Fatty Streak Formation Research Articles

Inflammatory Biomarkers for Cardiovascular Risk Stratification in Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a frequent autosomal genetic disease characterized by elevated concentrations of low-density lipoprotein cholesterol (LDL) from birth with increased risk of premature atherosclerotic complications. Accumulating evidence has shown enhanced inflammation in patients with FH. In vessels, the deposition of modified cholesterol lipoproteins triggers local inflammation. Then, inflammation facilitates fatty streak formation by activating the endothelium to produce chemokines and adhesion molecules. This process eventually results in the uptake of vascular oxidized LDL (OxLDL) by scavenger receptors in monocyte-derived macrophages and formation of foam cells. Further leukocyte recruitment into the sub-endothelial space leads to plaque progression and activation of smooth muscle cells proliferation. Several inflammatory biomarkers have been reported in this setting which can be directly synthetized by activated inflammatory/vascular cells or can be indirectly produced by organs other than vessels, e.g., liver. Of note, inflammation is boosted in FH patients. Inflammatory biomarkers might improve the risk stratification for coronary heart disease and predict atherosclerotic events in FH patients. This review aims at summarizing the current knowledge about the role of inflammation in FH and the potential application of inflammatory biomarkers for cardiovascular risk estimation in these patients.

Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies.

Background: The LRP1 (CR9) domain and, in particular, the sequence Gly1127-Cys1140 (P3) plays a critical role in the binding and internalization of aggregated LDL (agLDL). We aimed to evaluate whether immunization with P3 reduces high-fat diet (HFD)-induced atherosclerosis.Methods: Female New Zealand White (NZW) rabbits were immunized with a primary injection and four reminder doses (R1-R4) of IrP (irrelevant peptide) or P3 conjugated to the carrier. IrP and P3-immunized rabbits were randomly divided into a normal diet group and a HFD-fed group. Anti-P3 antibody levels were determined by ELISA. Lipoprotein profile, circulating and tissue lipids, and vascular pro-inflammatory mediators were determined using standardized methods while atherosclerosis was determined by confocal microscopy studies and non-invasive imaging (PET/CT and Doppler ultrasonography). Studies treating human macrophages (hMΦ) and coronary vascular smooth muscle cells (hcVSMC) with rabbit serums were performed to ascertain the potential impact of anti-P3 Abs on the functionality of these crucial cells.Results: P3 immunization specifically induced the production of anti-P3 antibodies (Abs) and did not alter the lipoprotein profile. HFD strongly induced cholesteryl ester (CE) accumulation in the aorta of both the control and IrP groups, and their serum dose-dependently raised the intracellular CE of hMΦ and hcVSMC, promoting TNFR1 and phospho-NF-kB (p65) overexpression. These HFD pro-inflammatory effects were dramatically decreased in the aorta of P3-immunized rabbits and in hMΦ and hcVSMC exposed to the P3 rabbit serums. Microscopy studies revealed that P3 immunization reduced the percentage of lipids, macrophages, and SMCs in the arterial intima, as well as the atherosclerotic extent and lesion area in the aorta. PET/CT and Doppler ultrasonography studies showed that the average standardized uptake value (SUVmean) of the aorta and the arterial resistance index (ARI) of the carotids were more upregulated by HFD in the control and IrP groups than the P3 group.Conclusions: P3 immunization counteracts HFD-induced fatty streak formation in rabbits. The specific blockade of the LRP1 (CR9) domain with Anti-P3 Abs dramatically reduces HFD-induced intracellular CE loading and harmful coupling to pro-inflammatory signaling in the vasculature.

Role of Free Radical-induced Oxidative Stress in the Pathogenesis of Coronary Artery Disease

Oxidative stress is associated with various pathophysiological events such as cancer, kidney diseases, and diabetes. Studies have shown that reactive oxygen species (ROS) also play a key role in the development of vasculopathies and can cause disorders such as atherosclerosis, hypertension, and coronary stenosis. Atherosclerosis, due to endothelial cell damage, results in at least impaired endothelial function and consequently macrophage infiltration and impaired smooth muscle function. Since then, many researchers have focused on low-density lipoprotein (LDL) oxidation and its interaction with the endothelium as the primary injury that leads to the formation of fatty streaks and eventually to atherogenesis. It has now become clear that different types of ROS are not only produced in the vessel wall but also contribute to the pathogenesis of a range of cardiovascular disorders individually and collectively.

Anti-Atherosclerotic and Anti-Inflammatory Effects of Curcumin on Hypercholesterolemic Male Rabbits.

