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PubMed2002

Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis.

BACKGROUND: Cardiac allograft arteriosclerosis is a complex process of alloimmune response, chronic inflammation, and smooth muscle cell proliferation that includes cross talk between cytokines and growth factors. METHODS AND RESULTS: Our results in rat cardiac allografts established alloimmune response as an alternative stimulus capable of inducing vascular endothelial growth factor (VEGF) mRNA and protein expression in cardiomyocytes and graft-infiltrating mononuclear inflammatory cells, which suggests that these cells may function as a source of VEGF to the cells of coronary arteries. Linear regression analysis of these allografts with different stages of arteriosclerotic lesions revealed a strong correlation between intragraft VEGF protein expression and the development of intimal thickening, whereas blockade of signaling downstream of VEGF receptor significantly reduced arteriosclerotic lesions. In addition, in cholesterol-fed rabbits, intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector that encoded mouse VEGF(164) enhanced the formation of arteriosclerotic lesions, possibly secondary to increased intragraft influx of macrophages and neovascularization in the intimal lesions. CONCLUSIONS: Our findings suggest a positive regulatory role between VEGF and coronary arteriosclerotic lesion formation in the allograft cytokine microenvironment.

Acute Disease↗
PubMed2002

Expression of CYR61, an angiogenic immediate early gene, in arteriosclerosis and its regulation by angiotensin II.

BACKGROUND: The renin-angiotensin system is thought to be involved in development and progression of arteriosclerosis, thereby contributing to adverse cardiovascular events. To elucidate the role of angiotensin II (Ang II) at a cellular level, we analyzed the Ang II-induced gene expression profile. METHODS AND RESULTS: Genes induced on Ang II stimulation (10(-7) mol/L, 45 minutes) in rat smooth muscle cells were analyzed by polymerase chain reaction selected subtraction. In addition to known genes, such as interleukin 6, leukemia inhibitory factor, and c-fos, we identified CYR61, an angiogenic immediate early gene. Northern blot analysis revealed a rapid 2.5-fold increase of CYR61 transcript levels by Ang II, peaking at 30 minutes, which was blunted by Ang II type 1 receptor blockade. Exposure of rat aortic rings to Ang II (30 minutes) revealed a 2-fold, and intraperitoneal injection of Ang II (30 minutes) in mice a 3-fold, increase of aortic CYR61 transcripts. In arteriosclerotic aortas of apolipoprotein E-deficient mice, CYR61 transcripts confirmed by in situ hybridization and proteins shown by immunohistochemistry were elevated, whereas they were hardly detectable in wild types. In human carotid atherectomies and arteriosclerotic coronary arteries, immunohistochemical analysis revealed expression of CYR61 within connective tissue in neointima, adventitia, and surrounding small capillaries and blood vessels, colocalized with ACE and Ang II. Normal human arteries showed no significant staining for CYR61. CONCLUSIONS: CYR61, an angiogenic factor, is induced by Ang II in vascular cells and tissue. The expression of CYR61, colocalized with Ang II and ACE, in small vessels of human arteriosclerotic lesions is consistent with the notion that the activated renin-angiotensin system may contribute to plaque neovascularization by enhancing regulators of microvessel formation and cell proliferation.

Angiogenesis Inducing Agents↗
PubMed2004

Stromal cell-derived factor-1 and CXCR4 interaction is critical for development of transplant arteriosclerosis.

BACKGROUND: Posttransplant chronic allograft deterioration associated with development of transplant arteriosclerosis (TA) remains an unresolved problem. Recent studies suggest that the smooth muscle cells (SMCs) constituting the neointima are derived from recipient hematopoietic stem cells (HSCs). However, the underlying mechanisms of the process are not yet fully elucidated. METHODS AND RESULTS: We examined the genes expressed in allografts at different stages of TA development using a mice aortic transplantation model. Genes were analyzed by a differential mRNA display technique. We show that stromal cell-derived factor-1alpha (SDF-1alpha) is a critical molecular target for the treatment of TA. During the course of TA, intragraft SDF-1alpha expression was upregulated with time, and the circulating HSCs expressing its counterreceptor CXCR4 increased in the recipients receiving allografts. CXCR4-positive HSCs, derived from transplant recipients, migrated into allografts via microvessels in the adventitia and then toward the luminal side. The HSCs differentiated into SMC-like cells, contributing to the in situ formation of the neointima. In support of a functional role for these molecules, in vivo neutralization of SDF-1alpha inhibited HSC mobilization and significantly attenuated neointimal formation. CONCLUSIONS: Interaction between SDF-1alpha and CXCR4 plays a key role in TA development. Blockade of SDF-1alpha may become a new therapeutic modality for TA.

