Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in ApoE-deficient mice

Previously we showed that a large number of endothelial cells in vein grafts undergo apoptosis or necrosis during the first few days followed by endothelial regeneration. In the present study, we investigated endothelial cell death and regeneration in vein grafts using transgenic mice carrying LacZ genes driven by an endothelial TIE2 promoter. When a vein fragment from TIE2-LacZ was isografted into the carotid artery of wild-type mice, the number of beta-gal+ cells were reduced at 3 days and disappeared completely by 4 weeks after grafting. Conversely, beta-gal+ cells were observed on the surface of vein segments donated by wild-type mice isografted into TIE2-LacZ mice at 1 week and reached confluence by 4 weeks, suggesting recipient origins of endothelial cells. Interestingly, beta-gal+ cells were evenly distributed on the surface of the whole vein segment grafted into TIE2-LacZ mice, indicating a contribution of circulating progenitor cells. When wild-type veins were grafted into a chimeric mouse carrying TIE2-LacZ genes in bone marrow cells, a proportion of cells displayed a beta-gal+ staining. Furthermore, the number of CD34+ and Flk+ progenitor cells in blood of apoE-deficient mice were significantly lower than those of wild-type controls, which coincided with diminished beta-gal+ endothelial cells on the surface of vein grafts in TIE2-LacZ/apoE-/- mice. Thus, we provide the first evidence that endothelial cells of vein grafts are derived from circulating progenitor cells, of which one-third are derived from bone marrow progenitor cells. Hyperlipidemia due to apoE deficiency results in a lower number of endothelial progenitors in blood and correlated with enhanced atherosclerosis. The full text of this article is available online at http://www.circresaha.org.     

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.     

Proteomic and metabolomic analysis of smooth muscle cells derived from the arterial media and adventitial progenitors of apolipoprotein E-deficient mice

We have recently demonstrated that stem cell antigen 1-positive (Sca-1(+)) progenitors exist in the vascular adventitia of apolipoprotein E-deficient (apoE(-/-)) mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis. Using a combined proteomic and metabolomic approach, we now characterize these local progenitors, which participate in the formation of native atherosclerotic lesions in chow-fed apoE(-/-) mice. Unlike Sca-1(+) progenitors from embryonic stem cells, the resident Sca-1(+) stem cell population from the vasculature acquired a mature aortic SMC phenotype after platelet-derived growth factor-BB stimulation. It shared proteomic and metabolomic characteristics of apoE(-/-) SMCs, which were clearly distinct from wild-type SMCs under normoxic and hypoxic conditions. Among the differentially expressed proteins were key enzymes in glucose metabolism, resulting in faster glucose consumption and a compensatory reduction in baseline interleukin-6 secretion. The latter was associated with a marked upregulation of insulin-like growth factor binding proteins (IGFBPs) 3 and 6. Notably, reconstitution of interleukin-6 to levels measured in the conditioned medium of wild-type SMCs attenuated the elevated IGFBP expression in apoE(-/-) SMCs and their vascular progenitors. This coregulation of apoE, interleukin-6, and IGFBPs was replicated in wild-type SMCs from hypercholesterolemic mice and confirmed by silencing apoE expression in SMCs from normocholesterolemic mice. In summary, we provide evidence that Sca-1(+) progenitors contribute to native atherosclerosis in apoE(-/-) mice, that apoE deficiency and hypercholesterolemia alter progenitor cell behavior, and that inflammatory cytokines such as interleukin-6 act as metabolic regulators in SMCs of hyperlipidemic mice.     

