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Masataka Sata

Publications and source records attributed to Masataka Sata.

At least 55 records · Page 3Linked to original sources
PubMed2004

Blockade of vascular endothelial growth factor suppresses experimental restenosis after intraluminal injury by inhibiting recruitment of monocyte lineage cells.

BACKGROUND: Therapeutic angiogenesis by delivery of vascular endothelial growth factor (VEGF) has attracted attention. However, the role and function of VEGF in experimental restenosis (neointimal formation) after vascular intraluminal injury have not been addressed. METHODS AND RESULTS: We report herein that blockade of VEGF by soluble VEGF receptor 1 (sFlt-1) gene transfer attenuated neointimal formation after intraluminal injury in rabbits, rats, and mice. sFlt-1 gene transfer markedly attenuated the early vascular inflammation and proliferation and later neointimal formation. sFlt-1 gene transfer also inhibited increased expression of inflammatory factors such as monocyte chemoattractant protein-1 and VEGF. Intravascular VEGF gene transfer enhanced angiogenesis in the adventitia but did not reduce neointimal formation. CONCLUSIONS: Increased expression and activity of VEGF are essential in the development of experimental restenosis after intraluminal injury by recruiting monocyte-lineage cells.

Adenoviridae↗
PubMed2004

Antimonocyte chemoattractant protein-1 gene therapy attenuates graft vasculopathy.

OBJECTIVE: Accelerated coronary arteriosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood, and there is no effective therapy. Transplant arteriosclerosis is characterized by early mononuclear cell attachment on the transplanted vessel followed by development of concentric neointimal hyperplasia. Early and persistent expression of monocyte chemoattractant protein-1 (MCP-1) in cardiac allografts has been implicated for the pathogenesis of transplant arteriosclerosis. METHODS AND RESULTS: We investigated whether anti-MCP-1 gene therapy can inhibit the development of intima hyperplasia in a mouse model of cardiac transplantation. Either the dominant-negative form of MCP-1 (7ND) or control vector was transfected into the skeletal muscles of B10.D2 mice. Cardiac allografts from DBA/2 mice were transplanted heterotopically into B10.D2 mice. 7ND gene transfer was associated with a significant reduction of the number of mononuclear cells accumulating in the lumen of the graft coronary arteries at 1 week and an attenuation of the development of the lesion at 8 weeks (intima/media ratio 0.79+/-0.05 versus 0.48+/-0.04). CONCLUSIONS: The MCP-1/chemokine receptor 2 (CCR2) signaling pathway plays a critical role in the pathogenesis of graft vasculopathy. This new anti-MCP-1 gene therapy might be useful to treat graft vascular disease.

Animals↗
PubMed2004

Contribution of bone-marrow-derived cells to choroidal neovascularization.

We investigated the involvement of bone-marrow derived cells to experimental choroidal neovascularization (CNV) in mice, whose bone marrow was reconstituted by either unfractionated bone-marrow cells or Lin-c(-)Kit(+)Sca-1+ enriched presumable hematopoietic stem cells from the green fluorescent protein (GFP) transgeneic mice. Immunohistochemical analysis demonstrated the presence of GFP-positive cells in the CNV lesion after unfractionated bone-marrow transplantation, as well as Lin-c(-)Kit(+)Sca-1+ cell transplantation. Some of the GFP-expressing cells also expressed CD-31 and PanEC antigen, markers of vascular endothelial cells. Our results suggest that bone-marrow derived cells may contribute endothelial cells in CNV.

Animals↗
PubMed2004

AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation.

BACKGROUND: AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. Here, we investigated whether AMPK signaling has a role in the regulation of the angiotensin II (Ang II)-induced proliferation signal in rat vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) activated AMPK in rat VSMCs and inhibited Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation but not that of p38 MAPK or Akt/PKB. Although Ang II activated AMPK, this activation was significantly inhibited by catalase, N-acetylcysteine, and diphenyleneiodonium chloride, an NADPH oxidase inhibitor. Moreover, the observation that AMPK was activated by H2O2 suggests that AMPK is redox sensitive. The Ang II type 1 receptor antagonist valsartan but not the Ang II type 2 receptor antagonist PD123319 significantly inhibited Ang II-induced AMPK activation, suggesting that Ang II-induced AMPK activation was Ang II type 1 receptor dependent. Whereas 3H-thymidine incorporation by VSMCs treated with Ang II was significantly inhibited when the cells were pretreated with 1 mmol/L AICAR, the inhibition of AMPK by dominant-negative AMPK overexpression augmented Ang II-induced cell proliferation. Subcutaneous injection of AICAR (1 mg/g body weight per day) for 2 weeks suppressed neointimal formation after transluminal mechanical injury of the rat femoral artery. CONCLUSIONS: Our findings indicate that Ang II-induced AMPK activation is synchronized with extracellular signal-regulated kinase signaling and that AMPK works as an inhibitor of the Ang II proliferative pathway. AMPK signaling might serve as a new therapeutic target of vascular remodeling in cardiovascular diseases.