Animals↗
PubMed1997

Hypercholesterolemia exacerbates transplant arteriosclerosis via increased neointimal smooth muscle cell accumulation: studies in apolipoprotein E knockout mice.

BACKGROUND: Hypercholesterolemia is thought to be a significant risk factor for coronary vasculopathy in cardiac transplant recipients. METHODS AND RESULTS: We examined the development of arteriosclerosis in mouse carotid artery loops allografted from B.10A(2R) (H-2h2) donors to normocholesterolemic C57BL/6J (H-2h) recipients and hypercholesterolemic C57BL/6J recipients in which the apolipoprotein (apo) E gene had been knocked out. Luminal occlusion and cross-sectional neointimal area were greater in arteries allografted into hypercholesterolemic recipients at 15 and 30 days after transplantation. We also measured cellular and extracellular matrix components of the neointima by computerized planimetry of the fractional areas subtended by smooth muscle cells (anti-alpha-actin stain), collagen (Masson's trichrome), lipid (oil red O), and leukocytes (anti-CD45). The neointimal area stained for smooth muscle cells was significantly greater in hypercholesterolemic recipients than in normocholesterolemic recipients at 15 and 30 days after allografting. Lipid contributed to neointimal area to a lesser degree, and there was no significant increase in the contribution of collagen or leukocytes. CONCLUSIONS: Smooth muscle cell accumulation appears to be the principal contributor to the increase in neointimal area observed in arteries allografted into hypercholesterolemic mice.

Animals↗
PubMed1983

Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons.

The effect of sulfinpyrazone on endothelial injury induced by homocysteine has been studied both in vitro, using cultured human umbilical vein endothelial cells, and in vivo, using a primate model of homocysteine-induced arteriosclerosis. Oral sulfinpyrazone (250 mumol/kg body weight per day in three divided doses) in eight chronically homocystinemic baboons (0.14 +/- 0.04 mM plasma homocystine) decreased the extent of aortic endothelial injury as measured morphometrically by silver staining techniques, compared with six untreated comparably homocystinemic animals (denuded surface averaged 0.5% with range 0-2.1 vs 7.7 +/- 1.6%, respectively; P less than 0.001). Sulfinpyrazone therapy to homocystinemic baboons also normalized platelet survival and turnover measurements (5.1 +/- 0.4 days and 70,000 +/- 11,000 platelets/microliter per day vs. 2.8 +/- 0.6 days and 179,000 +/- 19,000 platelets/microliter per day in untreated homocystinemic controls; P less than 0.001). Sulfinpyrazone therapy also reduced the size and frequency of homocysteine-induced intimal lesion formation (P less than 0.001). Although sulfinpyrazone reduced the amount of specific 51Cr release from cultured human umbilical vein endothelial cells induced by 10 mM homocysteine after 24 hours of co-incubation, no effect was observed in assays of endothelial cell detachment when sulfinpyrazone (10(-5) M) or its thioether metabolite were pre- or co-incubated during 24 hours with homocysteine (2.5-10 mM). These data suggest that sulfinpyrazone may protect endothelial cells from injury in vivo by some apparently indirect mechanism.

Animals↗
PubMed2001

Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis.

The development of transplant arteriosclerosis (TA) is today's most important problem in clinical organ transplantation. Histologically, TA is characterized by perivascular inflammation and progressive intimal thickening. Current thought on this process of vascular remodeling assumes that neointimal vascular smooth muscle (VSM) cells and endothelium in TA are graft-derived, holding that medial VSM cells proliferate and migrate into the subendothelial space in response to signals from inflammatory cells and damaged graft endothelium. Using MHC class I haplotype-specific immunohistochemical staining and single-cell PCR analyses, we show that the neointimal alpha-actin-positive VSM cells in rat aortic or cardiac allografts are of recipient and not of donor origin. In aortic but not in cardiac allografts, recipient-derived endothelial cells (ECs) replaced donor endothelium. Cyclosporine treatment prevents neointima formation and preserves the vascular media in aortic allografts. Recipient-derived ECs do not replace graft endothelium after cyclosporine treatment. We propose that, although it progresses beyond the needs of functional repair, TA reflects the activity of a normal healing process that restores vascular wall function following allograft-induced immunological injury.

Actins↗
PubMed1969

Studies of arteriosclerosis in Japanese and American men. I. Comparison of fatty acid composition of adipose tissue.