Reduced neointima in vein grafts following a blockage of cell recruitment from the vein and the surrounding tissue

OBJECTIVE: Accumulation of intimal smooth muscle cells (SMC) is an important event in vein graft-stenosis. Different SMC sources have been reported, but their interrelations have been poorly studied. In a mouse vein graft model we investigated whether recipient-derived intimal SMCs are recruited from the surrounding tissue and whether blockage of SMC recruitment from the surrounding tissue and/or the donor vein will reduce neointimal formation. METHODS: To detect recipient-derived cells, wild-type veins were implanted into ROSA26 transgenic mice. To block cell recruitment from the surrounding tissue, implanted veins were isolated with a tube-shaped plastic film. To exclude vein-derived cells in the neointimal formation, acellular veins were implanted. RESULTS: In vein grafts isolated from the surrounding tissue the recipient contribution became minimal, but the total number of SMCs was not decreased. Acellular grafts contained an equal number of intimal SMCs as cellular controls after 4 weeks. Isolation of acellular grafts from the surrounding tissue decreased the number of intimal SMCs by 90%. CONCLUSIONS: Recipient-derived SMCs are mainly recruited from the surrounding tissue. Cell recruitment from either the vein or the surrounding tissue is enough to form a neointima. Therefore, a simultaneous inhibition of both these sources is needed to reduce accumulation of intimal SMCs.     

Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model

Arterial inflammatory responses are thought to be a significant component of atherosclerotic disease. We describe here, using a transgenic approach, the mutual perpetuation of immune-mediated arterial inflammation and cholesterol-induced atherosclerosis. Mice expressing the bacterial transgene beta-galactosidase exclusively in cardiomyocytes and in smooth muscle cells in lung arteries and the aorta (SM-LacZ), and hypercholesterolemic apolipoprotein E-deficient SM-LacZ mice (SM-LacZ/apoE(-/-)) developed myocarditis and arteritis after immunization with dendritic cells presenting a beta-galactosidase-derived immunogenic peptide. Hypercholesterolemia amplified acute arteritis and perpetuated chronic arterial inflammation in SM-LacZ/apoE(-/-) mice, but had no major impact on acute myocarditis or the subsequent development of dilated cardiomyopathy. Conversely, arteritis significantly accelerated cholesterol-induced atherosclerosis. Taken together, these data demonstrate that the linkage of immune-mediated arteritis and hypercholesterolemia favors initiation and maintenance of atherosclerotic lesion formation. Therapeutic strategies to prevent or disrupt such self-perpetuating vicious circles may be crucial for the successful treatment of atherosclerosis.     

Thrombosis and neointima formation in vein grafts are inhibited by locally applied aspirin through endothelial protection

Vein graft failure within the first month after bypass surgery is largely because of thrombosis. However, systemic study of thrombus formation in vein grafts is still lacking, and few effective techniques are available to prevent this event. Herein, we analyzed the kinetics of thrombosis and tested the effectiveness of locally applied aspirin on prevention of the disease in a mouse model. En face analysis of vein grafts revealed that 67+/-12% and 54+/-17% of the surface areas were covered by microthrombi at 1 and 3 days, respectively. Thrombus generation was also identified by labeling of platelets and fibrin, which occurred in 35 grafts examined at 1 and 3 days and 1, 2, 4, and 8 weeks. In a fifth of grafts, the thrombus occluded the vessel lumen by > or =1/4. Furthermore, a significant loss of endothelial cells was evidenced by beta-gal staining for vein grafts in transgenic mice expressing LacZ gene controlled by TIE2-endothelial specific gene promoter. Following thrombosis, neointimal lesions were significantly increased by 4-fold 2 weeks after the operation. When vein grafts were treated locally with aspirin in pluronic gel-127, the thrombus area was significantly reduced (P<0.005) at 1, 4, and 8 weeks. Interestingly, neointimal lesions were markedly reduced in the local, but not oral, aspirin-treated group at 4 and 8 weeks by 50% to 70% (P<0.005). The mechanism of reduced lesions by locally applied aspirin involved the protection of vein graft endothelium. Thus, we provide strong evidence that thrombus formation occurs before the development of neointimal lesions in vein grafts and that local aspirin treatment successfully reduces vein graft arteriosclerosis through endothelial protection, resulting in reduction of thrombosis.     

