Biomedical subjects

Kensuke Egashira

Publications and source records attributed to Kensuke Egashira.

At least 73 records · Page 4Linked to original sources

PubMed2002

Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice.

BACKGROUND: Monocyte infiltration into the arterial wall and its activation is the central event in atherogenesis. Thus, monocyte chemoattractant protein-1 (MCP-1) might be a novel therapeutic target against atherogenesis. We and others recently reported that blockade or abrogation of the MCP-1 pathway attenuates the initiation of atheroma formation in hypercholesterolemic mice. It remains unclear, however, whether blockade of MCP-1 can limit progression or destabilization of established lesions. METHODS AND RESULTS: We report here that blockade of MCP-1 by transfecting an N-terminal deletion mutant of the MCP-1 gene limited progression of preexisting atherosclerotic lesions in the aortic root in hypercholesterolemic mice. In addition, blockade of MCP-1 changed the lesion composition into a more stable phenotype, ie, containing fewer macrophages and lymphocytes, less lipid, and more smooth muscle cells and collagen. This strategy decreased expression of CD40 and the CD40 ligand in the atherosclerotic plaque and normalized the increased chemokine (RANTES and MCP-1) and cytokine (tumor necrosis factor alpha, interleukin-6, interleukin-1beta, and transforming growth factor beta(1)) gene expression. These data suggest that MCP-1 is a central mediator in the progression and destabilization of established atheroma. CONCLUSIONS: The results of the present study suggest that the inflammatory responses mediated by MCP-1 are important in atherosclerosis and its complications.

Animals↗

PubMed2002

Anti-monocyte chemoattractant protein-1 gene therapy inhibits restenotic changes (neointimal hyperplasia) after balloon injury in rats and monkeys.

Prevention of restenosis after coronary intervention is a major clinical challenge, which highlights the need of new therapeutic options. Vascular injury may involve inflammatory responses that accelerate the recruitment and activation of monocytes through the activation of chemotactic factors, including monocyte chemoattractant protein-1 (MCP-1). However, there is no definitive evidence supporting the role of MCP-1 in restenosis. We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. We demonstrate here that this strategy suppressed monocyte infiltration/activation in the injured site and markedly inhibited restenotic changes (neointimal hyperplasia) after balloon injury of the carotid artery in rats and monkeys. This strategy also suppressed the local production of MCP-1 and inflammatory cytokines. Therefore, monocyte infiltration and activation mediated by MCP-1 are essential in the development of restenotic changes after balloon injury. This strategy may be a useful form of gene therapy against human restenosis.

Actins↗

PubMed2002

Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation.

BACKGROUND: Oxidative stress and inflammation are potentially involved in the pathogenesis of heart failure (HF). We examined whether antioxidant and antiinflammatory treatment with probucol decreases myocardial oxidative stress and inflammation and attenuates the progression of left ventricular (LV) dysfunction and remodeling (dilatation) in tachycardia-induced HF. METHODS AND RESULTS: We studied 3 groups of dogs: a sham-operated control group and 2 other groups that underwent ventricular pacing at 240 bpm with and without probucol treatment (100 mg/kg IP per week) for 4 weeks. Dogs that underwent ventricular pacing for 4 weeks developed signs of HF, such as a reduction in the LV ejection fraction and increases in the LV end-diastolic dimension and LV end-diastolic pressure. Myocardial oxidative stress, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO), was significantly increased. There was an increase in myocardial monocyte infiltration, monocyte chemoattractant protein-1 expression, and renin-angiotensin system and matrix metalloproteinase activity. Probucol treatment prevented increases in oxidative stress, inflammation, and matrix metalloproteinase activity and attenuated LV dysfunction and remodeling. CONCLUSIONS: Probucol attenuated LV dysfunction and remodeling, possibly through its antioxidant and/or antiinflammatory effects in ventricular pacing-induced HF. These data suggest that inflammatory disorders, which cause an abnormal interaction between failing myocardium and activated monocytes, have an important role in the progression of HF.

Animals↗

PubMed2002

Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats.