Curcumin has a potent antioxidant and anti-inflammatory properties that may suppress inflammatory component of atherosclerosis. It has been demonstrated that curcumin derivatives can reduce the formation of arterial fatty streaks in cholesterol-fed rabbits. Therefore in this study we evaluated the protective effects of Curcumin on the progression of atherosclerosis. 20 mature rabbits were included for this study; they were randomly divided into four groups each of 5. Group 1: (normal control) were fed corn pellets diet and tab water, group 2: (high cholesterol diet control) were kept on cholesterol rich diet (2% cholesterol) and tab water. Group 3: (cholesterol and rosuvastatin treated group) were kept on cholesterol rich diet (2% cholesterol) and 2.5mg/kg/day Rosuvastatin dispersed in DW and given orally, group 4: (cholesterol and curcumin treated group) were kept on cholesterol rich diet (2% cholesterol) and 0.2% curcumin added with corn pellets. The study continued for 12weeks then assessment of serum level of high sensitive C-reactive protein, ICAM1, VCAM1 and PCSK9 was carried out at the end of the study. Total antioxidant activity of curcumin was also determined. Histopathological examination of aortic tissues for atherosclerotic changes was also carried out. Atherogenic (cholesterol rich diet) induced an increment in serum level of TC, LDL, VLDL and TG with concomitant decrement in serum level of HDL and increased atherogenic index. Treatment with curcumin produced substantial reduction in serum TC, LDL, TG with no effect on HDL level thus decreased atherogenic index. Rabbits treated with curcumin showed a significant reduction in the serum level of high sensitive C-reactive protein, ICAM1, VCAM, PCSK9 serum expression and aortic total antioxidant capacity. Curcumin has a potent anti-inflammatory and anti- oxidant effects against atherosclerosis so exerts a protective role by decreasing lipid oxidation and inflammatory markers.

P3447Multimodal assessment and phenomapping of early atherosclerosis in children with chronic disease

Abstract Background Childhood survival of chronic disease steadily increased over the last decades. However, accumulating evidence suggests that survivors are at risk for early atherosclerosis. The “Cardiovascular Disease in Children with chronic disease” (CDC) study has two aims. First, multimodal assessment of early atherosclerosis was performed in adolescents with chronic inflammatory- and metabolic disorders in order to develop new diagnostic approaches. As fatty streak formation starts in the abdominal aorta, aortic wall thickness (AWT) and pulse wave velocity (PWV) were measured using cardiovascular magnetic resonance imaging (MRI), and compared with traditional carotid intima-media thickness (cIMT) and echocardiography. Second, comprehensive risk profiling was performed, including phenomapping of early risk factors, in order to establish cardiovascular risk profiles in childhood. Methods 113 adolescents aged 12–19 years old were enrolled*. The study population includes adolescents with juvenile idiopathic arthritis (JIA, n=19), cystic fibrosis (CF, n=24), obesity (n=20), corrected coarctation of the aorta (CoA, n=25), and corrected atrial septal defect as control group (ASD, n=25). The aorta was imaged on a 3.0 Tesla MR system using the 3D-T1-BB-VISTA sequence. Aortic PWV was assessed using velocity-encoded MRI. cIMT was measured in three directions for both the right- and left carotid artery using echography. Unbiased hierarchical clustering was performed on phenotypic data (phenomapping), including anthropomorphic-, metabolic-, and inflammatory parameters. Results* Aortic pulse wave velocity on MRI was highest in the obese group compared to controls (p=0.002), yet JIA patients (p=0.015), CoA patients (p=0.029), and CF patients (p=0.044) also showed increased PWV compared to controls. Aortic wall thickness was highest in obese adolescents (p=0.020) and in CF patients (p=0.043). cIMT was only increased in CoA patients (p=0.000). While PWV and AWT showed correlation with inflammatory- and metabolic parameters such as lymphocyte count (PWV, p=0.043), monocyte count (PWV, p=0.002; AWT, p=0.036), CRP (AWT, p=0.032), and QUICKI (PWV, p=0.026), cIMT correlated with systolic blood pressure (p=0.017). Phenomapping of risk factors will further define distinct cardiovascular risk profiles*. Conclusion Multimodal assessment of early atherosclerosis in children with chronic disease reveals differential vascular changes. While traditional cIMT is associated with increased systolic blood pressure in young CoA patients, aortic PWV and aortic wall thickness reflect early systemic inflammatory- and metabolic derangement. Phenomapping traditional risk factors alongside inflammatory- and metabolic parameters bears promise to establish early cardiovascular risk profiles in childhood chronic disease*. *Patient inclusion finishes May 2019, followed by phenomapping of patient characteristics. At the ESC, final data will be presented. Acknowledgement/Funding Wilhelmina Children's Hospital Research Fund, Dutch Topsector Life Sciences and Health TKI fund, Nutricia Research fund. HS was supported by VENI-NWO.