Hyperexpression and activation of extracellular signal-regulated kinases (ERK1/2) in atherosclerotic lesions of cholesterol-fed rabbits

A hallmark of hyperlipidemia-induced atherosclerosis is altered gene expression that initiates cell proliferation and (de)differentiation in the intima of the arterial wall. The molecular signaling that mediates this process in vivo has yet to be identified. Extracellular signal-regulated kinases (ERKs) are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation in vitro. The present studies were designed to investigate the activity, abundance, and localization of ERK1/2 in atherosclerotic lesions of cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant and heterogeneous distribution of ERK1/2, mainly localized in the cap and basal regions of atheromas. A population of ERK-enriched cells was identified as alpha-actin-positive smooth muscle cells (SMCs). ERK1 and 2 were heavily phosphorylated on tyrosyl residues and coexpressed with proliferating cell nuclear antigen in atherosclerotic lesions. ERK1/2 protein levels in protein extracts from atherosclerotic lesions were 2- to 3-fold higher than the vessels of chow-fed rabbits, and their activities were elevated 3- to 5-fold over those of the normal vessel. SMCs derived from atherosclerotic lesions had increased migratory/proliferative ability and higher ERK activity in response to LDL stimulation compared with cells from the normal vessel. Inhibition of ERK activation by PD98059, a specific inhibitor of mitogen-activated protein kinase kinases (MEK1/2), abrogated LDL-induced SMC proliferation in vitro. Taken together, our findings support the proposition that persistent activation and hyperexpression of ERK1/2 may be a critical element to initiate and perpetuate cell proliferation during the development of atherosclerosis.     

Accelerated atherosclerosis and calcification in vein grafts: a study in APOE*3 Leiden transgenic mice

Vein grafts fail due to development of intimal hyperplasia and accelerated atherosclerosis. Many murine genetic models in which genes are overexpressed, deleted, or mutated have been introduced recently. Therefore, mouse models are very well suited to dissect the relative contribution of different genes in the development of accelerated atherosclerosis. In the present study, we evaluated whether accelerated atherosclerosis in human vein grafts could be mimicked in hypercholesterolemic APOE*3 Leiden transgenic mice. Venous bypass grafting was performed in the carotid artery in APOE*3 Leiden mice fed either a standard chow diet or a high cholesterol-rich diet for 4 weeks. At several time points (0 hour to 28 days), mice were euthanized and the morphology of the vein grafts was analyzed. In normocholesterolemic mice, vein graft thickening up to 10-fold original thickness, predominantly consisting of alpha-smooth muscle cell actin-positive cells, was observed after 28 days. In hypercholesterolemic mice, accelerated atherosclerosis with accumulation of lipid-loaded foam cells was observed within 7 days after surgery. This accelerated atherosclerosis progressed in time and resulted in significant increase in vein graft thickening up to 50 times original thickness with foam cell-rich lesions and calcification within 28 days after surgery. The atherosclerotic lesions observed in these murine grafts show high morphological resemblance with the atherosclerotic lesions observed in human vein grafts. This accelerated, diet-dependent induction of atherosclerotic-like lesions in murine vein grafts provides a valuable tool in evaluating the mechanisms of accelerated atherosclerosis and therapeutic interventions of vein graft disease.     

Reduced neointima hyperplasia of vein bypass grafts in intercellular adhesion molecule-1-deficient mice

Recently, we established a new mouse model of vein graft arteriosclerosis through the grafting of vena cava to carotid arteries. In many respects, the morphological features of this murine vascular graft model resemble those of human venous bypass graft disease. With this model, we studied the role of intercellular adhesion molecule-1 (ICAM-1) in the development of vein graft arteriosclerosis in ICAM-1-deficient mice. Neointimal hyperplasia of vein grafts in ICAM-1 -/- mice was reduced 30% to 50% compared with that of wild-type control animals. Immmunofluorescent analysis revealed that increased ICAM-1 expression was observed on the endothelium and smooth muscle cells (SMCs) of the grafted veins in wild-type, but not ICAM-1 -/-, mice. MAC-1 (CD11b/18)-positive cells that adhered to the surface of vein grafts in ICAM-1 -/- mice were significantly less as identified with en face immunofluorescence, and these positive cells were more abundant in the intimal lesions of vein grafts in wild-type mice. Furthermore, aortic SMCs cultivated from wild-type mice exhibited high ICAM-1 expression in response to tumor necrosis factor-alpha. When tumor necrosis factor-alpha-stimulated SMCs were incubated with mouse spleen leukocytes, the number of cells that adhered to ICAM-1 -/- SMCs was significantly lower than the number that adhered to ICAM-1 +/+ SMCs, which was markedly blocked through pretreatment of leukocytes with the anti-MAC-1 antibody. Taken together, our findings demonstrate that ICAM-1 is critical in the development of venous bypass graft arteriosclerosis, which provides essential information for therapeutic intervention for vein graft disease in patients undergoing bypass surgery.     

