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Kensuke Egashira

Publications and source records attributed to Kensuke Egashira.

At least 19 recordsLinked to original sources
PubMed2006

Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys.

We have previously demonstrated great benefit from anti-monocyte chemoattractant protein-1 (MCP-1) gene therapy by "systemic" transfer of an N-terminal deletion mutant of human MCP-1 (called 7ND) gene into skeletal muscle for treatment of restenosis and atherosclerosis. However, recent evidence suggests that "local" gene transfer may be a clinically relevant approach. We therefore tested the hypothesis that catheter-based adenovirus-mediated anti-MCP-1 gene therapy attenuates stent-associated neointima formation. Bare metal stents were implanted in iliac arteries of cynomolgus monkeys fed a high cholesterol diet. Immediately after the stenting procedure, normal saline or recombinant adenoviral vector containing LacZ or the 7ND gene was administered locally into the stenting site through a Remedy channel-delivery catheter. Compared to saline infusion or LacZ gene transfer, 7ND gene transfer markedly reduced inflammatory changes at an early stage and attenuated neointima formation after 4 weeks. This strategy also reduced the increased production of pro-inflammatory and growth-promoting factors such platelet-derived growth factor. No systemic adverse effects of 7ND gene transfer were detected. There were no significant differences in serum cholesterol levels among the three groups. These data suggest that catheter-based adenovirus-mediated anti-MCP-1 gene therapy may be a clinically relevant and feasible strategy for treatment of in-stent restenosis.

Adenoviruses, Human↗
PubMed2006

Stent-based local delivery of nuclear factor-kappaB decoy attenuates in-stent restenosis in hypercholesterolemic rabbits.

BACKGROUND: Nuclear factor-kappaB (NF-kappaB) plays a critical role in the vascular response to injury. However, the role of NF-kappaB in the mechanism of in-stent restenosis remains unclear. We therefore tested the hypothesis that blockade of NF-kappaB by stent-based delivery of a cis-element "decoy" of NF-kappaB reduces in-stent neointimal formation. METHODS AND RESULTS: Stents were coated with a polymer containing or not containing NF-kappaB decoy, which represented a fast-release formulation (<7 days). Bare, polymer-coated, and NF-kappaB decoy-eluting stents were implanted in iliac arteries of hypercholesterolemic rabbits. Increased NF-kappaB activity was noted at early stages after stenting, which was suppressed by stent-based delivery of NF-kappaB decoy. NF-kappaB decoy-eluting stents also reduced monocyte infiltration and monocyte chemoattractant protein-1 expression and suppressed CD14 activation on circulating leukocytes. Importantly, NF-kappaB decoy-eluting stents attenuated neointimal formation on day 28. There was no evidence of an incomplete healing process (persistent inflammation, hemorrhage, fibrin deposition, impaired endothelial regeneration) at the site of NF-kappaB decoy-eluting stents. Transfection of NF-kappaB decoy suppressed proliferation of human coronary artery smooth muscle cells in vitro. No systemic adverse effects of NF-kappaB decoy were detected. CONCLUSIONS: Stent-based local delivery of NF-kappaB decoy reduced in-stent neointimal formation with no evidence of incomplete healing. These data suggest that this strategy may be a practical and promising means for prevention of in-stent restenosis in humans.

Angioplasty, Balloon, Coronary↗
PubMed2006

Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood-brain barrier permeability.

Brain edema is a major and often mortal complication of brain ischemia. Vascular endothelial growth factor (VEGF) is also known as a potent vascular permeability factor and may play detrimental roles at the acute stage of brain infarction. Our goal in this study was to explore protective effects of gene transfer of soluble flt-1 (sFlt-1), a natural inhibitor of VEGF, on focal brain ischemia. Adenoviral vector encoding sFlt-1 or beta-galactosidase as control was injected into the lateral ventricle 90 mins after photochemical distal middle cerebral artery occlusion in male spontaneously hypertensive rats. The transduced sFlt-1 was released to the cerebrospinal fluid from the ventricular wall and significantly increased 6 h, 1 and 7 days after sFlt-1 transfection. One day after brain ischemia, sFlt-1 gene transfer significantly reduced infarct volume (by 35%), brain edema (by 35%), and blood-brain barrier permeability (Evans blue extravasation; by 69%) with diminished phosphorylation of focal adhesion kinase (FAKtyr397 and FAKtyr861) in the ischemic vessels. Seven days after ischemia, sFlt-1 gene transfer also significantly attenuated infarct volume (by 29%) and monocyte/macrophage infiltration (by 27%), although there were no reductions in angiogenesis by sFlt-1 overexpression. These results suggest that sFlt-1 gene therapy targeting brain edema in acute stage of brain ischemia may be useful for brain infarction.

