Atherosclerosis-based Cardiovascular Disease Research Articles

Lipid Profile, Lp(a) Levels, and HDL Quality in Adolescents with Down Syndrome.

The improvement in the lifespan of individuals with Down syndrome (DS) has created interest in the context of the development of age-related diseases. Among them is atherosclerosis-based cardiovascular disease (CVD), which seems to be an especially urgent and important issue. The aim of the present study was to evaluate the lipid markers that may clarify cardiovascular risk profiles in individuals with DS. To this end, we analyzed lipid profile parameters, including lipoprotein(a) (Lp(a)) levels, protein composition, and the antioxidative properties of high-density lipoprotein (HDL), in 47 adolescents with DS and 47 individuals without DS. Compared with the control group (C), subjects with DS had significantly increased concentrations of low-density lipoprotein cholesterol (105 ± 31 vs. 90 ± 24 mg/dL, p = 0.014), non-high-density lipoprotein cholesterol (120 ± 32 vs. 103 ± 26 mg/dL, p = 0.006), and triglycerides (72 [55–97] vs. 60 [50–77] mg/dL, p = 0.048). We found that patients with DS were characterized by significantly higher Lp(a) levels (31.9 [21.5–54.3] vs. 5.2 (2.4–16.1) mg/dL, p < 0.001). In fact, 57% of individuals with DS had Lp(a) levels above 30 mg/dL, which was approximately four times higher than those in the control group (DS 57% vs. C 15%). Apart from decreased high-density lipoprotein cholesterol levels in the subjects with DS (53 ± 11 vs. 63 ± 12 mg/dL, p < 0.001), differences in parameters showing the quality of HDL particles were observed. The concentrations of the main proteins characterizing the HDL fraction, apolipoprotein A-I and apolipoprotein A-II, were significantly lower in the DS group (144 ± 21 vs. 181 ± 33 mg/dL, p < 0.001; 33 ± 6 vs. 39 ± 6 mg/dL, p < 0.001, respectively). No significant differences between the groups were observed for the concentration of paraoxonase-1 (DS 779 ± 171 vs. C 657 ± 340 ng/mL, p = 0.063), enzyme activities toward paraoxon (DS 219 [129–286] vs. C 168 [114–272] IU/L, p = 0.949), or phenyl acetate (DS 101 ± 20 vs. C 93 ± 21 kIU/L, p = 0.068). There were no differences in myeloperoxidase activity between the study groups (DS 327 [300–534] vs. C 426 [358–533] ng/mL, p = 0.272). Our results are the first to demonstrate an unfavorable lipid profile combined with higher Lp(a) levels and quality changes in HDL particles in individuals with DS. This sheds new light on cardiovascular risk and traditional healthcare planning for adolescents with DS.

Age-related changes of human serum Sirtuin6 in adults

BackgroundAging is a natural life process and with an aging population, age-related diseases (e.g. type 2 diabetes mellitus (T2DM), atherosclerosis-based cardiovascular diseases) are the primary mortality cause in older adults. Telomerase is often used as an aging biomarker. Detection and characterization of novel biomarkers can help in a more specific and sensitive identification of a person’s aging status. Also, this could help in age-related diseases early prevent, ultimately prolonging the population’s life span. Sirtuin 6 (Sirt6) - a member of the Sirtuins NAD+-dependent histone deacetylases family - is mainly intracellularly expressed, and is reported to be involved in the regulation of aging and aging-related diseases. Whether serum Sirt6 is correlated with aging and could be used as an aging biomarker is unknown. In the present study, we aimed to investigate the age-related Sirt6 changes in the serum of human adults.MethodsParticipants were divided into three groups according to age: 20–30 years (Young); 45–55 years (Middle-aged); and ≥ 70 years (Old). The Sirt6 and telomerase serum concentrations were determined by ELISA. The Sirt6 and human telomerase reverse transcriptase (hTERT) expression in vessels from amputated human lower limbs were analyzed using real-time quantitative PCR (RT-qPCR) and immunohistochemical staining. The relationships between variables were evaluated by Pearson correlation analysis.ResultsThe Sirt6 and telomerase serum levels reduced with an increase in age. A similar tendency was observed for Sirt6 and hTERT in the vessel. Serum levels of Sirt6 were higher in females compared with males. Pearson’s regression analysis revealed that the Sirt6 serum level positively correlated with telomerase (r = 0.5743) and both were significantly negatively correlated with age (r = − 0.5830 and r = − 0.5993, respectively).ConclusionsWe reported a negative correlation between serum Sirt6 concentration and aging in human beings. Therefore, the Sirt6 serum level is a potential sex-specific aging marker.