BACKGROUND: Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-beta in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. METHODS AND RESULTS: Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-beta mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti-TGF-beta neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. CONCLUSIONS: TGF-beta plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.

Animals↗

PubMed2002

Essential role of monocyte chemoattractant protein-1 in development of restenotic changes (neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits.

BACKGROUND: Renarrowing of dilated arterial sites (restenosis) hampers the clinical benefits of coronary angioplasty. Infiltration and activation of monocytes in the arterial wall mediated by monocyte chemoattractant protein-1 (MCP-1) might be a major cause of restenosis after angioplasty. However, there is no direct evidence to support a definite role of MCP-1 in the development of restenosis. Methods and Results- We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. We used this strategy to investigate the role of MCP-1 in the development of restenotic changes after balloon injury in the carotid artery in hypercholesterolemic rabbits. Intramuscular transfection of the mutant MCP-1 gene suppressed monocyte infiltration/activation in the injured arterial wall and thus attenuated the development of neointimal hyperplasia and negative remodeling. CONCLUSIONS: MCP-1-mediated monocyte infiltration is necessary in the development of restenotic changes to balloon injury in hypercholesterolemic rabbits. This strategy may be a useful and practical form of gene therapy against human restenosis.

Angioplasty, Balloon↗

PubMed2002

Importance of monocyte chemoattractant protein-1 pathway in neointimal hyperplasia after periarterial injury in mice and monkeys.

Neointimal hyperplasia is a major cause of restenosis after coronary intervention. Because vascular injury is now recognized to involve an inflammatory response, monocyte chemoattractant protein-1 (MCP-1) might be involved in underlying mechanisms of restenosis. In the present study, we demonstrate the important role of MCP-1 in neointimal hyperplasia after cuff-induced arterial injury. In the first set of experiments, placement of a nonconstricting cuff around the femoral artery of intact mice and monkeys resulted in inflammation in the early stages and subsequent neointimal hyperplasia at the late stages. We transfected with an N-terminal deletion mutant of the human MCP-1 gene into skeletal muscles to block MCP-1 activity in vivo. This mutant MCP-1 works as a dominant-negative inhibitor of MCP-1. This strategy inhibited early vascular inflammation (monocyte infiltration, increased expression of MCP-1, and inflammatory cytokines) and late neointimal hyperplasia. In the second set of experiments, the cuff-induced neointimal hyperplasia was found to be less in CCR2-deficient mice than in control CCR2(+/+) mice. The MCP-1/CCR2 pathway plays a central role in the pathogenesis of neointimal hyperplasia in cuffed femoral artery of mice and monkeys. Therefore, the MCP-1/CCR2 pathway can be a therapeutic target for human restenosis after coronary intervention.

Animals↗

PubMed2002

Vascular endothelial growth factor is necessary in the development of arteriosclerosis by recruiting/activating monocytes in a rat model of long-term inhibition of nitric oxide synthesis.

BACKGROUND: It remains unclear whether vascular endothelial growth factor (VEGF) is a proarteriosclerotic or an antiarteriosclerotic factor. We recently reported that long-term inhibition of nitric oxide by administering Nomega-nitro-L-arginine methyl ester (L-NAME) induces coronary vascular inflammation and arteriosclerosis. METHODS AND RESULTS: We used this animal model to investigate the role of VEGF in arteriosclerosis. We blocked VEGF activity in vivo by transfecting with plasmid DNA encoding the murine soluble FLT-1 (sFLT-1) gene into thigh muscle. Soluble FLT-1 can suppress VEGF activity both by sequestering VEGF and by functioning as a dominant-negative inhibitor of VEGF receptors. We observed vascular inflammation associated with increased VEGF expression within 3 days of L-NAME administration, which was prevented by pretreatment with ACE inhibitor, angiotensin II receptor antagonist, or neutralizing monocyte chemoattractant protein-1 antibody. The sFLT-1 gene transfer attenuated the early vascular inflammation and prevented late arteriosclerosis. The sFLT-1 gene transfer also inhibited increased expression of monocyte chemoattractant protein-1 and transforming growth factor-beta, indicating creation of a positive feedback loop to cause arteriosclerosis. CONCLUSIONS: VEGF is necessary in the development of arteriosclerosis by mediating monocyte recruitment and activation in this model.