Animals↗
PubMed2006

Gene transfer of soluble transforming growth factor type II receptor by in vivo electroporation attenuates lung injury and fibrosis.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) has the potential to induce acute inflammation and apoptosis in lung epithelial cells and plays a central role in subsequent fibrosis. AIMS: To examine a new anti-TGF-beta1 therapy against lung injury and fibrosis, which comprises the transfection of soluble TGF type II receptor (sTGFRII) gene into skeletal muscles by in vivo electroporation. METHODS: Soluble TGFRII was detectable between 1 and 14 days in the serum and significantly increased between 3 and 10 days after gene transfer into muscles. Based on these findings, the sTGFRII gene was injected at 3 days before or 4 days after the bleomycin instillation in order to examine the significance of TGF-beta1 on the early inflammatory phase (day 0 to day 7) or the fibrotic phase (day 7 to day 14) in this model. RESULTS: Transfection of sTGFRII gene at 3 days before or 4 days after bleomycin instillation significantly attenuated apoptosis, injury, and fibrosis at 7 or 14 days, respectively. This method does not require the use of viral vector or neutralising antibody, and it is therefore possible to avoid problems regarding the pathogenicity of the viral vector or immunocomplex. CONCLUSIONS: This novel anti-TGF-beta1 strategy may have clinical application in the treatment of lung injury and fibrosis.

Animals↗
PubMed2006

Therapeutic angiogenesis by ex vivo expanded erythroid progenitor cells.

Recent reports have demonstrated that erythroid progenitor cells contain and secrete various angiogenic cytokines. Here, the impact of erythroid colony-forming cell (ECFC) implantation on therapeutic angiogenesis was investigated in murine models of hindlimb ischemia. During the in vitro differentiation, vascular endothelial growth factor (VEGF) secretion by ECFCs was observed from day 3 (burst-forming unit erythroid cells) to day 10 (erythroblasts). ECFCs from day 5 to day 7 (colony-forming unit erythroid cells) showed the highest VEGF productivity, and day 6 ECFCs were used for the experiments. ECFCs contained larger amounts of VEGF and fibroblast growth factor-2 (FGF-2) than peripheral blood mononuclear cells (PBMNCs). In tubule formation assays with human umbilical vein endothelial cells, ECFCs stimulated 1.5-fold more capillary growth than PBMNCs, and this effect was suppressed by antibodies against VEGF and FGF-2. Using an immunodeficient hindlimb ischemia model and laser-Doppler imaging, we evaluated the limb salvage rate and blood perfusion after intramuscular implantation of ECFCs. ECFC implantation increased both the salvage rate (38% vs. 0%, P < 0.05) and the blood perfusion (82.8% vs. 65.6%, P < 0.01). In addition, ECFCs implantation also significantly increased capillaries with recruitment of vascular smooth muscle cells and the capillary density was 1.6-fold higher than in the control group. Continuous production of human VEGF from ECFCs in the skeletal muscle was confirmed at least 7 days after the implantation. Implantation of ECFCs promoted angiogenesis in ischemic limbs by supplying angiogenic cytokines (VEGF and FGF-2), suggesting a possible novel strategy for therapeutic angiogenesis.

Animals↗
PubMed2006

Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization: critical role of the inflammatory/arteriogenic pathway.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that is known as an inflammatory/arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated. METHODS AND RESULTS: Using murine models of fibroblast growth factor-2 (FGF-2)-mediated therapeutic neovascularization, we here show that FGF-2 targets nonendothelial mesenchymal cells (NEMCs) enhancing both angiogenic (vascular endothelial growth factor [VEGF]) and arteriogenic (MCP-1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor (TNF)-alpha stimulated MCP-1 expression in all cell types tested, whereas FGF-2-mediated upregulation of MCP-1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo. CONCLUSIONS: These results indicate that FGF-2 targets NEMCs independently, enhancing both angiogenic (VEGF) as well as inflammatory/arteriogenic (MCP-1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF-2-mediated therapeutic neovascularization.

