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PubMedDate not supplied

Molecular biology in arteriosclerosis research.

The topics discussed in this article illustrate how molecular biology will have a dramatic impact on arteriosclerosis research. DNA clones for a small number of relevant proteins have been isolated, and studies are underway in numerous laboratories to extend these initial studies. The techniques of molecular biology will provide major advances in our understanding of numerous proteins directly or indirectly involved in the atherogenic process. Cloning technology will solve the primary structures of many proteins that can not be purified in quantities sufficient for classical methods of analysis. Studies of regulation will benefit from the availability of DNA probes, the ability to generate site-directed antibodies, and the use of reverse genetics to identify nucleic acid sequences involved in the regulation of gene expression. Studies of gene structure and genetic polymorphisms will unravel the genetic basis for defects in lipid and lipoprotein metabolism and should provide valuable reagents for clinical screening and diagnosis. The reverse genetics approach will permit the systematic analysis of structure-function relationships at the protein level in a manner not previously possible. Each of these will contribute to our understanding of the atherogenic process and should provide insight into ways of preventing and treating arteriosclerosis.

Amino Acid Sequence↗

PubMedDate not supplied

Genetic aspects of arteriosclerosis.

This review discusses the genetic factors in the development of arteriosclerosis and coronary heart disease (CHD). In several studies, multivariate analysis of prospective mortality/morbidity data and angiographic findings have indicated that a family history of CHD contributed to CHD risk independently of the established risk factors. In addition, ethnic groups that differ in the prevalence and incidence of CHD also markedly differ in blood groups and protein-enzymatic markers. These or other genetic differences may affect CHD rates. Data from fraternal and identical twins, the source of some early genetic CHD findings, are reviewed. Genetic disorders of lipoprotein metabolism and transport, such as familial hypercholesterolemia, as well as other monogenic disorders are discussed. The role of apoprotein E polymorphism i other monogenic disorders are discussed. The role of apoprotein E polymorphism in determining plasma LDL variability among individuals is considered. Recombinant DNA technology, molecular cloning, and the identification of restriction fragment length polymorphisms are new tools for investigators who assess DNA polymorphism. Recent advances in that domain include: DNA polymorphisms affecting blood levels of apo A-I and A-II, association of a DNA insertion on chromosome 19 with severe premature atherosclerosis, and information concerning linkage of the genes for various apolipoproteins. In addition, the evidence for a major genetic component in diabetes mellitus and research into the genetic aspects of hypertension are reviewed. The male/female ratio in pathologically and epidemiologically assessed atherosclerosis may provide clues to the role of genetics. Early structural changes in the coronary artery intima are compatible with the ethnic and gender predilection. A key question in understanding underlying mechanisms in atherosclerosis is why coronary arteries are occluded in individuals whose other arterial systems are largely unaffected. The review concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on uncovering genetically determined differences in arterial wall response to blood flow. Subpopulations with different genetic risks may be identified, in which case universal preventive strategies might be replaced with specific ones.

ABO Blood-Group System↗

PubMed2002

Overexpression of soluble fas attenuates transplant arteriosclerosis in rat aortic allografts.

BACKGROUND: The killing of vascular cells by activated macrophages is an important step in the process of destabilization of the arterial wall. The death receptor Fas is implicated in vascular cell death. Hence, we extended our studies in a rat aortic allograft model, using adenovirus-mediated overexpression of soluble Fas (sFas) to block Fas binding to Fas ligand (Fas-L). The contribution of Fas to vascular cell injury and consequent transplant arteriosclerosis was investigated. METHODS AND RESULTS: Activated monocytes in the presence of macrophage colony-stimulating factor induce endothelial cell apoptosis in vitro, which was significantly inhibited by adenovirus-mediated sFas overexpression. Next, donor rat abdominal aortas were either untreated or transduced with adenoviruses encoding (1) rat soluble Fas (Ad3rsFas), (2) no insert (Ad3Null), and (3) beta-galactosidase (Ad3nBg). A total of 175 aortic grafts were harvested 2 to 90 days after transplantation. Vascular cell apoptosis and CD45+ cell infiltration were significantly reduced in Ad3rsFas-transduced aortas, as compared with control allografts. Moreover, the control allografts developed marked intimal thickening, whereas Ad3rsFas-transduced allografts had significantly less neointima until the 90-day time point. CONCLUSIONS: sFas overexpression protects the integrity of the vessel wall from immune injury and attenuates transplant arteriosclerosis.

