Fatty Streak Formation Research Articles

Developmental Programming: Maternal Hypercholesterolem and Immunity Influence Susceptibility to Atherosclerosis

It is increasingly recognized that the in utero environment is an important determinant of adult disease, and extensive epidemiological evidence links dysmetabolic conditions during pregnancy with increased hypertension, cardiovascular disease, and diabetes later in life. The original Barker Hypothesis focused on low birth weight as the primary indicator of postnatal risk, but low birth weight may arise from other, non-metabolic conditions. This has impeded the identification of developmental programming mechanisms. More recently, the focus has shifted to the impact of specific maternal risk factors, such as obesity, metabolic syndrome, and diabetes, on cardiovascular risk in offspring. Inflammation plays a central role in these maternal conditions as well as in offspring atherogenesis, and two key factors that influence inflammation, maternal hypercholesterolemia and maternal immune mechanisms, have been shown to affect the developmental programming of atherosclerosis. Maternal hypercholesterolemia in pregnancy, even if only temporary, is associated with increased fatty streak formation in human fetal arteries and accelerated progression of atherosclerosis in normocholesterolemic children. Conversely, immunization of experimental animals with oxidized low-density lipoprotein cholesterol, an antigen prevalent in atherosclerotic lesions, inhibits the progression of atherosclerosis in the offspring of hypercholesterolemic mothers. These findings indicate it is possible, in principle, to program postnatal immune responses and to reduce atherosclerosis, and potentially other immunomodulated diseases, by targeted maternal immunomodulation.

Diversity of Denizens of the Atherosclerotic Plaque

The atherosclerotic plaque typically harbors cells of several lineages whose conversations, mediated by extracellular or cell surface–associated messengers, influence decisively the biology and clinical consequences of the lesion. Early vascular biology studies defined the resting state of the endothelium, characterized by the elaboration of antithrombotic and vasodilatory mediators. The activated endothelium recruits inflammatory leukocytes, favors clot accumulation, participates in angiogenesis, and can influence the behavior of subjacent smooth muscle cells in ways that favor atherogenesis and vasoconstriction (Figure). More recently, we have come to appreciate that the endothelial cell not only can exhibit a spectrum of functions, but that some may arise postnatally from bone marrow–derived precursors.1 Thus, the heterogeneity of endothelial cells depends not only on the mutability of their function but also on their origin. The diversity of endothelium depends not only on lineage but also location, with increasingly well-understood differences between arterial, microvascular, and venous endothelial cells. Figure. Heterogeneity of major cell types in atherosclerotic plaques. Vascular biologists have long recognized heterogeneity of endothelial cells and smooth muscle cells, now understood to result from local mediator milieu, biomechanical stimuli, and different embryological origins. Indeed, recent data suggest that both of these intrinsic vascular cell types can arise in postnatal life from bone marrow–derived precursors. Immunological dogma recognizes several T-cell populations, exemplified here by the Th1 and Th2 subsets, which on the balance exert opposing influences on atherogenesis. New data now establish the relevance to atherosclerosis and hyperlipidemia of monocyte heterogeneity. Monocytes that bear high levels of the markers Ly6c/Gr-1 and P-selectin glycoprotein ligand exhibit more proinflammatory functions than their …

VON WILLEBRAND FACTOR, C-REACTIVE PROTEIN, NITRIC OXIDE, AND VASCULAR ENDOTHELIAL GROWTH FACTOR IN A DIETARY REVERSAL MODEL OF HYPERCHOLESTEROLEMIA IN RABBIT