Adaptation, Physiological↗
PubMed2006

Angiotensin II type 1 receptor blockade attenuates in-stent restenosis by inhibiting inflammation and progenitor cells.

The precise mechanism by which angiotensin II type 1 receptor blocker reduces in-stent restenosis in clinical trials is unclear. We, therefore, investigated the mechanism of in-stent neointima formation. Male cynomolgus monkeys and rabbits were fed a high-cholesterol diet and were allocated to untreated control and type 1 receptor blocker groups. Five days after grouping, multilink stents were implanted in the iliac artery. The type 1 receptor blocker reduced the development of in-stent neointima formation by approximately 30% in rabbits and monkeys. To investigate potential mechanisms, we examined the expression of renin-angiotensin system markers, all of which increased in monocytes and smooth muscle-like cells in the neointima and media within 7 days. The type 1 receptor blocker attenuated increased oxidative stress, the enhanced expression of markers of the rennin-angiotensin system and monocyte chemoattractant protein-1, and macrophage infiltration. The effects of type 1 receptor blocker on the differentiation of peripheral blood mononuclear cells into vascular progenitor cells were also examined. Treatment with type 1 receptor blocker suppressed the enhanced differentiation to smooth muscle progenitor cells induced by stenting. The type 1 receptor blocker attenuated in-stent neointima formation by inhibiting redox-sensitive inflammatory changes and by reducing recruitment of the progenitor cells. These potential actions of type 1 receptor blocker on inflammation and progenitor cells constitute a novel mechanism of suppression of in-stent restenosis by type 1 receptor blocker.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.

Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.

3T3 Cells↗
PubMed2006

A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates.

BACKGROUND: Calcium antagonists have been shown to reduce atherogenesis and improve clinical outcomes in atherosclerotic vascular disease. No study has so far, however, addressed the effects of calcium antagonists on stent-associated neointimal formation. We therefore investigated whether a third-generation calcium antagonist, azelnidipine, attenuates in-stent neointimal formation in non-human primates. METHOD: Male cynomolgus monkeys were fed a high cholesterol diet for 4 weeks, and were randomly assigned to three groups: a vehicle group and two other groups treated with azelnidipine at 3 and 10 mg/kg per day for an additional 24 weeks (n = 12 each). Multi-link stents were then implanted in the iliac artery. RESULTS: Azelnidipine at the high dose reduced neointimal thickness (0.25 +/- 0.02 versus 0.19 +/- 0.02 mm; P < 0.05). Azelnidipine also reduced local oxidative stress and monocyte chemoattractant protein 1 (MCP-1) expression. No difference was found between the three groups in the degrees of injury score, inflammation score, plaque neovascularization, or plasma lipid levels. Azelnidipine also reduced MCP-1-induced proliferation/migration of vascular smooth muscle cells in vitro. CONCLUSIONS: This study demonstrated for the first time that azelnidipine attenuates in-stent neointimal formation associated with the reduced expression of MCP-1 and smooth muscle proliferation/migration in the neointima. These data in non-human primates suggest potential clinical benefits of azelnidipine as a 'vasculoprotective calcium antagonist' in patients undergoing vascular interventions.

Aged↗
PubMed2005

Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy.