AMP-Activated Protein Kinases↗
PubMed2004

Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization.

BACKGROUND: Stromal cell-derived factor-1alpha (SDF-1alpha) is implicated as a chemokine for endothelial progenitor cells (EPCs). We therefore hypothesized that SDF-1alpha gene transfer would induce therapeutic neovascularization in vivo by functioning as a chemokine of EPC. METHODS AND RESULTS: To examine SDF-1alpha-induced mobilization of EPC, we used bone marrow-transplanted mice whose blood cells ubiquitously express beta-galactosidase (LacZ). We produced unilateral hindlimb ischemia in the mice and transfected them with plasmid DNA encoding SDF-1alpha or empty plasmids into the ischemic muscles. SDF-1alpha gene transfer mobilized EPCs into the peripheral blood, augmented recovery of blood perfusion to the ischemic limb, and increased capillary density associated with partial incorporation of LacZ-positive cells into the capillaries of the ischemic limb, suggesting that SDF-1alpha induced vasculogenesis and angiogenesis. SDF-1alpha gene transfer did not affect ischemia-induced expression of vascular endothelial growth factor (VEGF) but did enhance Akt and endothelial nitric oxide synthase (eNOS) activity. Blockade of VEGF or NOS prevented all such SDF-1alpha-induced effects. CONCLUSIONS: SDF-1alpha gene transfer enhanced ischemia-induced vasculogenesis and angiogenesis in vivo through a VEGF/eNOS-related pathway. This strategy might become a novel chemokine therapy for next generation therapeutic neovascularization.

Animals↗
PubMed2004

Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice.

Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) by cross-breeding HSL(-/-) mice with genetically obese Lep(ob/ob) mice. Unexpectedly, Lep(ob/ob)/HSL(-/-) mice ate less food, gained less weight, and had lower adiposity than Lep(ob/ob)/HSL(+/+) mice. Lep(ob/ob)/HSL(-/-) mice had massive accumulation of preadipocytes in white adipose tissues with increased expression of preadipocyte-specific genes (CAAT/enhancer-binding protein beta and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein alpha, peroxisome proliferator activator receptor gamma, and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y and agouti-related peptide was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.

Adipocytes↗
PubMed2004

Bone marrow mononuclear cell therapy limits myocardial infarct size through vascular endothelial growth factor.

No prior study has examined the effect of intravenous injection of bone marrow mononuclear cells (MNCs) on myocardial infarction size (IS). We tested the hypothesis that transplantation of MNCs decreases IS through the release of vascular endothelial growth factor (VEGF). Immediately after ligation of the left coronary artery of immunodeficient mice, PBS or MNCs were intravenously administered. Myocardial IS was significantly less in MNCs-treated mice than in PBS-treated mice. Trace experiments showed accumulation of exogenously administered MNCs into the vicinity of infarcted myocardium. Injection of MNCs did not affect capillary density after infarction, but did reduced myocardial cell apoptosis. Blockade of VEGF by a neutralizing antibody or by gene transfer of a soluble form of Flt-1 VEGF receptor diminished the IS-limiting effects of MNCs. In conclusion, injection of MNCs can reduce myocardial IS through the release of VEGF. The MNC therapy for acute myocardial infarction might improve prognosis of patients with myocardial infarction.

Animals↗
PubMed2004

Mechanical stress promotes the expression of smooth muscle-like properties in marrow stromal cells.