Adenoviridae↗

PubMed1994

Cytomegalovirus infection-enhanced allograft arteriosclerosis is prevented by DHPG prophylaxis in the rat.

BACKGROUND: Major risk factors for accelerated allograft arteriosclerosis include humoral and cellular immune response, hyperlipidemia, and viral infections. We demonstrated earlier that rat cytomegalovirus (RCMV) infection doubles smooth muscle cell proliferation and intimal thickening of rat aortic allografts. In this study, the effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on RCMV-enhanced rat allograft arteriosclerosis are investigated. METHODS AND RESULTS: Aortic allografts from the DA to the WF rat strain were used. The recipients were inoculated with 10(5) plaque-forming units of RCMV 1 day after transplantation. Two groups of RCMV-infected rats were treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP twice a day for a period of 14 days. In the DHPG prophylaxis group (n = 22), the drug administration started 1 day before infection, and in the DHPG treatment group (n = 17), 7 days after infection. One group of infected rats was left untreated (n = 21). The grafts were removed 7 and 14 days and 1, 3, and 6 months after transplantation. In the DHPG prophylaxis group, no virus could be recovered by plaque assays. In the treatment group, 50% of rats were virus-positive at 1 month and 40% at 3 months. DHPG prophylaxis prevented the infiltration of inflammatory cells and their proliferation in the adventitia of RCMV-infected recipients (P < .01), with a 60% reduction in the interleukin-2 receptor expression (P < .05) and a 30% decrease in major histocompatibility complex class II expression (P = NS). DHPG prophylaxis did not significantly alter the levels of insulin-like growth factor-1, epidermal growth factor, platelet-derived growth factor-BB, transforming growth factor-beta 1, acidic fibroblast growth factor, and basic fibroblast growth factor messages in the allograft vascular wall. Early media necrosis was reduced. Arteriosclerotic alterations and proliferation of smooth muscle cells were both reduced 50% to 70% by DHPG prophylaxis (P < .05 at 3 months). The responses in the DHPG treatment group were quite similar but less impressive and statistically nonsignificant. CONCLUSIONS: We consider it likely that DHPG inhibits arteriosclerotic alterations primarily by reducing the infectious virus and thereby the inflammatory response in the allograft vascular wall; another possibility is a direct antiproliferative effect on smooth muscle cell replication. A dose-dependent inhibitory effect of DHPG on smooth muscle cell replication was recorded in an in vitro study.

Animals↗

PubMed1998

Graft permeabilization facilitates gene therapy of transplant arteriosclerosis in a rabbit model.

BACKGROUND: Smooth muscle cell (SMC) replication plays a central role in the pathogenesis of transplant arteriosclerosis. One strategy to eliminate dividing cells is to express a herpesvirus thymidine kinase (tk) gene that phosphorylates the nucleoside analogue ganciclovir into a toxic form leading to cell killing. However, medial SMCs are resistant to gene transfer unless the artery undergoes deendothelialization. We hypothesized that manipulations that increase the "porosity" of the artery can make SMCs prone to gene transfer without denudation. METHODS AND RESULTS: In organ culture of rabbit aorta, longitudinal stretch and supraphysiological pressure applied for 3 hours during incubation with adenoviral vector facilitated gene transfer into medial SMCs without denudation. Of the SMCs, 10.2+/-3.8% expressed a reporter gene of human placental alkaline phosphatase (hpAP), whereas SMCs in control arteries did not express hpAP. To evaluate the feasibility of transgene expression in arterial grafts, we performed such permeabilization-assisted reporter gene transfer into aortas of donor Dutch Belted rabbits and transplanted them into carotid arteries of recipient New Zealand White rabbits. Unstretched transfected grafts were used as a control. SMCs expressed hpAP (7. 3+/-2.4% of cells in 2 days and 4.2+/-1.9% in 2 weeks) in stretched grafts only. In the next series of experiments, we transfected stretched grafts with ADV-tk and combined transplantation with systemic administration of ganciclovir. Stretched ADV-hpAP grafts were used as a control. In 2 weeks, the formation of intimal thickening in tk-expressing grafts was significantly reduced (P<0. 01) because of a decrease in proliferating SMCs. CONCLUSIONS: Manipulations within target tissues can enhance the efficiency of gene transfer into SMCs. Although mechanical permeabilization is clinically problematic, in principle, targeting SMC replication may provide a genetic approach to the treatment of transplant arteriosclerosis.