Smooth muscle cell phenotypic switching in atherosclerosis

Smooth muscle cells (SMCs) possess remarkable phenotypic plasticity that allows rapid adaptation to fluctuating environmental cues, including during development and progression of vascular diseases such as atherosclerosis. Although much is known regarding factors and mechanisms that control SMC phenotypic plasticity in cultured cells, our knowledge of the mechanisms controlling SMC phenotypic switching in vivo is far from complete. Indeed, the lack of definitive SMC lineage-tracing studies in the context of atherosclerosis, and difficulties in identifying phenotypically modulated SMCs within lesions that have down-regulated typical SMC marker genes, and/or activated expression of markers of alternative cell types including macrophages, raise major questions regarding the contributions of SMCs at all stages of atherogenesis. The goal of this review is to rigorously evaluate the current state of our knowledge regarding possible phenotypes exhibited by SMCs within atherosclerotic lesions and the factors and mechanisms that may control these phenotypic transitions.     

Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration

Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins beta-arrestin1 and -2 might regulate this pathological process. Deficiency of beta-arrestin2 in ldlr(-/-) mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that beta-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, beta-arrestin1(-/-), and beta-arrestin2(-/-) mice. Neointimal hyperplasia was enhanced in beta-arrestin1(-/-) mice, and diminished in beta-arrestin2(-/-) mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein-transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in beta-arrestin2(-/-) mice was not altered by transplantation with either wild-type or beta-arrestin2(-/-) bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in beta-arrestin1(-/-) and decreased in beta-arrestin2(-/-) mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in beta-arrestin1(-/-) SMCs and less in beta-arrestin2(-/-) SMCs. Proliferation was less than wild type in beta-arrestin2(-/-) SMCs but not in beta-arrestin2(-/-) endothelial cells. We conclude that beta-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by beta-arrestin2 and beta-arrestin1. These findings identify inhibition of beta-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.     

Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation

Smooth muscle cells (SMCs) are the main cell type in intimal thickenings and some stages of human atherosclerosis. Like monocyte-derived macrophages, SMCs accumulate excess lipids and contribute to the total intimal foam cell population. In contrast, apolipoprotein (Apo)E-deficient and LDL receptor-deficient mice develop atherosclerotic lesions that are macrophage- as opposed to SMC-rich. The lesser contribution of SMCs to lesion development in these mouse models has distracted attention away from the importance of SMC cholesterol homeostasis in the artery wall. Intimal SMCs accumulate excess amounts of cholesteryl esters when compared with medial layer SMCs, possibly explained by reduced ATP-binding cassette transporter A1 expression and ApoA-I binding to intimal-type SMCs. The aim of this review is to compare the relative contribution of monocyte-derived macrophages and SMCs to human vs. mouse atherosclerosis, and describe what is known about lipid uptake and removal mechanisms contributing to arterial macrophage and SMC foam cell formation. An increased understanding of the contribution of these cell types to lesion development will help to delineate their relative importance in atherogenesis and as potential therapeutic targets.     