Pleiotropic Effects of Acetylsalicylic Acid after Coronary Artery Bypass Grafting—Beyond Platelet Inhibition

Acetylsalicylic acid (ASA) is one of the most frequently used medications worldwide. Yet, the main indications for ASA are the atherosclerosis-based cardiovascular diseases, including coronary artery disease (CAD). Despite the increasing number of percutaneous procedures to treat CAD, coronary artery bypass grafting (CABG) remains the treatment of choice in patients with multivessel CAD and intermediate or high anatomical lesion complexity. Taking into account that CABG is a potent activator of inflammation, ASA is an important part in the postoperative therapy, not only due to ASA antiplatelet action, but also as an anti-inflammatory agent. Additional benefits of ASA after CABG include anticancerogenic, hypotensive, antiproliferative, anti-osteoporotic, and neuroprotective effects, which are especially important in patients after CABG, prone to hypertension, graft occlusion, atherosclerosis progression, and cognitive impairment. Here, we discuss the pleiotropic effects of ASA after CABG and provide insights into the mechanisms underlying the benefits of treatment with ASA, beyond platelet inhibition. Since some of ASA pleiotropic effects seem to increase the risk of bleeding, it could be considered a starting point to investigate whether the increase of the intensity of the treatment with ASA after CABG is beneficial for the CABG group of patients.

Role of Dipeptidyl Peptidase-4 in Atherosclerotic Cardiovascular Disease in Humans and Animals with Chronic Stress.

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular atherosclerosis-based cardiovascular disease (ACVD). Dipeptidyl peptidase-4 (DPP-4) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase. DPP-4 is upregulated in metabolic and inflammatory cardiovascular disorders. DPP-4 exhibits many physiological and pharmacological functions by regulating its extremely abundant substrates, such as glucagon-like peptide-1 (GLP-1). Over the last 10 years, emerging data have demonstrated unexpected roles of DPP-4 in extracellular and intracellular signaling, immune activation, inflammation, oxidative stress production, cell apoptosis, insulin resistance, and lipid metabolism. This mini-review focuses on recent novel findings in this field, highlighting a DPP-4-mediated regulation of GLP-1-dependent and -independent signaling pathways as a potential therapeutic molecular target in treatments of chronic psychological stress-related ACVD in humans and animals.

Olfactory receptor 2 (Olfr2) and its human ortholog OR6A2 expressed in macrophages drive NLRP3 inflammasome activation and exacerbate atherosclerosis in mice

Abstract Atherosclerosis is an inflammatory disease of the arterial wall driven by macrophages and other immune cells. Olfactory receptors (Olfrs) are G-protein coupled receptors expressed in olfactory epithelium and are responsible for the sense of smell. We found that macrophages in the wall of atherosclerotic mouse aortas express some olfactory receptors including Olfr2, a specific receptor for an 8 carbon fatty-aldehyde called octanal. Octanal is detectable in food, mouse and human blood plasma, elevated by western diet, and partially derived from gut microbiota. Ligation of Olfr2 or its human orthologue OR6A2, expressed in human atherosclerotic plaque and in human monocyte-derived macrophages, is strongly pro-inflammatory, activates the NLRP3 inflammasome and, in synergy with LPS, induces secretion of IL-1β. Knockdown of Olfr2/OR6A2 in macrophages significantly reduced inflammatory cytokine secretion. To test the role of Olfr2 in atherosclerosis, we treated Apoe−/− mice with octanal or the Olfr2 antagonist citral. Octanal significantly exacerbated while citral significantly inhibited atherosclerosis. We generated Olfr2−/− mice by Crispr-Cas9. Ldlr−/− mice reconstituted with Olfr2−/− bone marrow developed ~50% smaller lesions on high cholesterol diet than littermate controls reconstituted with Olfr2+/+ bone marrow. Our findings suggest that small molecule inhibitors of Olfrs like OR6A2 are promising targets for drug development to prevent and treat atherosclerosis-based cardiovascular diseases.