Adenoviridae↗

PubMed1999

Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor.

BACKGROUND: Increased immunoreactivity of platelet-derived growth factor (PDGF)-AA, -Ralpha, and -Rbeta in intimal cells correlates with the development of cardiac allograft arteriosclerosis, a condition for which there is little or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease. METHODS AND RESULTS: The hypothesis was tested in a rat model of heterotopic cardiac and aortic allografts using dark agouti (AG-B4, RT1(a)) donors and Wistar-Furth (AG-B2, RT1(u)) recipients. The recipients received CGP 53716, a selective PDGF-R protein tyrosine kinase inhibitor, 50 mg. kg-1. d-1, or vehicle for 60 days. Cardiac allograft recipients also received background cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac and aortic allograft recipients. When rat coronary smooth muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1beta or tumor necrosis factor-alpha, CGP 53716 significantly inhibited only AA-ligand-induced but not BB-ligand-induced replication. Concomitantly, in quantitative reverse transcriptase-polymerase chain reaction, interleukin-1beta or tumor necrosis factor-alpha stimulation specifically upregulated the expression of PDGF-Ralpha mRNA but not of other ligand or receptor genes in cultured smooth muscle cells. CONCLUSIONS: We conclude that a PDGF-AA/Ralpha-dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.

Animals↗

PubMed2002

PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis.

Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-gamma, represent a critical step in atherogenesis and arteriosclerosis. IFNgamma pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNgamma signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARalpha and PPARgamma mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNgamma protein secretion from 0 to 504+/-168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARalpha (WY14643 or fenofibrate) or PPARgamma (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNgamma secretion in a concentration-dependent manner. PPAR activators also inhibited TNFalpha and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARalpha and PPARgamma in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNgamma, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.

Anti-Inflammatory Agents↗

PubMed2005

Accelerated arteriosclerosis of vein grafts in inducible NO synthase(-/-) mice is related to decreased endothelial progenitor cell repair.

Inducible NO synthase (iNOS) is expressed by macrophages and smooth muscle cells in atherosclerotic lesions. Previously, we have established a mouse model for vein graft arteriosclerosis by grafting autologous jugular veins or vena cava to carotid arteries. Using this model, we studied the role of iNOS in the development of vein graft arteriosclerosis in iNOS(-/-) mice. Four weeks after grafting, neointimal hyperplasia of vein grafts in iNOS(-/-) mice was increased 2-fold compared with that of wild-type controls. Neointimal lesions contained mainly MAC-1+ macrophages and alpha-actin+ smooth muscle cells (SMCs) in both vein grafts of iNOS(-/-) and iNOS(+/+) mice. Immunofluorescence analysis revealed that increased iNOS expression in neointimal macrophages and SMCs of wild-type, but not iNOS(-/-), mice coincided with increased vascular endothelial growth factor (VEGF) expression in vein grafts. When vein grafts were performed in iNOS(-/-)/TIE2-LacZ transgenic mice expressing LacZ gene only in endothelial cells, the number of beta-galactosidase+ cells in iNOS(-/-) vein grafts were significantly decreased. Furthermore, treatment with the NOS inhibitor NG-nitro-L-arginine methyl ester resulted in delayed endothelial progenitor cell attachment, whereas L-arginine intake through drinking water enhanced endothelial repair. Interestingly, local application of VEGF to iNOS(-/-) vein grafts restored endothelial progenitor homing and reduced neointimal lesions, whereas the VEGF receptor inhibitor SU1498 increased the lesion formation. Additionally, iNOS-deficient SMCs showed a low level of VEGF production in response to interleukin 1beta stimulation. Thus, iNOS deficiency accelerates neointima formation by abrogating VEGF production and endothelial progenitor cell attachment and differentiation.