Enhanced superoxide production in experimental venous bypass graft intimal hyperplasia: role of NAD(P)H oxidase

-Vein graft intimal hyperplasia, due to smooth muscle cell (SMC) proliferation, remains a limiting factor in long-term vein graft patency. Increased superoxide production regulates SMC mitogenesis and contributes to reduced NO bioactivity in systemic models of vascular disease. We compared superoxide production in experimental venous bypass grafts with ungrafted veins and determined its enzymatic sources and cellular localization. Vascular superoxide production was measured in vein grafts and control jugular veins obtained from normocholesterolemic rabbits undergoing jugular vein-carotid artery interposition bypass grafting. Surgical isolation of the contralateral jugular vein, without bypass grafting, provided an additional control for the effects of surgical manipulation. Superoxide production was increased 3-fold in vein grafts compared with control veins. Systematic stimulation and inhibition of specific oxidases revealed that the major source of increased vein graft superoxide production was a membrane-associated NAD(P)H-dependent oxidase. Western blotting of vascular homogenates demonstrated corresponding increases in NAD(P)H oxidase p22phox (membrane-associated) and p67phox (cytosolic) subunits in vein grafts compared with jugular veins. There was marked intimal hyperplasia in vein grafts, and immunohistochemical staining of vessel cryosections revealed increased p22phox-expressing cells in vein grafts that were predominantly intimal SMCs. Superoxide generation is increased in experimental vein grafts compared with ungrafted veins. The principal source of increased superoxide generation in vein grafts is an NAD(P)H oxidase, expressed by intimal SMCs. These findings suggest a role for NAD(P)H oxidase-mediated superoxide production in the proliferative response to vascular injury in vein grafts.     

Selective neointimal gene transfer in an avian model of vascular injury.

Avian models of atherosclerosis helped pioneer the study of vascular biology, and offer economic and technical advantages over mammalian models. As an initial step towards investigating important molecular pathways involved in avian atherogenesis and restenosis, we developed a recombinant adenovirus (Ad) which expresses the reporter gene beta-galactosidase (beta-gal), and applied it to cultured chicken vascular smooth muscle cells (SMCs) and a rooster model of acute vascular injury. In cultured chicken SMCs, recombinant gene expression increased as a function of multiplicity of infection (MOI) and incubation time. Maximal expression occurred at an MOI of 10(4) plaque-forming units (pfu)/cell with approximately 50% of quiescent and non-quiescent chicken SMCs expressing beta-gal. Human aorta SMCs had two- to four-fold increased beta-gal expression compared with chicken SMCs at all MOI and incubation times. In vivo instillation of recombinant Ad into uninjured rooster femoral artery segments revealed low efficiency endothelial cell expression of the reporter gene. In contrast, recombinant Ad infection of rooster femoral artery segments 3-21 days after balloon injury revealed up to 60% of luminal surface beta-gal expression, confined predominantly to the neointimal layer. Peak reporter gene expression efficiencies occurred in arterial segments infected 3 days after balloon injury. Uninfected and control Ad infected arteries had no detectable beta-gal expression. Rooster neointimal cells targeted by the recombinant Ad were identified as alpha-smooth muscle actin containing cells by immunohistochemistry. We conclude that Ad-mediated gene transfer is efficient and selective for the neointima in the rooster acute vascular injury model, and offers the potential to efficiently introduce exogenous genes that may impact on the injury response. This model of acute vascular injury may also be manipulated into more established avian models of atherosclerosis, permitting the investigation of acute injury progression to chronic injury.     