Air Pollution Exposure and Progression of Atherosclerosis in Different Vessel Beds

Background: Air pollution (AP) is an important environmental risk factor and atherosclerosis-based cardiovascular diseases are the leading cause of death in the westernized world. Epidemiological s...

Cysteine Protease Cathepsins in Atherosclerotic Cardiovascular Diseases.

Atherosclerotic cardiovascular disease (ASCVD) is an inflammatory disease characterized by extensive arterial wall matrix protein degradation. Cysteine protease cathepsins play a pivotal role in extracellular matrix (ECM) remodeling and have been implicated in the development and progression of atherosclerosis-based cardiovascular diseases. An imbalance in expression between cathepsins (such as cathepsins S, K, L, C) and their inhibitor cystatin C may favor proteolysis of ECM in the pathogenesis of cardiovascular disease such as atherosclerosis, aneurysm formation, restenosis, and neovascularization. New insights into cathepsin functions have been made possible by the generation of knock-out mice and by the application of specific inhibitors. Inflammatory cytokines regulate the expression and activities of cathepsins in cultured vascular cells and macrophages. In addition, evaluations of the possibility of cathepsins as a diagnostic tool revealed that the circulating levels of cathepsin S, K, and L, and their endogenous inhibitor cystatin C could be promising biomarkers in the diagnosis of coronary artery disease, aneurysm, adiposity, peripheral arterial disease, and coronary artery calcification. In this review, we summarize the available information regarding the mechanistic contributions of cathepsins to ASCVD.

Stress and Atherosclerotic Cardiovascular Disease

Recent major advances in medical science have introduced a wide variety of treatments against atherosclerosis-based cardiovascular diseases, which has led to a significant reduction in mortality associated with these diseases. However, atherosclerosis-based cardiovascular disease remains a leading cause of death. Furthermore, progress in medical science has demonstrated the pathogenesis of cardiovascular disease to be complicated, with a wide variety of underlying factors. Among these factors, stress is thought to be pivotal. Several types of stress are involved in the development of cardiovascular disease, including oxidative stress, mental stress, hemodynamic stress and social stress. Accumulating evidence indicates that traditional risk factors for atherosclerosis, including diabetes, hyperlipidemia, hypertension and smoking, induce oxidative stress in the vasculature. Oxidative stress is implicated in the pathogenesis of endothelial dysfunction, atherogenesis, hypertension and remodeling of blood vessels. Meanwhile, mental stress is a well-known major contributor to the development of cardiovascular disease. The cardiovascular system is constantly exposed to hemodynamic stress by the blood flow and/or pulsation, and hemodynamic stress exerts profound effects on the biology of vascular cells and cardiomyocytes. In addition, social stress, such as that due to a lack of social support, poverty or living alone, has a negative impact on the incidence of cardiovascular disease. Furthermore, there are interactions between mental, oxidative and hemodynamic stress. The production of reactive oxygen species is increased under high levels of mental stress in close association with oxidative stress. These stress responses and their interactions play central roles in the pathogenesis of atherosclerosis-based cardiovascular disease. Accordingly, the pathophysiological and clinical implications of stress are discussed in this article.