Animals↗

PubMed2002

Augmented vasodilator response to L-arginine after coronary angioplasty may attenuate restenosis.

Nitric oxide (NO) plays an important role in the control of vascular tone as well as structure. This study examined the possibility that the extent of restenosis 3 months after percutaneous transluminal coronary angioplasty (PTCA) might be correlated with the magnitude of NO production at the PTCA sites on the day following PTCA. In 23 consecutive patients who underwent PTCA, we examined the coronary artery diameter response to intracoronary administration of L-arginine (1 microg/kg) and isosorbide dinitrate (ISDN, 40 microg/kg) at the sites of PTCA (n = 25) and at untreated sites distal to the PTCA sites approximately 18 h after PTCA. The coronary artery diameter at the PTCA site was determined 3 months after PTCA in all patients. Normalized vasodilator responses to L-arginine (responses to L-arginine/those to ISDN) were greater at the PTCA sites than at the untreated sites (P = 0.05), whereas vasodilator responses to ISDN did not differ between the PTCA and untreated sites. These results suggest a greater production of NO at the PTCA sites despite presumable loss of the endothelium due to the PTCA. Furthermore, the magnitude of normalized vasodilator responses to L-arginine examined at 18 h after PTCA correlated with the coronary artery diameter 3 months after PTCA (r = 0.592, P = 0.002). These results suggest that augmented NO production after PTCA may protect against the development of coronary restenosis. Treatment that enhances local NO production may be clinically useful in preventing restenosis after PTCA.

Angina Pectoris↗

PubMed2002

Post-beta-receptor impairment in the regulation of myofibrillar Ca2+ sensitivity in tachypacing-induced canine failing heart.

Although one of the salient abnormalities in signal transduction of failing myocardium is downregulation of the beta-adrenergic receptor, the extent of presentation of downstream pathways distal to beta-receptors is misunderstood. We addressed this question in tachypacing-induced canine failing heart by assessing changes in myofibrillar Ca2+ sensitivity and troponin I phosphorylation. At a basal state, no significant difference in myofibrillar Ca2+ sensitivity was found between normal and failing hearts. Isoproterenol 8-bromo-cylic adenosine monophosphate (cAMP), and 8-bromo-cAMP isobutylmethylxantine all significantly decreased the Ca2+ sensitivity in the normal, but not in the failing, heart. EMD57033 (10 microM ), a myofibrillar Ca2+ sensitizer increased the Ca2+ sensitivity to a similar extent in both groups. The troponin I phosphorylation levels were significantly decreased in the failing heart. These results suggest that abnormalities of the beta-adrenergic signaling system exist not only at the receptor level but also at downstream steps after cAMP production.

Animals↗

PubMed2002

Long-term inhibition of nitric oxide synthesis increases arterial thrombogenecity in rat carotid artery.

Reduced activity of endothelial nitric oxide (NO) may be involved in thrombus formation on atherosclerotic plaques, a major cause of acute coronary syndrome. However, mechanisms of such increase in arterial thrombogenecity have not been fully understood. We previously reported that long-term inhibition of NO synthesis by administration of N(G)-nitro-L-arginine methyl ester (L-NAME) causes hypertension and activates vascular tissue angiotensin-converting enzyme (ACE) activity. We used this model to investigate the mechanism by which long-term impairment of NO activity increases arterial thrombogenecity. We observed cyclic flow variations (CFVs), a reliable marker of platelet thrombi, after the production of stenosis of the carotid artery in rats treated with L-NAME for 4 wk. The thrombin antagonist argatroban suppressed the CFVs. The CFVs were detected in rats receiving L-NAME plus hydralazine but not in rats receiving L-NAME plus an ACE inhibitor (imidapril). Treatment with the ACE inhibitor imidapril, but not with hydralazine, prevented L-NAME-induced increases in carotid arterial ACE activity and attenuated tissue factor expression. These results suggest that long-term inhibition of endothelial NO synthesis may increase arterial thrombogenecity at least in part through angiotensin II-induced induction of tissue factor and the resultant thrombin generation. These data provide a new insight as to how endothelial NO exhibits antithrombogenic properties of the endothelium.