The proportions of fatty acids in lipids of subcutaneous adipose tissue was compared in closely age-matched, urban men from two populations with a great difference in mortality from arteriosclerosis, namely in 50 Americans and 56 Japanese aged 15-65 yr who had died suddenly and unexpectedly. Specimens from both groups were analyzed side by side for fatty acids by gas-liquid chromatography. Compared with Japanese, Americans had significantly (P<0.01) higher proportions of lauric (+ 0.2%), myristic (+ 0.4%), palmitic (+ 1.4%), stearic (+ 2.2%), and oleic (+ 5.3%) and lesser of palmitoleic (- 1.8%), linoleic (-6.3%), and linolenic (-0.4%) acids. Japanese had higher proportions of longer chain polyunsaturated fatty acids. The distributions of fatty acids for the groups at ages 35-44 yr had significant differences. With age, Americans showed significant increases of palmitic and oleic acids and decreases of lauric, myristic, stearic, and linoleic acids; Japanese showed no correlations of proportions of fatty acids with age. The significant correlations between per cent standard body weight and fatty acids in Americans were positive for palmitic and negative for lauric and stearic acids, and in Japanese, negative for myristic acid. The patterns of interacid correlations were dissimilar for the groups. These patterns may be stable characteristics of these groups providing further insight into their fatty acid metabolism. The relationships with the fatty acid compositions of the American and Japanese diets are discussed.

Adipose Tissue↗
PubMed1976

Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis.

The atherogenic mechanism of homocystinemia has been defined by measuring endothelial cell loss and regeneration, platelet consumption, and intimal lesion formation in a primate model. Three groups of baboons were studied: (a) 8 control animals; (b) 15 animals after 3 mo of continuous homocystinemia; and (c) 11 animals after 3 mo of combined homocystinemia and oral treatment with dipyridamole. Experimental homocystinemia caused patchy endothelial desquamation comprising about 10% of the aortic surface despite a 25-fold increase in endothelial cell regeneration. Neither endothelial cell loss nor regeneration was changed significantly by dipyridamole. Homocystine-induced vascular deendothelialization produced a threefold increase in platelet consumption that was interrupted by dipyridamole inhibition of platelet function. All homocystinemic animals developed typical arteriosclerotic or preatherosclerotic intimal lesions composed of proliferating smooth muscle cells averaging 10-15 cell layers surrounded by large amounts of collagen, elastic fibers, glycosaminoglycans, and sometimes lipid. Intimal lesion formation was prevented by dipyridamole therapy. We conclude that homocystine-induced endothelial cell injury resulted in arteriosclerosis through platelet-mediated intimal proliferation of smooth muscle cells that can be prevented by drug-induced platelet dysfunction.

Animals↗
PubMed1987

Herpes simplex virus infection in human arterial cells. Implications in arteriosclerosis.

Herpesviruses have been implicated as etiologic factors in the pathogenesis of human arteriosclerosis. We have examined the pathobiological effects of human herpes simplex virus (HSV-1) infection in influencing lipid accumulation and metabolism in human and bovine arterial smooth muscle cells (SMC). Significantly greater amounts of saturated cholesteryl esters (CE) and triacylglycerols (TG) accumulate in HSV-1-infected human and bovine arterial SMC than uninfected cells. This CE accumulation results, in part, from decreased CE hydrolysis. Furthermore, arachidonate-stimulated, HSV-1-infected arterial SMC have a reduced capacity to produce prostacyclin (an agonist of intracellular CE hydrolytic activity) than uninfected, stimulated SMC. It appears that HSV-1 may induce lipid accumulation in arterial SMC similar, in part, to the lipid accumulation observed in vivo during human atherogenesis. Thus, herpesviruses may contribute to lipid accumulation, which is a characteristic feature of atherosclerosis.

Animals↗
PubMed1994

Identification and upregulation of galactose/N-acetylgalactosamine macrophage lectin in rat cardiac allografts with arteriosclerosis.