New mouse model of vein bypass graft atherosclerosis

Animal models of vein graft disease are used as preliminary tools to study and understand the pathogenesis of the disease in humans and improve its diagnosis, prevention and therapy. Several animal models that manifest lesions resembling neointimal hyperplasia of human vein grafts have been developed, but there are limitations in studying the mechanism of this disease in these models. We previously established a mouse model of vein bypass graft atherosclerosis that allows us to take advantage of transgenic and knockout techniques. Using this model, we studied the pathogenesis of vein graft atherosclerosis. The lesion in the grafts was characterised by mononuclear cell infiltration followed by smooth muscle cell (SMC) proliferation and matrix protein deposition, which is similar to the human lesion. Studies of the molecular mechanism of pathogenesis in this model revealed that physical force initiated signal pathways, particularly mitogen-activated protein kinases (MAPK), leading to vascular cell death and an inflammatory response, followed by SMC proliferation, which contributed to the development of arteriosclerosis. Suramin inhibited SMC migration and proliferation in vivo and in vitro by blocking platelet-derived growth factor (PDGF)-initiated PDGF receptor activation and MAPK-AP-1 signalling, and was also effective in inhibition of neointima hyperplasia in mouse vein bypass grafts. This new mouse model of vein bypass graft atherosclerosis affords us with a valuable new approach to attain further understanding of the mechanism of vein graft disease with the use of transgenic mice, and in evaluating the effects of drugs and gene therapy on vascular diseases.     

Fibrinogen deficiency reduces vascular accumulation of apolipoprotein(a) and development of atherosclerosis in apolipoprotein(a) transgenic mice

To test directly whether fibrin(ogen) is a key binding site for apolipoprotein(a) [apo(a)] in vessel walls, apo(a) transgenic mice and fibrinogen knockout mice were crossed to generate fibrin(ogen)-deficient apo(a) transgenic mice and control mice. In the vessel wall of apo(a) transgenic mice, fibrin(ogen) deposition was found to be essentially colocalized with focal apo(a) deposition and fatty-streak type atherosclerotic lesions. Fibrinogen deficiency in apo(a) transgenic mice decreased the average accumulation of apo(a) in vessel walls by 78% and the average lesion (fatty streak type) development by 81%. Fibrinogen deficiency in wild-type mice did not significantly reduce lesion development. Our results suggest that fibrin(ogen) provides one of the major sites to which apo(a) binds to the vessel wall and participates in the generation of atherosclerosis.     

Role of group II secretory phospholipase A2 in atherosclerosis: 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2.

Some observations have suggested that the extracellular group IIa phospholipase A2 (sPLA2), previously implicated in chronic inflammatory conditions such as arthritis, may contribute to atherosclerosis. We have examined this hypothesis by studying transgenic mice expressing the human enzyme. Compared with nontransgenic littermates, the transgenic mice exhibited dramatically increased atherosclerotic lesions when maintained on a high-fat, high-cholesterol diet. Surprisingly, the transgenic mice also exhibited significant atherosclerotic lesions when maintained on a low-fat chow diet. Immunohistochemical staining indicated that sPLA2 was present in the atherosclerotic lesions of the transgenic mice. On both chow and atherogenic diets, the transgenic mice exhibited decreased levels of HDLs and slightly increased levels of LDLs compared with nontransgenic littermates. These data indicate that group IIa sPLA2 may promote atherogenesis, in part, through its effects on lipoprotein levels. These data also provide a possible mechanism for the observation that there is an increased incidence of coronary artery disease in many chronic inflammatory diseases.     

Smooth muscle cell apoptosis in arteriosclerosis

Arteriosclerosis, a paradigmatic age-related disease, encompasses (spontaneous) atherosclerosis, restenosis after percutaneous transluminal coronary angioplasty, autologous arterial or vein graft arteriosclerosis and transplant arteriosclerosis. In all types of arteriosclerosis, vascular smooth muscle cell (SMC) accumulation in the intima is a key event, but abundant evidence also indicates the importance of SMC apoptosis in the development of arteriosclerosis. Because SMC proliferation and apoptosis coincide in arteriosclerotic lesions, the balance between these two processes could be a determinant during vessel remodeling and disease development. Various stimuli, including oxidized lipoproteins, altered hemodynamic stress and free radicals, can induce SMC apoptosis in vitro. As risk factors for arteriosclerosis, these stimuli may also lead to vascular cell apoptosis in vivo. The presence of apoptotic cells in atherosclerotic and restenotic lesions could have potential clinical implications for atherogenesis and contributes to the instability of the lesion. Based on the progress in this field, this review focuses on the mechanism and impact of SMC apoptosis in the pathogenesis of arteriosclerosis and highlights the role of biomechanical stress in SMC apoptosis.