Endothelial dysfunction is considered a sign of the early vascular changes preceding atherosclerosis. We studied the alteration of von Willebrand Factor (vWF), C - reactive protein (CRP), nitrite and Vascular Endothelial Growth Factor (VEGF) in a dietary reversal model of hypercholesterolemia in rabbit. This project was designed in two phases. In phase I, male rabbits (n = 11) were fed a 1% high cholesterol diet for 30 days. Then the diet was replaced with normal rabbit chow for other 30 days (cholesterol withdrawal phase, phase II). To compare the fatty streak formation with normal condition, a control group (n = 6) received normal diet during the study. The serum lipid levels, vWF, CRP, nitrite, and VEGF were measured before the experiment and by the end of each phase. Fatty streak formation in the walls of the aortas in both groups (high cholesterol diet and control group) was determined using intima thickness/media thickness (IMT) ratio. The results indicate that the level of cholesterol, Low Density Lipoproteins (LDL), vWF and CRP increased significantly in phase I, and decreased after hypercholesterolemic diet withdrawal (p < 0.05). No statistically significant changes were found in VEGF levels but the serum level of nitrite increased significantly during both phases of the study (p < 0.05). The IMT ratio in the walls of aortas was significantly different between the groups in both phases of studies (p < 0.05). There was a significant correlation between nitrite and cholesterol levels in both phases (r = 0.62 and r = 0.98, p < 0.05). Nitrite concentration also correlated with IMT ratio in both phases of the study (r = 0.75 and r = -0.99, p < 0.05). vWF did not correlate with cholesterol but it correlated with IMT ratio in both phases of the study (r = 0.87 and r = 0.84, p < 0.05). CRP only correlated with cholesterol in the first phase (r = 0.91, p < 0.05). Among the endothelial biomarkers, vWF was found to be a biological marker for identifying the risk of developing atherosclerosis; however a single biomarker may not provide appropriate information.

The effect of chronic degradation of the endothelial glycocalyx on atherosclerosis progression in ApoE knockout mice

The protective barrier between flowing blood and the vessel wall is formed by endothelial glycocalyx.We investigated the effect of chronic damage to glycocalyx through enzymatic degradation of its major component hyaluronan on atherosclerosis progression.Male ApoE‐KO mice (14 wks) received 10 U/hr of active or inactivated hyaluronidase intravenously via an osmotic minipump for 4 wks, after being on a Western diet for 6 wks. Systemic glycocalyx volume (Vg) was estimated by tracer dilution techniques using labeled erythrocytes and 40kDa dextran. We are evaluating atherosclerotic lesions in the aortic root and arch.ApoE‐KO tolerated chronic infusion with hyaluronidase well. Within 4 wks Vg was reduced to 9.1 ± 8.9 ml/kg (n=11) as compared to Vg before infusion of 16.0 ± 4.8 ml/kg (n=12, p=0.03) and inactive hyaluronidase infusion of 12.1 ± 5.3 ml/kg (n=6, ns). Diet for 6 wks resulted in fatty streak formation within the aortic root (lesion area 0.5 ± 0.0 mm2). Infusion of hyaluronidase resulted in advanced lesions (area 1.3 ± 0.2 mm2) with intimal thickening, cholesterol accumulation and necrotic cores.These preliminary results suggest a possible association between reduced glycocalyx and atherogenic acceleration.Supported by NHF 2005T037 to H. Vink and 2006B08 to E. Stroes

Atheroprotective Signaling Mechanisms Activated by Steady Laminar Flow in Endothelial Cells

Many studies of the human vascular tree have shown that atherosclerosis develops at an early age, with areas of the posterior aorta and branch sites showing the earliest fatty streaks. Closer analysis of the branch points showed that the flow dividers, regions of high shear stress with laminar flow, were relatively protected from fatty streak formation. In contrast, there was a predilection for atherosclerosis at the curvatures and lateral walls of branch points.1 These are regions where disturbed flow occurs; importantly, when the time-averaged shear stress is low, the spatial shear stress gradient is very high.1,2 Both monocyte adhesion and endothelial cell (EC) apoptosis also are highest in these areas.3–6 Recently, Cheng et al7 developed a vascular occluder that induced 3 different regions of altered flow: low, high, and low with oscillatory flow. They observed that lesions always developed in regions of low compared with high shear stress. However, the low shear stress was more likely to develop larger lesions with more lipids, expression of inflammatory mediators, and matrix metalloprotease activity than oscillatory flow. When viewed in concert with a study that showed that regions of low shear stress already had a greater number of inflammatory cells resident in the artery wall as a result of increased trafficking,8 it is clear that low flow is proinflammatory and atherogenic. More sophisticated 3-dimensional analysis of flow patterns in human carotid bifurcations has identified prototypic arterial waveforms, “atheroprone” and “atheroprotective,” representing the wall shear stresses in the carotid sinus, which is susceptible to atherosclerotic lesion development, and the distal internal carotid artery, which is resistant.9 Characteristics of the atheroprone waveform include a high oscillatory shear index (≈0.45) and low time-averaged shear stress amplitude (≈0 dyne/cm2). Thus, both the amplitude and flow pattern are key determinants of …