Using differential mRNA display to uncover potential mediators associated with chronic rejection, we identified a cDNA fragment induced in Lewis to F344 rat cardiac allografts with arteriosclerosis but not Lewis syngrafts. The full-length cDNA (1.4 kb) isolated from a rat cardiac allograft cDNA library was 99% identical to galactose/N-acetylgalactosamine (Gal/GalNAc) macrophage lectin, a cell-surface receptor. This cDNA hybridized in Northern analysis with total RNA from eight cardiac allografts but not with host hearts, syngrafts, or other organs. There was a significant allograft-specific increase in transcript levels measured by reverse transcriptase PCR at days 7, 14, 28, and 75 in comparison with paired F344 host hearts (subject to same circulation but histologically normal), day-0 hearts, and syngrafts (P < 0.008, n = 4 at each time). Transcript levels in cardiac allografts were higher than those in paired host spleens (a major source of inflammatory cells) (P < 0.0001), indicating the localized nature of Gal/GalNAc lectin induction. By in situ hybridization and immunostaining, Gal/GalNAc lectin expression localized to a subset of inflammatory cells in cardiac allografts. These findings link Gal/GalNAc macrophage lectin to the chronic rejection process, as a possible mediator of macrophage infiltration.

Acetylgalactosamine↗
PubMed1985

Validity of out-patient screening in arteriosclerosis to identify multiple lesions.

A total of 594 patients admitted for cerebrovascular disease (CVD) and for peripheral vascular disease (PVD), were examined in a study aimed at clarifying by a simple, inexpensive out-patient method, a) the relationship existing between the different locations of the vascular disease: brain, lower limbs, coronaries; b) the prevalence in the patients studied of risk factors such as hypertension, hyperlipidaemia and diabetes, and of migraine. The results were as follows: a) of the patients admitted for CVD, 44% also presented arteriosclerosis in other locations; this figure was 32% for PVD cases; b) hypertension was found in 38.5% of CVD and 27% of PVD cases; diabetes in 11.5% of CVD and in 18% of PVD cases; hyperlipidaemia in 31% of CVD and 24% of PVD cases; migraine in 11% of CVD and 1% of PVD cases.

Adult↗
PubMed1987

Systolic hypertension in patients with arteriosclerosis obliterans of the lower limbs.

Intraarterial blood pressure, brachial artery compliance and diameter, and pulse wave velocity were determined in 20 patients with arteriosclerosis obliterans of the lower limbs (AOD) in comparison with 10 age- and sex-matched controls. With the same mean arterial pressure as in controls, patients with AOD exhibited a significant increase in systolic pressure and decrease in diastolic pressure, resulting in an increase in pulse pressure. While brachial artery diameter and pulse wave velocity remained nearly within the normal range, arterial compliance was significantly reduced and was negatively correlated with the level of pulse pressure. The study provided evidence that: atherosclerotic modifications in patients with AOD are associated with an increase in pulse pressure, which predominates on the increase in mean arterial pressure, increased pulse pressure is related to decreased arterial compliance, which reflects intrinsic modifications of the viscoelastic properties of the arterial wall.

Adult↗
PubMed1987

31P in-vivo spectroscopic study by high-field whole-body MR system--an application to a case with arteriosclerosis obliterans.

31P in-vivo spectroscopy was performed by a 1.5-tesla whole-body MR system. The 31P spectrum for the calf muscle in a patient with arteriosclerosis obliterans having intermittent claudication was obtained every two minutes. When the spectrum after the workload was compared with that at rest, an increase in inorganic phosphate (Pi) and a decrease in phosphocreatine (PCr) were observed, resulting in a strong decrease in the PCr/Pi ratio. This method can measure the ischemic and recovery stages of energy metabolism in skeletal muscle noninvasively and continuously in addition to magnetic resonance imaging.

Aged↗
PubMed1989

Diagnosis of arteriosclerosis obliterans by impedance technique with special reference to relative blood flow of the lower extremity.

Simultaneous recordings of impedance cardiography of the chest and impedance plethysmography of the lower extremity were performed on 105 limbs with or without arteriosclerosis obliterans (ASO) documented by angiography. The ratios of blood flow to the lower extremity--leg stroke volume/cardiac stroke volume--(LSV/CSV) were 11.2 +/- 3.3% in normal male subjects, 11.1 +/- 5.5% in normal female subjects, and 3.1 +/- 1.2% in lower extremities with ASO, respectively. The normal value (range) for LSV/CSV calculated from the normal groups by the percentile method was between 4.9% and 17.8%, and the diagnostic accuracy of this value was 100% for sensitivity and 97.5% for specificity. LSV/CSV is a good index for the diagnosis of ASO and makes it possible to minimize error when expressed as an absolute value.

Arteriosclerosis Obliterans↗
PubMed1994

Long-term effects of ticlopidine on lower limb blood flow, ankle/brachial index and symptoms in peripheral arteriosclerosis. A double-blind study. The STIMS Group in Lund. Swedish Ticlopidine Multicenter Study.