BAFF Receptor mAb Treatment Ameliorates Development and Progression of Atherosclerosis in Hyperlipidemic ApoE−/− Mice

AimsOption to attenuate atherosclerosis by depleting B2 cells is currently limited to anti-CD20 antibodies which deplete all B-cell subtypes. In the present study we evaluated the capacity of a monoclonal antibody to B cell activating factor-receptor (BAFFR) to selectively deplete atherogenic B2 cells to prevent both development and progression of atherosclerosis in the ApoE−/− mouse.Methods and ResultsTo determine whether the BAFFR antibody prevents atherosclerosis development, we treated ApoE−/− mice with the antibody while feeding them a high fat diet (HFD) for 8 weeks. Mature CD93− CD19+ B2 cells were reduced by treatment, spleen B-cell zones disrupted and spleen CD20 mRNA expression decreased while B1a cells and non-B cells were spared. Atherosclerosis was ameliorated in the hyperlipidemic mice and CD19+ B cells, CD4+ and CD8+ T cells were reduced in atherosclerotic lesions. Expressions of proinflammatory cytokines, IL1β, TNFα, and IFNγ in the lesions were also reduced, while MCP1, MIF and VCAM-1 expressions were unaffected. Plasma immunoglobulins were reduced, but MDA-oxLDL specific antibodies were unaffected. To determine whether anti-BAFFR antibody ameliorates progression of atherosclerosis, we first fed ApoE−/− mice a HFD for 6 weeks, and then instigated anti-BAFFR antibody treatment for a further 6 week-HFD. CD93− CD19+ B2 cells were selectively decreased and atherosclerotic lesions were reduced by this treatment.ConclusionAnti-BAFFR monoclonal antibody selectively depletes mature B2 cells while sparing B1a cells, disrupts spleen B-cell zones and ameliorates atherosclerosis development and progression in hyperlipidemic ApoE−/− mice. Our findings have potential for clinical translation to manage atherosclerosis-based cardiovascular diseases.

Atherosclerosis

Atherosclerosis-based cardiovascular diseases have a devastating impact on public health. Therefore, exploring molecular mechanisms of atherosclerosis is an important focus for development of effective therapeutic strategies [1]. This Bimonthly Update summarizes recent publications that have provided new insights into leukocyte-related mechanisms in the development of atherosclerosis. Macrophage accumulation is a dominant feature of early atherosclerosis and could be due to changes in recruitment, emigration, proliferation, or death. To gain insights into mechanisms provoking macrophage emigration, van Gils et al.[2▪▪] investigated netrin-1, a protein involved in chemorepulsion and chemoattraction of axons. Netrin-1 was present in macrophages of atherosclerotic lesions. Several in-vitro studies were consistent with this protein being an active participant in the atherosclerotic process including lipid loading of cultured macrophages increasing the abundance of netrin-1. Netrin-1 also inhibited macrophage migration by preventing responses to a number of chemokines. In addition, netrin-1 expression in macrophages was a chemoattractant for smooth muscle cells. Supported by these in-vitro data, the authors performed in-vivo studies demonstrating that netrin-1 deficiency in hematopoietic cells reduced hypercholesterolemia-induced atherosclerosis in LDL receptor −/− mice. A macrophage-tracking technique provided evidence that netrin-1 deficiency in hematopoietic cells led to less retention of macrophages in atherosclerotic lesions. Despite not being directly demonstrated, these data inferred that inhibition of netrin-1 might be able to remove lipid-laden macrophages from established atherosclerotic lesions. The effects of netrin-1 in atherosclerosis have been explored previously. In contrast to the studies of van Gils et al.[2▪▪], others reported that netrin-1 delivered via infection with adeno-associated viruses prevented atherosclerosis by reducing leukocyte accumulation [3▪]. Part of the contradiction may be the result of the unusual approach used by Khan et al.[3▪] to measuring atherosclerosis. However, there may also be a context-based explanation because netrin-1 inhibits migration of circulating leukocytes into tissues, thereby it may exert anti-inflammatory effects [4,5]. Since netrin-1 may have multifunctional roles in regulating leukocyte functions, it requires further work to fully explore the effects of this potentially important molecule in the development and progression of atherosclerosis. Macrophage polarization has been recognized as a critical mechanism in the development of atherosclerosis. Nur77, a nuclear receptor, controls the differentiation and survival of a subtype of Ly6C monocytes, which may regulate macrophage polarization [6]. As simultaneously demonstrated by two research groups [7▪▪,8▪▪], Nur77 deficiency in bone marrow-derived cells augmented hypercholesterolemia-induced atherosclerosis. Although findings from both groups imply that increased atherosclerosis induced by Nur77 deficiency is associated with enhanced polarization of macrophages toward a M1 phenotype, mechanisms explored in the two studies were different and somewhat conflicting [9]. Hanna et al.[7▪▪] found that increased inflammatory responses were associated with enhanced Toll-like receptor 4 and 9 expression and NF-κB-mediated signaling. In contrast, Hamers et al.[8▪▪] defined a mechanism relating to increased expression of stromal cell-derived factor (SDF)-1α. Additionally, the two studies provided contradicting results on whether Nur77 deficiency in macrophages influenced Dil-oxLDL uptake and macrophage migration. Despite the consistent findings on atherosclerosis, the discrepancies of mechanisms in these two studies indicate potentially complex mechanisms and roles of Nur77 in the development of atherosclerosis. Therefore, it is uncertain whether Nur77 could be a desirable target for treating atherosclerosis [9]. The current literature adds another exciting layer to understand the molecular mechanisms of atherosclerotic development. While pharmacological modulation of macrophage functions by targeting certain critical molecules may provide promising therapeutic approaches for atherosclerosis, the pros and cons of manipulating these components should be assessed thoroughly in order to translate the current findings into effective therapies in clinical patients. Acknowledgements The authors’ research work is supported by the grants from NIH (HL062846 and HL107319). Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: ▪ of special interest ▪▪ of outstanding interest