Animals↗

PubMedDate not supplied

Cerebrovascular arteriopathy (arteriosclerosis) and ischemic childhood stroke.

The aim of this report is to describe the intracranial cerebrovascular abnormalities and clinical status of 8 children who had familial lipoprotein disorders and evidence of thromboembolic cerebrovascular disease. Six of the 8 children had low levels of plasma high density lipoprotein cholesterol, two had high triglyceride levels, and all came from kindreds characterized by familial lipoprotein abnormalities and premature cardio- and/or cerebrovascular atherosclerosis. Vascular occlusion, irregularities of the arterial lumen, beading, tortuosity, and evidence of collateralization were consistently noted. We speculate that cerebrovascular arteriosclerosis in pediatric ischemic stroke victims who have familial lipoprotein abnormalities may be related to lipoprotein-mediated endothelial damage and thrombosis formation, or to the failure to restore endothelial cells' integrity following damage. The apparent association of lipoproteins and strokes in children and their families merits further exploration, particularly when assessing cerebral angiograms in pediatric ischemic stroke victims. In children with unexplained ischemic cerebrovascular accidents, the diagnostic possibility of occlusive arteriosclerosis with thrombosis must be entertained.

Adolescent↗

PubMed1996

Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis.

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.

Abatacept↗

PubMed1998

Reduced transplant arteriosclerosis in plasminogen-deficient mice.

Recent gene targeting studies indicate that the plasminogen system is implicated in cell migration and matrix degradation during arterial neointima formation and atherosclerotic aneurysm formation. This study examined whether plasmin proteolysis is involved in accelerated posttransplant arteriosclerosis (graft arterial disease). Donor carotid arteries from wild-type B10.A2R mice were transplanted into either plasminogen wild-type (Plg+/+) or homozygous plasminogen-deficient (Plg-/-) recipient mice with a genetic background of 75% C57BL/6 and 25% 129. Within 15 d after allograft transplantation, leukocytes and macrophages infiltrated the graft intima in Plg+/+ and Plg-/- recipient mice to a similar extent. In Plg+/+ recipients, the elastic laminae in the transplant media exhibited breaks through which macrophages infiltrated before smooth muscle cell proliferation, whereas in Plg-/- recipients, macrophages failed to infiltrate the transplant media which remained structurally more intact. After 45 d of transplantation, a multilayered smooth muscle cell-rich transplant neointima developed in Plg+/+ hosts, in contrast to Plg-/- recipients, in which the transplants contained a smaller intima, predominantly consisting of leukocytes, macrophages, and thrombus. Media necrosis, fragmentation of the elastic laminae, and adventitial remodeling were more pronounced in Plg+/+ than in Plg-/- recipient mice. Expression of the plasminogen activators (PA), urokinase-type PA (u-PA) and tissue-type PA (t-PA), and expression of the matrix metalloproteinases (MMPs), MMP-3, MMP-9, MMP-12, and MMP-13, were significantly increased within 15 d of transplantation when cells actively migrate. These data indicate that plasmin proteolysis plays a major role in allograft arteriosclerosis by mediating elastin degradation, macrophage infiltration, media remodeling, medial smooth muscle cell migration, and formation of a neointima.

Animals↗

PubMed1995

Improved skin blood flow and cutaneous temperature in the foot of a patient with arteriosclerosis obliterans by vasopressin V1 antagonist (OPC21268). A case report.