BACKGROUND: Autoimmune myocarditis is a principal cause of heart failure among young adults and is often a precursor of dilated cardiomyopathy. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) are potent chemotactic factors for mononuclear cells. The inflammatory infiltrate observed in myocardial lesions of myocarditis consists of >70% mononuclear cells. To determine their critical role in the pathogenesis of myocarditis, we inhibited mononuclear cell activation and migration to see if it would affect disease severity and disease prevalence in experimental autoimmune myocarditis (EAM). METHODS AND RESULTS: In this report, we demonstrated that blockade of MCP-1 or MIP-1alpha with monoclonal antibodies significantly reduced severity of myocarditis in BALB/c mice immunized with cardiac myosin. Similar results were obtained when CCR2-/- and CCR5-/- mice were used. In CCR2-/- mice, not only disease severity but also disease prevalence was reduced. To further inhibit mononuclear cell activation and migration, we transfected the mice before inducing EAM with a dominant-negative inhibitor of MCP-1 gene (7ND). This transfection significantly reduced the disease severity, decreased mRNA expression levels, especially of the chemokines RANTES, MIP-2, IP-10, MCP-1, T-cell activation gene 3, and eotaxin in the myocardium, and resulted in a reduction in cardiac myosin-induced interleukin-1 and interleukin-4 and in an increase in interferon-gamma and interleukin-10 cytokine production by splenocytes. CONCLUSIONS: Overall, these findings suggest that the chemokines MCP-1 and MIP-1alpha, acting through their receptors CCR2 and CCR5, are important in the induction of EAM and that inhibition of MCP-1 with 7ND gene transfection significantly reduced disease severity. This strategy may be a new feasible form of gene therapy against autoimmune myocarditis.

Animals↗
PubMed2005

Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice.

Vascular endothelial growth factor (VEGF) is an angiogenesis factor with proinflammatory roles. Flt-1 is one of the specific receptors for VEGF, and soluble flt-1 (sflt-1) binds to VEGF and competitively inhibits it from binding to the receptors. We examined the role of VEGF in the pathophysiology of bleomycin-induced pneumopathy in mice, using a new therapeutic strategy that comprises transfection of the sflt-1 gene into skeletal muscles as a biofactory for anti-VEGF therapy. The serum levels of sflt-1 were significantly increased at 3-14 days after the gene transfer. Transfection of the sflt-1 gene at 3 days before or 7 days after the intratracheal instillation of bleomycin decreased the number of inflammatory cells, the protein concentration in the bronchoalveolar lavage fluid and with von Willebrand factor expression at 14 days. Transfection of the sflt-1 gene also attenuated pulmonary fibrosis and apoptosis at 14 days. Since the inflammatory cell infiltration begins at 3 days and is followed by interstitial fibrosis, it is likely that VEGF has important roles as a proinflammatory, a permeability-inducing, and an angiogenesis factor not only in the early inflammatory phase but also in the late fibrotic phase. Furthermore, this method may be beneficial for treating lung injury and fibrosis from the viewpoint of clinical application, since it does not require the use of a viral vector or neutralizing Ab.

Animals↗
PubMed2005

Endogenous NO blockade enhances tissue factor expression via increased Ca2+ influx through MCP-1 in endothelial cells by monocyte adhesion.

OBJECTIVE: Ca2+ plays an important role in tissue factor (TF) gene expression. We investigated the role of endogenous nitric oxide (NO) in the induction of TF expression in endothelial cells (ECs) by monocyte adhesion and the mechanisms of NO action. METHODS AND RESULTS: Inhibition of endogenous NO by Nomega-nitro-L-arginine methyl ester (L-NAME) enhanced TF promoter activity and protein expression induced in human coronary ECs by monocyte adhesion, as well as EC surface TF activity. L-NAME also induced monocyte chemoattractant protein-1 (MCP-1) expression, which was blocked by an NO donor, NOC18. Exogenous MCP-1 enhanced TF expression induced by monocyte adhesion, whereas adenovirus-mediated expression of the mutant MCP-1, 7ND, abolished the L-NAME enhancement of TF expression induced by monocyte adhesion. Monocyte attachment to L-NAME-treated ECs increased Ca2+ influx, which was prevented by NOC18, anti-MCP-1 antibody or 7ND. These results indicate that the binding of increased MCP-1 induced by endogenous NO blockade to CCR2 mediated the enhancement of Ca2+ influx only when monocytes adhered to ECs, which upregulated TF expression in ECs triggered by monocyte adhesion. CONCLUSIONS: MCP-1/CCR2 may play a role in Ca2+ influx-dependent TF regulation in the monocyte-EC interaction in the impairment of NO synthesis.

