregnant rats. Ghrelin peptide concentrations in the stomach did not change significantly during pregnancy. In the hypothalamus, ghrelin mRNA levels were significantly lower on day 15 of pregnancy than in the non-pregnant rats. Also, plasma ghrelin levels were significantly lower in lactating dams than non-lactating controls on days 3 and 8 of lactation. We examined the possible involvement of prolactin and oxytocin in the regulation of plasma ghrelin concentrations during lactation. Although plasma prolactin levels were decreased by the administration of bromocriptine, plasma ghrelin levels did not differ significantly between vehicle- and drug-treated lactating rats. Administration of haloperidol produced a marked increase in plasma prolactin levels as compared with the non-lactating controls. However, plasma ghrelin levels were not significantly different between vehicle- and drug-treated rats. Administration of an oxytocin antagonist into the lateral ventricle significantly inhibited the increase in the plasma oxytocin level induced by acute suckling. However, plasma ghrelin levels did not significantly between the groups. These observations indicated that the decrease in serum ghrelin is caused by a loss of the contribution of hypothalamic ghrelin. Furthermore, the present results suggested that the suckling stimulus itself, but the release of prolactin or oxytocin, is the factor most likely to be responsible for the suppression of ghrelin secretion during lactation.

Animals↗
PubMed2004

Disassociated increases of adrenomedullin in the rat cerebrospinal fluid and plasma after salt loading and systemic administration of lipopolysaccharide.

To determine the role of adrenomedullin (AM) in the fluid electrolyte homeostasis and endotoxin shock, cerebral spinal fluid (CSF) and plasma were sampled from rats after respective challenges. The AM levels were measured by a highly sensitive immunoassay. The AM levels in the CSF of the rats anesthetized with ether (10.7 +/- 0.60 fmol/ml) were significantly higher than those with isoflurane 5.17 +/- 0.70 fmol/ml, P < 0.01), while the plasma level did not differ significantly. The CSF levels of the rats received 2% saline drinking increased to 3 and 4 folds at day 5 and day 7, respectively, while the plasma levels did not differ from controls at both time points. The AM levels in CSF or plasma increased to 1.5 and 3 folds at 1.5 h after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS, 5 mg/kg), reached 6.5 and 30 folds at 6 h, respectively, while no change was observed in the controls. The present findings suggest that AM in the CSF is regulated independently from that in the plasma, the centrally synthesized AM plays and important role in the regulation of the fluid electrolyte homeostasis. Furthermore, the circulatory AM plays an important role in the endotoxin shock.

Adrenomedullin↗
PubMed2004

Adrenomedullin as a sensitive marker for coronary and peripheral arterial complications in patients with atherosclerotic risks.

Plasma adrenomedullin (AM) levels are elevated in various pathological states including cardiovascular and inflammatory diseases. The present study investigated whether an increased AM level is a marker of vascular complications in patients with atherosclerotic risks. In 114 patients with cardiovascular risks and/or diseases including ischemic heart disease (IHD) and peripheral arterial disease (PAD), plasma AM concentration and other inflammatory markers such as high sensitive C-reactive protein (CRP) and interleukin (IL)-6 were examined. The plasma AM level was not altered by the absence or presence of each of four major risk factors, i.e., hypertension, diabetes mellitus, hyperlipidemia, and smoking and its level was not significantly correlated with blood pressure, plasma glucose, or serum lipid levels. The patients with IHD had a significantly higher concentration of plasma AM than those without IHD. The AM level in subjects with PAD was also increased significantly compared with those without PAD. The plasma AM was strongly correlated with inflammatory parameters such as CRP and IL-6. Among AM, CRP, and IL-6, however, only AM was an independent predictor for both IHD and PAD by multiple logistic regression analysis. Our findings suggest the possibility that plasma AM is a novel sensitive marker for the presence of vascular lesions in patients with atherosclerotic risks.

Adrenomedullin↗
PubMed2004

Adrenomedullin in the treatment of pulmonary hypertension.

Adrenomedullin (AM) is a potent, long-lasting pulmonary vasodilator peptide. Plasma AM level is elevated in patients with primary pulmonary hypertension (PPH), and circulating AM is partially metabolized in the lungs. These findings suggest that AM plays an important role in the regulation of pulmonary vascular tone and vascular remodeling. We have demonstrated the effects of three types of AM delivery systems: intravenous administration, inhalation, and cell-based gene transfer. Despite endogenous production of AM, intravenously administered AM at a pharmacologic level decreased pulmonary vascular resistance in patients with PPH. Inhalation of AM improved hemodynamics with pulmonary selectivity and exercise capacity in patients with PPH. Cell-based AM gene transfer ameliorated pulmonary hypertension rats. These results suggest that additional administration of AM may be effective in patients with pulmonary hypertension. AM may be a promising endogenous peptide for the treatment of pulmonary hypertension.