A seventy-four-year-old woman with arteriosclerosis obliterans, diabetes mellitus, and hypertension was admitted for the treatment of intermittent claudication and coldness and pain in the right lower extremity. After the administration of a vasopressin V1 antagonist, OPC21268, the symptoms were markedly improved. Furthermore, blood flow in the dorsalis pedis artery and the cutaneous temperature in the right foot increased in response to acute and chronic administration of OPC21268. OPC21268 may be a new useful therapeutic tool for the treatment of arteriosclerosis obliterans.

Aged↗

PubMed1997

Hemodynamic changes in the lower limbs during treadmill walking in normal subjects and in patients with arteriosclerosis obliterans.

The effects of arteriosclerosis obliterans on the hemodynamic changes that occur during walking are largely unknown. For this reason, the authors measured blood pressure by transducer from the posterior tibial artery and vein at both ankles in 23 patients with arteriosclerosis obliterans of different severity and at the left ankle in 8 normal subjects. Radial artery pressure was also measured, and the differences between mean radial and ankle arterial pressures (pressure gradient) and between mean arterial and venous ankle pressures (foot perfusion pressure) were calculated. All measurements were made simultaneously and continuously during standing, treadmill walking at five different speeds, and during recovery. Compared with the normal subjects, the patients exhibited a greater pressure gradient and lower ankle arterial pressure and foot perfusion pressure at rest. During walking and recovery these intergroup hemodynamic differences were markedly enhanced, and ankle venous pressure was lower in the patients than in the normal subjects. In the patients the hemodynamic pattern depended on disease severity at rest and on both disease severity and walking speed during walking and recovery.

Adult↗

PubMed1999

The exercise pressor reflex and changes in radial arterial pressure and heart rate during walking in patients with arteriosclerosis obliterans.

Little is known about the time course and extent of the changes in radial arterial pressure and heart rate taking place in patients with arteriosclerosis obliterans during walking, as well their subtending mechanisms. For this reason the authors measured these variables in 23 patients with arteriosclerosis obliterans and in nine normal subjects (control group), during treadmill walking and several tests. In the patients a rapid and marked increase in radial arterial pressure was recorded during walking, whereas the same parameter either fell abruptly or persisted at elevated levels during recovery. This pattern markedly differed from that recorded in normal subjects, and it was mainly brought about by the activation of the exercise pressor reflex. The following findings suggested that the exercise pressor reflex was activated: the conditions required for activation of the reflex were present in our patients; the pressure changes observed during walking tightly paralleled the changes due to this reflex activation; the hypertensive response to walking was enhanced by increases in severity of disease and in walking speed and duration; the reflex activity persisted during recovery; and the pressure pattern during walking was reproduced by walking with arrested blood circulation to a lower limb. On the contrary, the behavior of heart rate was similar in patients and normal subjects both during walking and recovery because it was not influenced by the exercise pressor reflex.

Adult↗

PubMedDate not supplied

Effect of the serotonin blocker sarpogrelate on circulating interleukin-18 levels in patients with diabetes and arteriosclerosis obliterans.

We aimed to evaluate the effect of treatment with sarpogrelate, a serotonin 2A receptor antagonist, on circulating interleukin (IL)-18 levels in patients with diabetes and arteriosclerosis obliterans. Patients received sarpogrelate (100 mg 3 times daily) for 2 months. We evaluated the degree of cryaesthesia (a feeling of cold in the foot and toes) as the clinical outcome, and measured circulating IL-18, IL-6 and lipid protein concentrations. An improvement in clinical outcome occurred after initiation of sarpogrelate therapy; a significant decrease in IL-18 levels was observed after 2 months of therapy. Levels of IL-6 and lipid proteins, including triglyceride, total cholesterol and high-density lipoprotein cholesterol, were not significantly altered by treatment. Our data suggest that by reducing circulating IL-18 levels, sarpogrelate treatment may contribute to the inhibition of arteriosclerosis obliterans progression in patients with diabetes.