Pleiotropic Effects of ARB in Vascular Metabolism - Focusing on Atherosclerosis-Based Cardiovascular Disease

The renin-angiotensin system (RAS) plays an essential role in fluid and electrolyte homeostasis and the regulation of vascular tone; however, dysregulation and over-activation of the RAS lead to the pathogenesis of various cardiovascular diseases. The RAS is closely associated with NADPH oxidase, a major enzymatic source of reactive oxygen species (ROS) in vasculature, and angiotensin II, the final effecter of the RAS, is a potent stimulator of this oxidase. There are accumulating evidences to support the significance of NADPH oxidase in the pathogenesis of atherosclerosis. We demonstrated that the expression of NADPH oxidase is markedly enhanced in human atherosclerotic coronary arteries, and the distribution of oxidized oxidized low-density lipoprotein (LDL) in vasculature is closely associated with NAPDH oxidase and ROS. Our series of observations indicate there is a vicious circle consisting of vascular NADPH oxidase, the RAS, ROS, and oxidized LDL. Furthermore, we demonstrated that angiotensin II type 1 receptor blockers (ARBs) significantly suppressed the expression of NADPH oxidase p22(phox) in the aortic walls of patients with thoracic aortic aneurysm. ARBs, widely used for treatment of hypertension and hypertension-related organ damage, have succeeded in reducing the onset of cardiovascular diseases, preventing organ damage, and cardiac death. These beneficial effects of ARBs are largely dependent upon their primary effects of blood pressure lowering. However, this group of agents exerts a wide variety of biological effects on vascular metabolism, including antioxidative and anti-inflammatory actions. These pleiotropic actions play a role in cardiovascular protection. From a viewpoint of oxidative stress, we discuss pleiotropic effects of ARBs on vascular metabolism focusing on pathogenesis of atherosclerosis-based cardiovascular diseases.