OBJECTIVE: It is poorly understood what kind of factors are involved in lineage commitment and maturation of mesenchymal stem cells. The present study investigates whether mechanical stress promotes expression of smooth muscle cell (SMC)-specific cytoskeletal protein in marrow stromal cells. METHODS: Fibroblast-like stromal cells expressing STRO-1 antigen were isolated from rat bone marrow by density gradient separation. After preincubation for 7, 14, or 21 days in static condition, cells were exposed to one of three types of fluid flow-induced mechanical forces (flow dominant, pressure dominant, or combined) for 36 hours. The expression of SMC-specific cytoskeletal protein [alpha smooth muscle actin (alphaSMA) and smooth muscle myosin heavy chain (SMMHC)] was evaluated by immunofluorescence staining and Western blotting. RESULTS: The proportion of SMMHC-positive cells was increased with longer preincubation periods (p < 0.01 vs 7-day incubation) and by any types of mechanical stimulation (p < 0.01 vs static control condition). The SMMHC-positive fraction after exposure to pressure-dominant forces (0.9% +/- 0.2%, 2.9% +/- 0.9%, and 12.6% +/- 0.8% for 7, 14, and 21 days of preincubation) or to combined forces (1.2% +/- 0.2%, 3.1% +/- 1.6%, and 15.5% +/- 2.8%) was higher than after flow-dominant stimulation (0, 1.2% +/- 0.1%, and 7.2% +/- 2.0%) (p < 0.01). In Western blotting, pressure-dominant or combined stimulation upregulated alphaSMA and SMMHC expression compared to static control condition. CONCLUSION: The long-term cell incubation and subsequent mechanical stimulation, especially compressive strain, promote expression of SMC-specific cytoskeletal protein in marrow stromal cells.

Actins↗
PubMed2004

Lp3/Hapln3, a novel link protein that co-localizes with versican and is coordinately up-regulated by platelet-derived growth factor in arterial smooth muscle cells.

Link proteins (LPs) belong to the link-module superfamily, which can stabilize and enhance the binding of lecticans to hyaluronan. We report here the identification and characterization of a novel rat link protein gene (Lp3/Hapln3). The deduced protein sequence shares the typical modular elements of link proteins and has an estimated mass of 39 kDa. Examination of the rat genomic DNA sequence revealed that Lp3/Hapln3 and aggrecan genes were paired on chromosome 1q31. Another LP gene and the lectican gene were also paired at a different locus, as they are in the human and mouse genomes. Immunohistochemical analysis showed the prominent expression of Lp3/Hapln3 in the smooth muscle tissues of the vascular wall and gastrointestinal tract. Further comparative studies revealed that Lp3/Hapln3 was well co-localized with versican around the smooth muscle cells of blood vessels but not around endothelial cells. In vitro experiments using primary cultured rat arterial smooth muscle cells (ASMCs) demonstrated the coordinated up-regulation of Lp3/Hapln3 and versican by platelet-derived growth factor (PDGF). These data were supported by in vivo studies of a mechanical vascular injury model in mice. Altogether, our results suggest that Lp3/Hapln3 is involved, together with versican and hyaluronan, in the formation of the pericellular matrix of vascular smooth muscle cells.

Amino Acid Sequence↗
PubMed2004

Iron dextran causes renal iron deposition but not renal dysfunction in angiotensin II-treated and untreated rats.

BACKGROUND: Angiotensin II infusion into rats causes iron deposition in the kidney, which may augment the pro-proteinuric effects of this octapeptide. We have investigated whether administration of iron mimics the renal damage induced by angiotensin II. METHODS: Rats were treated with iron dextran at a total dose of 960 mg/kg either with or without angiotensin II treatment at a dose of 0.7 mg/kg/day for 7 days. Protein expression of ferritin and heme oxygenase-1, an oxidative stress-sensitive gene, was determined by Western blot analysis and immunohistochemistry. RESULTS: Administration of iron dextran did not significantly increase proteinuria or decrease creatinine clearance in the rats with or without angiotensin II treatment. Prussian blue staining showed that iron deposition was observed mainly in the glomerular and medullar regions in the iron dextran-treated rats, but in the tubular epithelial cells in angiotensin II-infused rats. Administration of iron dextran upregulated ferritin, but not heme oxygenase-1. CONCLUSION: Iron dextran did not enhance or cause the renal dysfunction in the angiotensin II-treated or untreated rats, respectively. The distribution of deposited iron and presumably the type of iron compound administered may be important determinants of the development of renal injury.

Angiotensin II↗
PubMed2004

Statins augment collateral growth in response to ischemia but they do not promote cancer and atherosclerosis.

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.

Animals↗
PubMed2004

Role of aberrant iron homeostasis in the upregulation of transforming growth factor-beta1 in the kidney of angiotensin II-induced hypertensive rats.