Administration, Oral↗

PubMed2002

Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats.

Monocyte/macrophage chemoattractant protein-1 (MCP-1), a potent chemoattractant chemokine and an activator for mononuclear cells, may play a role in the initiation and/or progression of pulmonary hypertension (PH). To determine whether blockade of a systemic MCP-1 signal pathway in vivo may prevent PH, we intramuscularly transduced a naked plasmid encoding a 7-NH(2) terminus-deleted dominant negative inhibitor of the MCP-1 (7ND MCP-1) gene in monocrotaline-induced PH. We also simultaneously gave a duplicate transfection at 2-wk intervals or skeletal muscle-directed in vivo electroporation (EP) to evaluate whether a longer or higher expression might be more effective. The intramuscular reporter gene expression was enhanced 10 times over that by EP than by simple injection, and a significant 7ND MCP-1 protein in plasma was detected only in the EP group. 7ND MCP-1 gene transfer significantly inhibited the progression of MCT-induced PH as evaluated by right ventricular systolic pressure, right ventricular hypertrophy, medial hypertrophy of pulmonary arterioles, and mononuclear cell infiltration into the lung. Differential effects of longer or higher transgene expression were not apparent. Although the in vivo kinetics of 7ND MCP-1 gene therapy should be studied further, these encouraging results suggest that an anti-inflammatory strategy via blockade of the MCP-1 signal pathway may be an alternative approach to treat subjects with PH.

Animals↗

PubMed2002

Antiinflammatory and antiarteriosclerotic effects of pioglitazone.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPARgamma activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPARgamma ligand) in this rat model to determine whether PPARgamma activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPARgamma activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes). Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state.

Animals↗

PubMed2002

Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats.

Chronic inhibition of endothelial NO synthesis by the administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 expression) as well as subsequent arteriosclerosis. The small GTPase Rho controls cell adhesion, motility, and proliferation and is activated by several growth factors such as angiotensin II. We investigated the effect of a specific inhibitor of Rho-kinase, Y-27632, in rats treated with L-NAME to determine the role of the Rho/Rho-kinase pathway in the development of arteriosclerosis. We found here increased activity of Rho/Rho-kinase after L-NAME administration and its prevention by angiotensin II type 1 receptor blockade. Hydralazine or lecithinized superoxide dismutase (l-SOD) did not affect Rho/Rho-kinase activity. Co-treatment with Y-27632 did not affect the L-NAME-induced increase in cardiovascular tissue ACE activity or L-NAME-induced decrease in plasma NO concentrations, but did prevent the L-NAME-induced early inflammation and late coronary arteriosclerosis. In addition, Y-27632 prevented the increased gene expression of monocyte chemoattractant protein-1 and transforming growth factor-beta1 as well as cardiac fibrosis and glomerulosclerosis. These findings suggest that increased activity of Rho/Rho-kinase pathway mediated via the angiotensin II type 1 receptor may thus be important in the pathogenesis of early vascular inflammation and late remodeling induced by chronic inhibition of NO synthesis. The beneficial effects of Rho-kinase inhibition are not mediated by restoration of NO production. The Rho-kinase pathway could be a new therapeutic target for treatment of vascular diseases.

Actins↗

PubMed2002

Clinical importance of endothelial function in arteriosclerosis and ischemic heart disease.

The vascular endothelium is a dynamic endocrine organ that regulates vascular tone, local homeostasis, and the fibro-inflammatory-proliferative process. These responses are mediated by various substances released from the endothelium in response to physiologic stimuli, including prostacyclin, endothelin and, most importantly, nitric oxide (NO). NO mediates vasodilation and inhibits platelet aggregation, thrombus formation, expression of adhesion molecules and chemokines for leukocytes, and oxidative stress. It also attenuates growth and proliferation of vascular smooth muscle cells. Risk factors for atherosclerosis, such as hypercholesterolemia, hypertension, diabetes and cigarette smoking, impair endothelial function, which leads to atherosclerosis and results in ischemic manifestations such as acute coronary syndrome and stroke. Thus, therapeutic intervention aimed at increasing NO bioavailability by statins or angiotensin-converting enzyme inhibitors might improve patient prognosis. Vascular endothelial function is an important and clinically relevant therapeutic target for cardiovascular disease.