Aged↗

PubMed1985

Beneficial results of pentoxifylline ('Trental') therapy in arteriosclerosis obliterans: possible mechanism of action.

A study was carried out in 17 patients with arteriosclerosis obliterans to assess the effectiveness of treatment with pentoxifylline ('Trental') and to investigate its possible mechanism of action. Patients received pentoxifylline on a combined intravenous/oral dosage regimen for 3 weeks and then were maintained on 800 mg orally for a further 2 weeks. The results showed that there was clinical improvement in 16 patients which was evident as a significant increase in the pain-free walking distance and blood flow in ischaemic legs, and the disappearance of rest pain. These changes were seen as soon as 1 week after the start of treatment. At the same time, an increase was observed in platelet sensitivity to the anti-aggregatory action of endogenous PGI2, as well as an activation of fibrinolysis in blood. After 5 weeks of treatment, further improvement was observed; however, platelets were no more hypersensitive to PGI2, and fibrinolytic activity of blood returned to the previous value. In experiments ex vivo, no release of a disaggregatory substance into blood was observed after a single bolus intravenous injection of pentoxifylline in patients with arteriosclerosis obliterans. It is concluded that the beneficial results of pentoxifylline therapy in such patients may be explained partially by a potentiation of the action of endogenous PGI2.

Adenosine Diphosphate↗

PubMed1976

Quantitative detection of cerebral arteriosclerosis by means of the pressure-velocity hysteresis technique.

The quantitative detection of cerebral arteriosclerosis by means of the pressure-velocity hysteresis technique composed of the cerebral blood velocity pattern (blood velocity pattern in the internal carotid artery measured by the ultrasonic Doppler technique) and the cerebral pressure pulse pattern (common carotid arteriogram measured by non-invasive sphygmography) was investigated in 17-normal young males, normal middle-aged males and patients with cerebral vascular disorders. The ratio of blood pressure/blood velocity in the maximum blood velocity was used as a measure of resistance of the blood flow. The resistance of the cerebral blood flow was significantlpy increased in the patients with cerebral vascular disorders compared to that in the normal young males. The resistance of cerebral blood flow in the middle-aged males was prone to be intermediate between the former two. The results suggest that the pressure-velocity hysteresis technique is useful for the quantitative detection of cerebral vascular resistance as well as cerebral arteriosclerosis. Several factors related to the technique were discussed.

Adult↗

PubMed2002

A role of oxidative stress-generated eicosanoid in the progression of arteriosclerosis in type 2 diabetes mellitus model rats.

Diabetes mellitus (DM) is a well-established risk factor of cardiovascular diseases. We investigated the mechanism of the progression of arteriosclerosis in DM, focusing on the role of oxidative stress and insulin resistance in vivo. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an experimental model of type 2 DM, were assigned to 3 groups, based on supplementation with vitamin E (VE) or troglitazone (TR), a VE-derived agent which improves insulin-resistance. At 36 weeks, plasma and aortic tissue 8-iso-PGF2alpha contents, a vascular proliferating eicosanoid produced in vivo by oxidative stress, were measured by EIA. TGF-beta1 and TGF-beta1 receptor II were immunohistochemically analyzed. Histopathologically, medial area and the nuclear number of smooth muscle cells of the aorta were measured. The tissue 8-iso-PGF2alpha content (pg/g tissue) was significantly decreased by either VE or TR in the aorta (untreated-OLETF, 15,332+/-3,254 vs. TR-treated-OLETF, 7,092+/-1,992 or VE-treated-OLETF, 5,394+/-836, both p<0.01), but that in plasma decreased by only VE. VE and TR improved the increased the level of the actual medial area and the number of smooth muscle cells. The expression of TGF-beta1 was reduced, but TGF-beta1 receptor II was not. 8-iso-PGF2alpha may play an important role in the progression of arteriosclerosis. Antioxidant treatment may promise significant clinical benefits in the early diabetic stage.

Animals↗