Molecular Mechanisms of Felodipine Suppressing Atherosclerosis in High-Cholesterol-Diet Apolipoprotein E-Knockout Mice

Oxidative stress and inflammation processes are key components of atherosclerosis, from fatty streak formation to plaque rupture and thrombosis. Evidence has revealed that calcium-channel blockers (CCB) could retard atherogenesis, but the exact mechanisms have not been fully elucidated. The present study was undertaken to investigate the potential effects and molecular mechanisms of the CCB felodipine on the process of atherosclerosis in high-cholesterol-diet (HCD) apolipoprotein E-knockout (ApoE KO) mice. Adult male ApoE KO mice were given a normal diet (ND) or HCD and were randomized to no treatment or felodipine (5 mg / kg per day for 12 weeks). The ApoE KO mice with HCD were associated with a marked increase in plasma lipid levels, atherosclerotic lesion area, and the expressions of NADPH oxidase subunits (p47 and Rac-1), nuclear factor-kappaB (NF-kappaB) in nucleus, phosphor-inhibitors of kappaB (p-IkappaB), tumor necrosis-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and vascular cell-adhesion molecule-1 (VCAM-1). These changes were suppressed in mice that were treated with felodipine (5 mg/kg per day for 12 weeks) concomitant with HCD administration, with no significant change in systolic blood pressure and plasma lipid levels. The results suggest that felodipine can attenuate atherosclerosis, and this effect is partly related to inhibition of oxidative stress and inflammatory signal-transduction pathways, which lead to decreases in the expression of inflammatory cytokines.

Impaired Fetal Growth, Cardiovascular Disease, and the Need to Move on

The final step in the acceptance of a new medical hypothesis is often the approval of significant funding to investigate it. In the case of developmental programming (ie, the notion that the in utero environment determines susceptibility to many diseases later in life), this has recently come in the form of support by the US Congress for the National Children’s Study, a $3 billion project to follow the impact of environmental factors before, during, and after pregnancy on disease manifestation in some 100 000 children up to the age of 25 years.1 This initiative will, no doubt, yield a wealth of correlative data and identify many new factors potentially affecting developmental programming. Article p 405 Much of the concept underlying the National Children’s Study stems from the pioneering work of Barker and colleagues,2 whose epidemiological observation of increased cardiovascular risk in children with low birth weight has spurred a large number of retrospective studies during the past 30 years. Despite some conflicting results, most of these studies support the notion that reduced birth weight is indeed associated with increased hypertension, diabetes mellitus, and cardiovascular disease. However, the strong correlation between birth weight and duration of gestation, plus the fact that a short gestation also may be associated with cardiovascular risk,3 poses the question to what extent low birth weight is truly responsible. In this issue of Circulation , an article by Kaijser and coworkers4 at the Karolinska Institute in Stockholm provides a convincing answer. By scanning 250 000 records of birth at 4 major delivery units in Sweden between 1925 and 1949, they identified a cohort of 6437 subjects, which included 2937 children born preterm (<37 weeks of gestation) and 2181 with a birth weight <2000 g for girls or <2100 g for boys. During the …

Effect of Aging on Fatty Streak Formation in a Diet-Induced Mouse Model of Atherosclerosis

Age is considered to be a major risk factor for atherosclerosis, but it is unclear whether age has a direct effect on susceptibility to atherosclerosis. Wild-type mice develop fatty streak lesions in the aortic root only when fed a cholate-containing high fat/cholesterol diet. To investigate the influence of age on fatty streak formation, young (10 weeks) and old (53 weeks) female C57BL/6 mice were fed an atherogenic diet containing 15% fat, 1.25% cholesterol and 0.5% sodium cholate for 12 weeks. Atherosclerotic lesions at the aortic root were measured after cryosections were stained with oil red O. Results showed that old mice developed a comparable size of aortic lesions with young counterparts (5,600 ± 2,480 vs. 6,457 ± 1,537 µm²/section; p = 0.77), although old mice had significantly higher plasma cholesterol levels than young mice on the atherogenic diet (p < 0.05). Plasma levels of soluble vascular cell adhesion molecule 1 were significantly higher in old mice than in young mice on both chow and Western diets (p < 0.005). These data indicate that age has no direct effect on atherosclerosis susceptibility although it is accompanied by elevations in plasma cholesterol and vascular cell adhesion molecule 1 levels in C57BL/6 mice. Thus, increased cardiovascular events with age are probably related to a progressive increase in plaque size rather than to an increase in atherosclerosis susceptibility.