We have previously shown that abnormal iron metabolism might be one underlying mechanism of the renal damage observed in the angiotensin II-infused rat. Transforming growth factor-beta1 (TGF-beta1) is known to play a crucial role in the development of renal damage induced by activation of the renin-angiotensin-aldosterone system. The purpose of the present study was to examine the effects of an iron chelator and a free radical scavenger on the angiotensin II-induced upregulation of TGF-beta1 in the kidney. Rats were given angiotensin II (0.7 mg/kg/day) via osmotic minipumps for 7 days. The expressions of the mRNAs of TGF-beta1 and collagen types I and IV were significantly increased in response to angiotensin II treatment. Histologic analysis showed that TGF-beta1 expression was upregulated mainly in tubular epithelial cells, and occasionally in glomerular and perivascular cells, some of which were identified as monocytes and/or macrophages. Although tubular cells that overexpressed TGF-beta1 did not contain iron particles, angiotensin II-induced TGF-beta1 upregulation was suppressed by the iron chelator and the free radical scavenger. The free radical scavenger also suppressed angiotensin II-induced upregulation of heme oxygenase-1, an oxidative-stress sensitive gene. By contrast, administration of iron dextran to rats induced upregulation of TGF-beta1 mRNA. Collectively, these data suggest that the renal iron overload and presumed subsequent increase in oxidative stress play a role in angiotensin II-induced upregulation of the mRNAs of TGF-beta1 and collagen types I and IV in the kidney.

Angiotensin II↗
PubMed2003

Identification of gene expression profile in tolerizing murine cardiac allograft by costimulatory blockade.

The induction of specific tolerance would be the ultimate achievement in transplant immunology, but the precise mechanisms of immunologic tolerance remain largely unknown. Here, we investigated global gene expression analysis in tolerizing murine cardiac allografts by means of oligonucleotide microarrays. Tolerance induction was achieved in cardiac allografts from BALB/c to C57BL/6 mice by daily intraperitoneal injection of anti-CD80 and anti-CD86 monoclonal antibodies (mAbs). Comparative analysis revealed 64 genes to be induced more extensively in the tolerizing than in the syngeneic isografts, and 16 genes than in the rejecting allografts. Two genes were specifically upregulated in the tolerizing allografts. In the tolerizing allografts there were induced marked expressions of a number of genes for pro-inflammatory factors, including interferon-gamma-inducible cytokines and chemokines, as well as apoptosis-related genes, which were also upregulated in the rejecting allografts. Moreover, these gene expression patterns continued to be upregulated more than 70 days posttransplant. These results provide evidence that immunologic tolerance can be induced and maintained in the presence of prominent pro-inflammatory gene expression in vivo.

Animals↗
PubMed2003

Nicotine enhances neovascularization and promotes tumor growth.

Solid tumors require vascularization for their growth. Bone marrow-derived endothelial progenitor cells participate in tumor angiogenesis. Here, we show that nicotine markedly accelerated growth of colon cancer cells inoculated subcutaneously in mice but had no effect on proliferation of carcinoma cells in vitro. We found that the tumor growth was associated with increased vascularization of the tumor and that bone marrow-derived cells contributed to the formation of the new blood vessels. Our findings show that nicotine promotes tumor growth, at least in part, by stimulating tumor-associated neovascularization.

Animals↗
PubMed2003

Genetic background influences therapeutic effectiveness of VEGF.

Therapeutic angiogenesis has emerged as a promising therapy, but some patients are refractory to exogenous growth factors. In order to identify the genetic determinants of post-natal angiogenesis and physiological vessel formation, we investigated the genetic factors that affected ischemia-induced development of collaterals in mice. An ischemic hindlimb model was generated in C57BL/6, C3H/He, and BALB/c mice. Angiogenesis was markedly different among the mice as determined by the restoration of blood perfusion and capillary density of the ischemic muscle. Impaired collateral vessel formation in BALB/c mice was associated with reduced expression of vascular endothelial cell growth factor (VEGF). Intramuscular gene transfer of VEGF promoted collateral formation in C57BL/6J mice, but not in BALB/c mice. Ineffectiveness of VEGF in BALB/c mice was associated with impaired expression of VEGF receptor. Our findings suggest that genetic background may influence spontaneous collateral formation and therapeutic effectiveness of exogenous VEGF. Alternative strategies other than administration of VEGF alone might be needed to attain optimal angiogenesis in some patients.

Animals↗
PubMed2003

Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries.

We and others have suggested that bone marrow-derived progenitor cells may contribute to the pathogenesis of vascular diseases. On the other hand, it was reported that bone marrow cells do not participate substantially in vascular remodeling in other experimental systems. In this study, three distinct types of mechanical vascular injuries were induced in the same mouse whose bone marrow had been reconstituted with that of GFP or LacZ mice. All injuries are known to cause smooth muscle cell (SMC) hyperplasia. At 4 weeks after wire-mediated endovascular injury, a significant number of the neointimal and medial cells derived from bone marrow. In contrast, marker-positive cells were seldom detected in the lesion induced by perivascular cuff replacement. There were only a few bone marrow-derived cells in the neointima after ligation of the common carotid artery. These results indicate that the origin of intimal cells is diverse and that contribution of bone marrow-derived cells to neointimal hyperplasia depends on the type of model.

Actins↗