The aim was to test within a randomized double-blind trial whether the platelet inhibitor ticlopidine might improve peripheral blood flow and distal pressures in patients with aortofemoral arteriosclerosis. One hundred and one patients with intermittent claudication were studied after one year, after two to three years, and after five years of treatment with ticlopidine, 500 mg/day, or placebo. Analysis was performed according to years on treatment. Baseline flow values as assessed by venous occlusion plethysmography were significantly and similarly deranged in the ticlopidine and placebo groups as compared with a reference group of healthy subjects. Ankle/brachial index was unrelated to either leg blood flow variables or walking distance. After five years of treatment (median follow-up time) a slight tendency to a slower progression of disease was observed in the ticlopidine group as compared with placebo. However, intergroup differences were not significant. Therefore, the potential benefit of ticlopidine in this respect is from a clinical point of view certainly only marginal. Minor increases in claudication distances were found with no difference between groups. Smoking habits and lipoproteins were mainly unaltered at the end of the study. It is concluded that platelet inhibition for up to five years has no clear beneficial effect on leg blood flow variables, ankle/brachial index, or walking distances and probably no clinically relevant retarding effect on the slow progression of atherosclerosis. This lack of influence must be distinguished from the antithrombotic effect of ticlopidine, shown as a decreased incidence of acute cardiovascular events and mortality in the authors' multicenter study, STIMS (the Swedish Ticlopidine Multicenter Study).

Adult↗
PubMed1996

A rare case of arteriosclerosis obliterans without prominent risk factors complicated by idiopathic thrombocytopenic purpura. A case report.

An eighty-four-year-old man was admitted to the hospital because of pain at rest in the lower extremities. On physical examination, trophic changes of the skin and petechiae in the limbs were observed. Computed tomographic scan of the abdomen showed focal renal infarctions and calcification of the descending aorta. Moreover, radionuclide imaging of the arterial system revealed complete obstructions of the two right iliac arteries and the left external iliac artery, where collateral flows were observed. Laboratory examination showed a severe thrombocytopenia caused by immunoglobulin G (IgG)-type autoantibody against platelets. He was diagnosed as having arteriosclerosis obliterans complicated by idiopathic thrombocytopenic purpura, although no known risk factors promoting atherosclerosis other than age were evident. In such a case with hemorrhagic diathesis, a hemorheologic agent and the vasodilator prostaglandin could confer advantages in relieving and controlling the ischemic leg pain without hemorrhagic complications. Moreover, small doses of the initial prednisolone therapy for ITP might also be recommended to avoid thrombus formations in the atherosclerotic lesions.

Aged↗
PubMed1997

The use of multisite high resolution arterial imaging to assess arteriosclerosis.

This article presents a model for the use of multisite, sonographic imaging to assess arteriosclerosis. The arteries of 100 randomly selected patients were scanned in three anatomical areas (carotid, femoral-popliteal, aorta-iliac) in conjunction with measurement of selected risk factors (smoking, cholesterol, triglycerides, high density lipoproteins, antioxidant levels). Arteries were interrogated for intimal wall hyperplasia, plaque, and ulceration. Multisite scanning (24 sites) detected the presence of pathology in all sites surveyed. The model was developed at the Cardiovascular Wellness Center in Westbury, NY.

Abdomen↗
PubMed1998

LDL apheresis for arteriosclerosis obliterans with occluded bypass graft: change in prostacyclin and effect on ischemic symptoms.

To study the mechanism of efficacy of low-density lipoprotein (LDL) adsorption for arteriosclerosis obliterans (ASO), eight ASO patients without indication for bypass surgery underwent LDL apheresis twice a week for 5 weeks and the change in prostaglandin 12 (PGI2) and thromboxane A2 (TXA2) due to LDL apheresis was measured. The concentration of 6-keto-PGF1alpha, a metabolite of PGI2, in systemic venous blood significantly increased from 10.4 +/- 1.8 to 42.0 +/- 10.6 pg/mL (P<0.05) after one session of LDL apheresis, while no significant change of TXB2, a metabolite of TXA2, was encountered. The ratio of 6-keto-PGF1alpha/TXB2 also rose dramatically from 0.213 +/- 0.044 to 0.522 +/- 0.128 (P<0.05). In five patients, the ischemic clinical symptoms improved and both the concentration of 6-keto-PGF1alpha and the ratio of 6-keto-PGF1alpha/TXB2 increased significantly, whereas in three patients there was no effect on clinical symptoms and neither parameter changed. These results suggest that elevated production of PGI2 from vascular cells due to LDL apheresis might contribute to improvement of ischemic symptoms.

Aged↗