Physiological Testosterone Replacement Therapy Attenuates Fatty Streak Formation and Improves High-Density Lipoprotein Cholesterol in the Tfm Mouse

Research supports a beneficial effect of physiological testosterone on cardiovascular disease. The mechanisms by which testosterone produces these effects have yet to be elucidated. The testicular feminized (Tfm) mouse exhibits a nonfunctional androgen receptor and low circulating testosterone concentrations. We used the Tfm mouse to determine whether testosterone modulates atheroma formation via its classic signaling pathway involving the nuclear androgen receptor, conversion to 17beta-estradiol, or an alternative signaling pathway. Tfm mice (n=31) and XY littermates (n=8) were separated into 5 experimental groups. Each group received saline (Tfm, n=8; XY littermates, n=8), physiological testosterone alone (Tfm, n=8), physiological testosterone in conjunction with the estrogen receptor alpha antagonist fulvestrant (Tfm, n=8), or physiological testosterone in conjunction with the aromatase inhibitor anastrazole (Tfm, n=7). All groups were fed a cholesterol-enriched diet for 28 weeks. Serial sections from the aortic root were examined for fatty streak formation. Blood was collected for measurement of total cholesterol, high-density lipoprotein cholesterol (HDLC), non-HDLC, testosterone, and 17beta-estradiol. Physiological testosterone replacement significantly reduced fatty streak formation in Tfm mice compared with placebo-treated controls (0.37+/-0.07% versus 2.86+/-0.39%, respectively; P < or = 0.0001). HDLC concentrations also were significantly raised in Tfm mice receiving physiological testosterone replacement compared with those receiving placebo (2.81+/-0.30 versus 2.08+/-0.09 mmol/L, respectively; P = 0.05). Cotreatment with either fulvestrant or anastrazole completely abolished the improvement in HDLC. Physiological testosterone replacement inhibited fatty streak formation in the Tfm mouse, an effect that was independent of the androgen receptor. The observed increase in HDLC is consistent with conversion to 17beta-estradiol.

Role of the JAK/STAT Pathway in the Regulation of Interleukin-8 Transcription by Oxidized Phospholipids in Vitro and in Atherosclerosis in Vivo

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine, induce endothelial cells (EC) to synthesize chemotactic factors, such as interleukin 8 (IL-8). Previously, we demonstrated a role for c-Src kinase activation in Ox-PAPC-induced IL-8 transcription. In this study, we have examined the mechanism regulating IL-8 transcription by Ox-PAPC downstream of c-Src. Our findings demonstrate an important role for JAK2 in the regulation of IL-8 transcription by Ox-PAPC. Treatment of human aortic EC with Ox-PAPC and 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine induced a rapid yet sustained activation of JAK2; activation of JAK2 by Ox-PAPC was dependent on c-Src kinase activity. Furthermore, pretreatment with selective JAK2 inhibitors significantly reduced Ox-PAPC-induced IL-8 transcription. In previous studies, we also demonstrated activation of STAT3 by Ox-PAPC. Here we provide evidence that STAT3 activation by Ox-PAPC is dependent on JAK2 activation and that STAT3 activation regulates IL-8 transcription by Ox-PAPC in human EC. Transfection with small interfering RNA against STAT3 significantly reduced Ox-PAPC-induced IL-8 transcription. Using chromatin immunoprecipitation assays, we demonstrated binding of activated STAT3 to the sequence flanking the consensus gamma-interferon activation sequence (GAS) in the IL-8 promoter; site-directed mutagenesis of GAS inhibited IL-8 transcription by Ox-PAPC. Finally, these studies demonstrate a role for STAT3 activation in atherosclerosis in vivo. We found increased staining for activated STAT3 in the inflammatory regions of human atherosclerotic lesions and reduced fatty streak formation in EC-specific STAT3 knock-out mice on the atherogenic diet. Taken together, these data demonstrate an important role for the JAK2/STAT3 pathway in Ox-PAPC-induced IL-8 transcription in vitro and in atherosclerosis in vivo.