Adrenomedullin↗
PubMed2004

Structural determination and histochemical localization of ghrelin in the red-eared slider turtle, Trachemys scripta elegans.

We purified ghrelin peptide and determined the cDNA sequence encoding the precursor protein from the stomach of the red-eared slider turtle, Trachemys scripta elegans. The Trachemys ghrelin is comprised of 25-amino acids and has the sequence GSSFLSPEYQNTQQRKDPKKHTKLN. The third serine residue was modified by n-octanoic (C8:0), decanoic (C10:0) or unsaturated decanoic acid (C10:1). The carboxyl-terminal end of the peptide was not amidated, as seen in the ghrelins of other land vertebrates. Quantitative real-time PCR analysis revealed high levels of gene expression in the stomach and moderate levels in the large intestine and pancreas. Histochemical studies of turtle stomach revealed that ghrelin-immunopositive (ghrelin-ip) cells, which were small and round, were observed in the mucosal layer of the stomach but not in the myenteric plexus, and ghrelin-mRNA-expressing (ghrelin-ex) cells detected by in situ hybridization were scattered in a similar distribution as ghrelin-ip cells. These results indicate that ghrelin is present in reptiles.

Amino Acid Sequence↗
PubMed2004

The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats.

BACKGROUND: Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy. METHODS: Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release. RESULTS: STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 +/- 360 fmol/day vs. control 110 +/- 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, d-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides. CONCLUSION: Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.

Adrenomedullin↗
PubMed2004

[The regulatory mechanism for neuron specific expression of PACAP gene].

Pituitary adenylate cyclase-activating polypeptide (PACAP), a pleiotropic neuropeptide, is present abundantly in the central nervous system. In the 5'-flanking region of the PACAP gene, we found and characterized two negative regulatory elements, which are homologous to the neural-restrictive silencer element (NRSE). Their sequence and position were significantly conserved among mouse, human, and rat PACAP genes. NRSE is a crucial negative-acting DNA regulatory element for neuron-specific gene expression. NRSE acts through the transcription factor known as neural-restrictive silencer factor (NRSF). In non-neuronal cells, NRSF suppresses the expression of neuron-specific genes. On the other hand, in neuronal cells, NRnV, a NRSF truncated form, repress their expressions in a dominant negative manner. The electrophoretic mobility shift assay with 3T3 cells extract demonstrated the identical complexes among NRSLE-1, NRSLE2, and the NRSE of rat type II sodium channel gene. In the luciferase reporter assay, NRSLEs suppressed SV40 promoter activity in 3T3 cells, but not in PC12 cells. RT-PCR analysis revealed that PACAP and NRnV mRNAs are expressed in neuronal cells (differentiated PC12), but not in non-neuronal cells (3T3 or C6). These results suggested that the NRSE-NRSF system might be involved in the regulatory mechanism of neuron-specific expression of the PACAP gene.

Animals↗
PubMed2004

Identification of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible and -suppressive genes in the rat placenta: induction of interferon-regulated genes with possible inhibitory roles for angiogenesis in the placenta.

Exposure to a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a variety of toxic manifestations, including fetal death. In order to evaluate the effects of low dose TCDD on placental function, pregnant Holtzman rats were given a single oral dose of 1600 ng TCDD/kg body wt or an equivalent volume of vehicle (control) on gestation day 15 (GD15), and changes in the gene expression in the placenta on GD20 were analyzed by two comprehensive methods, representational difference analysis (RDA) and DNA microarray technology. Candidates of TCDD-inducible and -suppressive genes were selected. Quantitative real-time PCR analysis was then performed to verify the induction or suppression levels of the candidate genes. Finally, we identified 81 TCDD-inducible and 21 TCDD-suppressive genes from the placenta of TCDD-treated Holtzman rats on GD20. One of the remarkable profiles of the gene expression was that glucose transporters were strongly up-regulated by the TCDD treatment. Furthermore, many interferon-inducible genes were also up-regulated by the treatment. They included several cytokines such as IP-10 known as a potent angiogenesis inhibitor. In addition, interferon molecules are known to suppress angiogenesis. The above observations suggest that activation of the interferon signaling pathway and the induction of anti-angiogenic factors by TCDD might have a role in causing the inhibition of neovascularization, resulting in the hypoxic state of placenta and increased incidence of fetal death.

Animals↗