Effects of Selaginellin on Homocysteine-Induced Senescence in Human Umbilical Vein Endothelial Cells

Homocysteine plays a key role in endothelial cell senescence associated with atherosclerosis-based cardiovascular diseases. Selaginellin, a component extracted from Selaginella pulvinata (Hook. et Grev.) Maximo, was assessed for its ability to protect human umbilical vein endothelial cells against homocysteine-induced senescence. The endothelial cells were pretreated with various concentrations (10(-7), 3 x 10(-7), or 10(-6) M) of selaginellin for 1 hour before exposure to homocysteine. Selaginellin was shown to protect endothelial cells against homocysteine-induced senescence, as determined by senescence-associated beta-galactosidase activity, telomerase activity, and cell cycle distribution. In addition, the increase in levels of intracellular reactive oxygen species and downregulation of SIRT1 gene expression induced by homocysteine were significantly reversed by selaginellin. Our study suggests that selaginellin has a protective effect against homocysteine-induced senescence through mechanisms related to antioxidation via scavenging reactive oxygen species and upregulating the expression of SIRT1 gene.

Impact of NAD(P)H Oxidase-Derived Reactive Oxygen Species on Coronary Arterial Remodeling

Background— Coronary arterial remodeling, which is a response to the growth of atherosclerotic plaques, is associated with plaque vulnerability. Oxidative stress induced by reactive oxygen species (ROS) via NAD(P)H oxidase in the vasculature also plays a crucial role in the pathogenesis of atherosclerosis-based cardiovascular disease. In this study, the relationship between coronary arterial remodeling and ROS generation was examined by comparing preinterventional intravascular ultrasound findings of atherosclerotic lesions to the histochemical findings of corresponding specimens obtained by directional coronary atherectomy. Methods and Results— Predirectional coronary atherectomy intravascular ultrasound images of 49 patients were analyzed. The remodeling index was calculated by dividing the target-lesion external elastic membrane cross-sectional area by the reference-segment external elastic membrane cross-sectional area. Expansive remodeling was defined as a remodeling index of &gt;1.0. ROS generation and NAD(P)H oxidase p22 phox expression in directional coronary atherectomy specimens were evaluated using the dihydroethidium staining method and immunohistochemistry as the ratio of the positive area to the total surface area in each specimen, respectively. ROS generation and p22 phox expression were significantly greater in lesions with expansive remodeling than in lesions without remodeling (0.18�0.12 versus 0.03�0.02, P &lt;0.0001, 0.10�0.08 versus 0.04�0.05, P =0.0039, respectively). Both ROS generation and p22 phox expression significantly correlated with the intravascular ultrasound-derived remodeling index ( r =0.77, P &lt;0.0001, r =0.53, P &lt;0.0001, respectively). Conclusions— Simultaneous examination with intravascular ultrasound and immunohistochemistry analyses suggests that NAD(P)H oxidase-derived ROS is related to the coronary arterial remodeling process associated with plaque vulnerability.

Lectin-like oxidized LDL receptor-1 as extracellular chaperone receptor: Its versatile functions and human diseases

Well-known coronary risk factors such as hyperlipidemia, hypertension, smoking, and diabetes are reported to induce the oxidative stress. Under the oxidative stress, low-density lipoprotein (LDL) is oxidatively modified in the vasculature, and formed oxidized LDL induces endothelial dysfunction, expression of adhesion molecules and apoptosis of vascular smooth muscle cells. It has become evident that these cellular responses induced by oxidized LDL are mediated by lectin-like oxidized LDL receptor-1 (LOX-1). LOX-1 was originally identified from cultured aortic endothelial cells as a receptor for oxidized LDL; however, recent investigations revealed that LOX-1 has diverse roles in the host-defense system and inflammatory responses, and it is involved in the pathogenesis of various diseases such as atherosclerosis-based cardiovascular diseases and septic shock. Beside oxidized LDL, LOX-1 recognizes multiple ligands including apoptotic cells, platelets, advanced glycation end products, bacteria, and heat shock proteins (HSPs). The HSPs function as a chaperone to affect protein folding of newly synthesized or denatured proteins. There are accumulating evidences that the HSPs released into the extracellular space have potent biological activities and it may work as a kind of cytokines. It is demonstrated that LOX-1 works as a receptor for HSP70, since it has high affinity for HSP70. The interaction of LOX-1 with HSP70 is involved in the cross-presentation of antigen. Given the potent and wide variety of biological activities, more understanding their interaction provides potential therapeutic strategy for various human diseases.