The role of inflammation in coronary artery calcification

Vascular calcification is an age-dependent, common finding in human coronary arteries and begins as early as the second decade of life, just after fatty streak formation. Previous studies have showed that the severity of coronary calcification is closely related to atherosclerotic plaque burden and cardiac event rate. In the past few decades, coronary calcification has been considered passive and degenerative. With recent clinical and basic research, however, there is increasing recognition that coronary calcification is an active, regulated process. Current diagnostic methods for coronary artery calcification (CAC) are usually traditional coronary angiography, intravascular ultrasound (IVUS), electron beam computed tomography (EBCT) and multi-slice computed tomography (MSCT) while treatment for patients with calcified coronary arteries is troublesome. Several lines of evidence suggest that inflammation plays a major role in the development of atherosclerosis as well as its clinical manifestations. Recent study showed that inflammatory process might be also involved in coronary calcification. Accordingly, measurements of inflammatory markers such as C-reactive protein (CRP) may in part reflect indices of atherosclerosis, such as coronary calcification, and are likely to provide distinct information regarding cardiovascular risk. In this article, we review the current evidence of relationship between coronary calcification and inflammation for purpose of drawing the more attention on the inflammatory mechanism of coronary calcification, which may change our research as well as therapeutic strategies for coronary calcification in the future.

Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome

Acute coronary syndrome (ACS) represents a series of indications of sudden cardiac ischemia that involve a variety of causes, including acute myocardial infarction and unstable angina.1 ACS usually is associated with thrombus formation in the coronary artery or coronary artery vasospasm, resulting in myocardial ischemia. 2 Thrombus formation may involve platelet adhesion and degranulation on damaged or dysfunctional endothelium overlying the intact or ruptured atherosclerotic plaque, as well as microthrombi.3 Atherosclerotic plaque rupture represents a series of deleterious events linked to the breakdown of the fibrous cap. This process may occur as a result of the increased secretion of matrix metalloproteinases by lesion resident macrophages or enhanced apoptotic cell death within the fibrous cap. However, viable smooth muscle cells (SMCs) within the fibrous cap synthesize interstitial collagen fibers that enhance the structural integrity of the plaque and prevent its rupture.4

Intrauterine Exposure to Maternal Atherosclerotic Risk Factors Increases the Susceptibility to Atherosclerosis in Adult Life

Maternal hypercholesterolemia is associated with a higher incidence and faster progression of atherosclerotic lesions in neonatal offspring. We aimed to determine whether an in utero environment exposing a fetus to maternal hypercholesterolemia and associated risk factors can prime the murine vessel wall to accelerated development of cardiovascular disease in adult life. To investigate the epigenetic effect in utero, we generated genetically identical heterozygous apolipoprotein E-deficient progeny from mothers with a wild-type or apolipoprotein E-deficient background. A significant increase in loss of endothelial cell volume was observed in the carotid arteries of fetuses of apolipoprotein E-deficient mothers, but fatty streak formation was absent. Spontaneous atherosclerosis development was absent in the aorta and carotid arteries in adult life. We unilaterally placed a constrictive collar around the carotid artery to induce lesion formation. In offspring from apolipoprotein E-deficient mothers, collar placement resulted in severe neointima formation in 9 of 10 mice analyzed compared with only minor lesion volume (2 of 10) in the progeny of wild-type mothers. We conclude that the susceptibility to neointima formation of morphologically normal adult arteries is already imprinted during prenatal development and manifests itself in the presence of additional atherogenic risk factors in adult life. Future research will concentrate on the mechanisms involved in this priming process, as well as on prevention strategies.

Oxidative stress, inflammation and atherosclerotic plaque development

Abstract Although the pathophysiological mechanisms underlying atherosclerosis are not completely understood, it is widely recognized that both inflammation and oxidative stress play important roles in all of the phases of atherosclerosis evolution. The oxidative modification hypothesis of atherosclerosis supports the concept that oxidation of circulating low density lipoprotein (LDL) plays a key role in the early phases of atherogenesis. However, in addition to LDL oxidation, other oxidative events are worth noting in the setting of atherosclerosis, such as the generation of oxygen reactive species. These compounds are crucial mediators in the signaling pathways underlying vascular inflammation, from the initial phases of fatty streak formation to atherosclerotic plaque evolution toward instability and rupture. In this manuscript, we summarize the newest evidence linking oxidative signaling to inflammation and atherosclerosis evolution.