Arteriosclerosis↗

PubMed2002

Angiotensin-converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus.

The renin-angiotensin system plays an important role in the elevation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in hypertensive patients, so the present study was designed to examine whether angiotensin-converting enzyme (ACE) activity is also involved in the mechanism of ADMA elevation in type 2 diabetes mellitus (NIDDM). A crossover study was performed to determine if ACE inhibition with perindopril (4 mg/day) for 4 weeks decreases serum ADMA concentration and plasma von Willebrand factor (vWF) level (a marker of endothelial injury) in 11 patients with NIDDM. None of the patients was treated with insulin or oral hypoglycemic drugs, and none had major diabetic complications. Before the protocol began, serum ADMA and plasma vWF were significantly higher in the 11 NIDDM patients, when compared with 8 control subjects without diabetes. Perindopril did not affect blood pressure or glucose metabolism, but did significantly decrease serum ADMA and plasma vWF. These results suggest that endothelial injury associated with ADMA elevation may be present even in patients with non-complicated NIDDM, and that increased activity of ACE may be involved in such endothelial dysfunction.

Aged↗

PubMed2002

Severe pulmonary hypertension in a patient with systemic lupus erythematosus and minimal lupus activity.

Pulmonary hypertension (PH) sometimes occurs in patients with systemic lupus erythematosus (SLE). We report a case of 51-year-old-woman with PH associated with SLE. She had been diagnosed as SLE on the basis of pericardial effusion, hematological disorder, positive antinuclear antibody, and hypocomplementemia. Despite minimal lupus activity, she had marked elevation of pulmonary arterial pressure (101/53 mmHg) and decreased cardiac index (1.5 l/min/m2). Symptoms related to PH were progressive under treatment with oral corticosteroids, oxygen, calcium antagonists, and warfarin. After 17 months of epoprostenol treatment, she died of pulmonary infarction. SLE-associated PH is often severe and progressive even in association with minimal activity.

Anticoagulants↗

PubMed2002

Gene therapy targeting monocyte chemoattractant protein-1 for vascular disease.

Monocyte chemoattractant protein-1 (MCP-1) has been shown to play an essential role in the pathogenesis of arteriosclerosis and other vascular diseases, such as restenosis after arterial injury, by recruiting monocytes into the arterial wall. We devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (7ND), which lacks the amino-terminal amino acids 2 to 8 of the human MCP-1 gene, into a remote organ (skeletal muscles). Intramuscular transduction with the mutant MCP-1 gene suppressed inflammatory and proliferative changes and arteriosclerosis formation induced by the chronic inhibition of nitric oxide synthesis in rats. 7ND gene transfection also inhibited the initiation, progression, and destabilization of atherosclerosis in Apolipoprotein E-knockout mice. Moreover, the strategy reduced restenosis after balloon injury in rabbits, rats, and monkeys, or neointimal formation after stent implantation in monkeys. This new strategy may be a useful and feasible gene therapy against atherosclerosis and restenosis after angioplasty.

Animals↗

PubMed2002

[Angiotensin II receptor and oxidative stress].

Angiotensin II(AngII) activates NADH/NAPDH oxidase activity and stimulates reactive oxygen species(ROS) production, which induces many proinflammatory genes such as vascular cell adhesion molecule-1(VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1(MCP-1) mainly via AngII type I receptor(AT1). ROS are important in cardiovascular disease because many of these preinflammatory cytokines play a critical role in the initiation and progression of atherosclerosis. AT1 receptor blockade is important to prevent cardiovascular disease. AngII type 1 receptor blocker(ARB) and/or AngII converting enzyme inhibitor(ACEI) are useful for preventing cardiovascular disease. The role of AngII type II receptor(AT2) for producing ROS and/or cardiovascular damage has been studied.

Animals↗