Calcium↗
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

Essential role of vascular endothelial growth factor and Flt-1 signals in neointimal formation after periadventitial injury.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is upregulated after arterial injury. Its role in the pathogenesis of neointimal formation after periadventitial injury, however, has not been addressed. METHODS AND RESULTS: Expression of VEGF and its receptors but not that of placental growth factor markedly increased with the development of neointimal formation in hypercholesterolemic mice after cuff-induced periarterial injury. Transfection with the murine soluble Flt-1 (sFlt-1) gene to block VEGF in vivo in mice inhibited early inflammation and later neointimal formation. The sFlt-1 gene transfer did not affect plasma lipid levels but attenuated increased expression of VEGF, Flt-1, Flk-1, monocyte chemoattractant protein-1, and other inflammation-promoting factors. Mice with Flt-1 kinase deficiency also displayed reduced neointimal formation. CONCLUSIONS: Inflammatory changes mediated by VEGF and Flt-1 signals play an important role in the pathogenesis of neointimal formation after cuff-induced periadventitial injury. VEGF might promote neointimal formation by acting as a proinflammatory cytokine.

Animals↗
PubMed2004

Bone marrow-derived monocyte chemoattractant protein-1 receptor CCR2 is critical in angiotensin II-induced acceleration of atherosclerosis and aneurysm formation in hypercholesterolemic mice.

UNLABELLED: Angiotensin II (Ang II) is implicated in atherogenesis by activating inflammatory responses in arterial wall cells. Ang II accelerates the atherosclerotic process in hyperlipidemic apoE-/- mice by recruiting and activating monocytes. Monocyte chemoattractant protein-1 (MCP-1) controls monocyte-mediated inflammation through its receptor, CCR2. The roles of leukocyte-derived CCR2 in the Ang II-induced acceleration of the atherosclerotic process, however, are not known. We hypothesized that deficiency of leukocyte-derived CCR2 suppresses Ang II-induced atherosclerosis. METHODS AND RESULTS: A bone marrow transplantation technique (BMT) was used to develop apoE-/- mice with and without deficiency of CCR2 in leukocytes (BMT-apoE-/-CCR2+/+ and BMT-apoE-/-CCR2-/- mice). Compared with BMT-apoE-/-CCR2+/+ mice, Ang II-induced increases in atherosclerosis plaque size and abdominal aortic aneurysm formation were suppressed in BMT-apoE-/-CCR2-/- mice. This suppression was associated with a marked decrease in monocyte-mediated inflammation and inflammatory cytokine expression. CONCLUSIONS: Leukocyte-derived CCR2 is critical in Ang II-induced atherosclerosis and abdominal aneurysm formation. The present data suggest that vascular inflammation mediated by CCR2 in leukocytes is a reasonable target of therapy for treatment of atherosclerosis.

Angiotensin II↗
PubMed2004

Roles of endogenous monocyte chemoattractant protein-1 in ischemia-induced neovascularization.

OBJECTIVES: We sought to investigate the role of endogenous monocyte chemoattractant protein (MCP)-1 in ischemia-induced neovascularization. BACKGROUND: Roles of inflammatory changes including macrophage infiltration are suggested in ischemic neovascularization. METHODS: Unilateral hindlimb ischemia was induced by excising surgically the entire femoral artery and vein in mice. Immediately after operation, plasmid deoxyribonucleic acid encoding a dominant negative mutant of MCP-1 (7ND) or the empty plasmid (mock) was injected into the ipsilateral thigh adductor muscle. RESULTS: In mock-treated mice, MCP-1 was upregulated transiently in ischemic hindlimb peaking at day 3. Serial laser Doppler blood flow (LDBF) analysis showed an abrupt decrease in blood flow, followed by a recovery to the near-normal levels in mock-treated mice; 7ND treatment had no effects on the initial decrease in LDBF but deteriorated the recovery. At day 3, macrophage infiltration and inductions of tumor necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF) were prominent in the ischemic adductor muscle in mock-treated mice; 7ND treatment significantly reduced macrophage infiltration and suppressed TNF-alpha and VEGF inductions in response to ischemia. At day 21, postmortem angiography and anti-CD31 immunohistostaining revealed well-developed collateral vessels and capillary formation, respectively, in the ischemic muscle of mock-treated mice; 7ND overexpression remarkably suppressed the collateral vessel formation and capillary formation. CONCLUSIONS: Endogenous MCP-1 may play a role in ischemia-induced neovascularization by recruiting macrophages that activate TNF-alpha and VEGF inductions.

Animals↗
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↗