Effects of dietary red clover on blood factors and cardiovascular fatty streak formation in hypercholesterolemic rabbits

Phytoestrogens with a biological activity like estradiol are naturally found in many plants. This study was designed to investigate the effect of red clover, a phytoestrogen-rich member of the legume family (Trifolium pratense) on the development of atherosclerosis in male hyperlipidemic rabbits. Twenty rabbits were semi-randomly distributed into four groups of five each. Two groups received either normal diet or normal diet supplemented with red clover. Two other groups received similar diets to both of which 1% cholesterol was added. Dietary use of red clover (RC) in hyperlipidemic rabbits significantly decreased C-reactive protein (CRP), triglyceride (TG), total cholesterol and LDL-cholesterol (LDL-C) whereas, HDL-cholesterol (HDL-C) was significantly increased in those animals (p < 0.05). Fatty streak formation was also significantly lower in aorta and left and right coronary arteries in the same animals due to use of dietary RC supplementation. These findings suggest that dietary RC may reduce cardiovascular risk factors.

Diabetes mellitus as a prothrombotic condition

Diabetes mellitus (DM) is characterized by fasting hyperglycaemia and a high risk of atherothrombotic disorders affecting the coronary, cerebral and peripheral arterial trees. The risk of myocardial infarction (MI) is 3-5 fold higher in Type 2 DM and a DM subject with no history of MI has the same risk as a non-DM subject with a past history of MI. In total around 70% of deaths are vascular with poorer outcomes to both acute events and cardiological interventions. It was proposed that clustering of vascular risk factors (hyperinsulinaemia, dysglycaemia, dyslipidaemia and hypertension) around insulin resistance (IR) accounted for the increase in risk with Type 2 DM. The importance of this became apparent with the recognition that risk clustering occurs in normoglycaemic and impaired glucose tolerance (IGT) subjects with IR, in total around 25% of the population in addition to long-standing Type 1 subjects with renal disease. Evidence indicates that thrombotic risk clustering also occurs in association with IR, suppression of fibrinolysis due to elevated concentrations of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1) is invariable with IR and there is evidence that this is regulated by the effects of triglyceride on the PAI-1 gene promoter. Other studies indicated that prothrombotic risk (coagulation factors VII, XII and fibrinogen) also associates with the IR syndrome. The development of endothelial cell dysfunction with suppression of nitric oxide and prostacyclin synthesis, combined with platelet resistance to the anti-aggregatory effects of these hormones leads to loss of control over platelet activation. In addition, hyperglycaemia and glycation have marked effects on fibrin structure function, generating a clot which has a denser structure, resistant to fibrinolysis. The combination of increased circulating coagulation zymogens, inhibition of fibrinolysis, changes in fibrin structure/function and alterations in platelet reactivity creates a thrombotic risk clustering which underpins the development of cardiovascular disease.

C-Reactive Protein and Reendothelialization

See related article, pages 1452–1459 Disruption of the endothelium and its subsequent dysfunction appears to set the stage for atherogenesis.1 The maintenance of vascular homeostasis depends in part on a balance between endothelium-derived relaxing and contracting factors. Alterations in this balance lead to inflammation and the formation of fatty streaks and fibrous plaques. The diminished production or availability of nitric oxide (NO) appears paramount to setting the stage for inflammation and vascular injury. In addition to its vasodilatory effect on the vasculature, endothelium-derived NO promotes endothelial cell growth, survival and migration,2 stimulates angiogenesis and neovascularization in part by endothelial progenitor cell (EPC) recruitment,3 inhibits leukocyte adhesion to the endothelium,4 maintains vascular smooth muscle in a nonproliferative state,5 and limits platelet aggregation and thrombosis.6 Maintenance of an intact and functional endothelium protects against vascular disease while its disruption is detrimental. The study by Schwartz et al,7 in this issue of Circulation Research , adds to our understanding of how C-reactive protein (CRP) works to promote vascular pathology by inhibiting NO synthesis. CRP, long regarded as an acute phase protein and an active participant in the innate immune system, has more recently been linked to the development of cardiovascular disease.8 On the basis of several prospective epidemiologic studies, circulating high sensitivity CRP has emerged as an independent predictor of cardiovascular disease risk in various subgroups of patients, including those without overt cardiovascular disease, patients with stable angina or acute coronary syndromes, and in those with the metabolic syndrome.9–12 In primary prevention, CRP confers additional prognostic value at all levels of Framingham risk score and blood pressure.13,14 However, whether or not CRP plays a direct biological role in the initiation and progression of atherosclerosis is controversial.15,16 …

Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Multi-organ whole-genome measurements and reverse engineering to uncover gene networks underlying complex traits

Together with computational analysis and modeling, the development of whole-genome measurement technologies holds the potential to fundamentally change research on complex disorders such as coronary artery disease. With these tools, the stage has been set to reveal the full repertoire of biological components (genes, proteins, and metabolites) in complex diseases and their interplay in modules and networks. Here we review how network identification based on reverse engineering, as applied to whole-genome datasets from simpler organisms, is now being adapted to more complex settings such as datasets from human cell lines and organs in relation to physiological and pathological states. Our focus is on the use of a systems biological approach to identify gene networks in coronary atherosclerosis. We also address how gene networks will probably play a key role in the development of early diagnostics and treatments for complex disorders in the coming era of individualized medicine.

Evaluation of TERT mRNA alternative spliced variants in aortic endothelial cells of the rabbit, in the fatty streaks stage of atherosclerosis

Objectives — There are some lines of evidence about the role of telomeres in atherosclerotic plaque formation and development. Despite the role of telomerase in telomere elongation and protection, its role in atherosclerosis is not fully understood. The present study was designed to evaluate the importance of alternative splicing variants of TERT (telomerase reverse transcriptase) in the atherosclerosis process.Methods and results — Six Dutch-Polish rabbits were fed a high-cholesterol diet, and six control animals a normal diet. Alternative splicing was assessed by RT-PCR in aortic endothelial cells of these rabbits. Fatty streaks formation was assessed by H & E staining of aortic tissues. There were no significant differences in variants of TERT in control and test animals; neither in endothelial cells nor in aortic vessel wall.Conclusion — Our results demonstrated that a decrease in telomerase activity in atherosclerosis formation is not due to TERT gene alternative splicing.

Rethinking Primary Prevention of Atherosclerosis-Related Diseases

Crucial advances in our understanding of basic pathogenic mechanisms involved in atherogenesis have been achieved during the past 2 decades. The historical hypothesis of pathogenesis (“lipid accumulation”) has evolved to integrate several causal events contributing to the initiation and evolution of atherosclerosis. Vascular inflammation and apoptosis may play a joint pivotal role in its progression and onset. Hypercholesterolemia and hypertension have synergistic deleterious effects on coronary endothelial function.1 Impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and high-sensitivity C-reactive protein (hsCRP) might contribute to an increased risk of atherosclerosis.2 The disease also has been related to infiltration of immune cells, which are involved in both systemic and local, innate as well as adaptive, immune responses.3 Distinct pathways of atherothrombosis seem to develop at different sites of the vascular system (brain, heart, and peripheral circulation). Endothelial dysfunction induced by cardiovascular risk factors is considered to be 1 of the earliest stages in vascular damage and is associated independently with cardiovascular events.4 There is a synergic action between genetic, ambient, local, and systemic factors, and ultimately the progression of atherosclerosis is responsible for coronary heart disease (CHD) and its complications (such as unstable “in crescendo” angina, myocardial infarction, and sudden death), peripheral arterial disease, and ischemic stroke. The evolution of atherosclerosis, however, is characterized by a long lag time between onset and clinical manifestation, thereby providing an opportunity for implementation of early detection, prevention, and intervention strategies. Because the development of atherosclerosis commences early in humans, we need to rethink the timing of what is currently considered to be “primary” prevention of atherosclerosis-related diseases. It is likely that we need to start administering effective treatments much earlier than previously assumed. Indeed, much attention would be important when subjects are in a state of wellness before the …