Potential Cardio-Protective Effects of Green Grape Juice: A Review

Unripe grape juice (verjuice) may offer health benefits, including the treatment of cardiovascular disease. The presence of bioactive compounds in verjuice influences blood pressure, inflammatory markers, oxidative stress, endothelial function, fatty streak formation and glycemic level. Studies have shown that the bioactive compounds also affect serum lipid profile, raising LDL cholesterol under certain circumstances. The health-promoting effects of verjuice have been investigated through human and animal trials. This review paper provides a comprehensive summary of the literature on the pharmacological and phytochemical properties of green grape juice. Further research on this juice is needed to quantify the phytochemical composition and support the current findings. Furthermore, future studies are needed to determine the exact amount of verjuice required to exhibit the optimal health effects on humans, as this is currently unknown.

SAT-001 Supra-Physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy

Supra-physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy The impact of testosterone on the cardiovascular system is controversial and concerns have been raised in regard to the safety of testosterone replacement therapy (TTh) in hypogonadal men with cardiovascular disease. We have examined the effects of supra-physiological concentrations of testosterone upon aortic fatty streak formation in high-fat diet-fed testicular feminized (Tfm) mice, which exhibit non-functional androgen receptors (AR) and low circulating testosterone levels. Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received fortnightly intramuscular injections of either saline (Tfm, n=8, XY, n=8), 10uL of 250mg/mL testosterone alone (Tfm, n=8, XY, n=8), or in conjunction with either a 30uL intramuscular injection of 50mg/ml estrogen receptor-alpha antagonist fulvestrant (Tfm, n=8), or with 10mg/kg/day of aromatase inhibitor anastrazole in drinking water (Tfm, n=7). Cardiac tissue mRNA was analysed by qPCR for markers of hypertrophy (ANP, BNP, alpha-actin, MYH7, Gsk3-beta, SM22-alpha). A significant reduction in aortic fatty streak formation was observed in Tfm mice receiving supra-physiological testosterone compared to those receiving saline; 1.25+0.36% versus 2.85+0.37% respectively (p<0.01). No significant increase in aortic lipid deposition was observed in XY littermates administered supra-physiological testosterone compared to those receiving saline; 0.22+0.13% versus 0.32+0.12% respectively (p=ns). Aortic fatty streak formation in Tfm mice receiving supra-physiological testosterone in conjunction with fulvestrant or anastrazole was similar to that observed in Tfm mice receiving supra-physiological testosterone therapy alone; 0.71+0.18% and 1.09+0.81% respectively versus 1.25+0.36% (both p=ns) indicating non-genomic actions of testosterone. Hypertrophic markers and heart weights were elevated in XY littermates receiving supra-physiological testosterone but not in Tfm mice compared to placebo suggesting AR-dependent actions. This evidence suggests that supra-physiological levels of testosterone protect against diet induced aortic atheroma formation, at least in part, via non-genomic mechanisms but incur increased cardiovascular risk by potentially inducing cardiac hypertrophy via AR-dependent actions. Dose titration to physiological levels and careful monitoring of patients throughout treatment is key to eliciting the beneficial cardiovascular effects of TTh in hypogonadal men.

Recent Advances in Understanding the Pathogenesis of Cardiovascular Diseases and Development of Treatment Modalities.

Cardiovascular Diseases (CVDs) are a leading cause of morbidity and mortality worldwide. The underlying pathology for cardiovascular disease is largely atherosclerotic in nature and the steps include fatty streak formation, plaque progression and plaque rupture. While there is optimal drug therapy available for patients with CVD, there are also underlying drug delivery obstacles that must be addressed. Challenges in drug delivery warrant further studies for the development of novel and more efficacious medical therapies. An extensive understanding of the molecular mechanisms of disease in combination with current challenges in drug delivery serves as a platform for the development of novel drug therapeutic targets for CVD. The objective of this article is to review the pathogenesis of atherosclerosis, first-line medical treatment for CVD, and key obstacles in an efficient drug delivery.

Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis.

Inflammatory mediators, including blood cells and their products, contribute critically to atherogenesis, but the igniting triggers of inflammation remain elusive. Atherosclerosis develops at sites of flow perturbation, where the enhanced haemodynamic stress could initiate the atherogenic inflammatory process due to the occurrence of mechanic injury. We investigated the role of haemodynamic stress-induced breaches, allowing the entry of blood cells in the arterial intima, in triggering inflammation-driven atherogenesis. Human coronary samples isolated from explanted hearts, (n = 47) displayed signs of blood entry (detected by the presence of iron, ferritin, and glycophorin A) in the subintimal space (54%) as assessed by histology, immunofluorescence, high resolution episcopic microscopy, and scanning electron microscopy. Computational flow dynamic analysis showed that intimal haemorrhagic events occurred at sites of flow disturbance. Experimental carotid arteries from Apoe deficient mice showed discrete endothelial breaches and intimal haemorrhagic events specifically occurring at the site of flow perturbation, within 3 days after the exacerbation of the local haemodynamic stress. Endothelial tearing was associated with increased VCAM-1 expression and, within 7 days, substantial Ly6G+ leucocytes accumulated at the sites of erythrocyte-derived iron and lipids droplets accumulation, pathological intimal thickening and positive oil red O staining. The formation of fatty streaks at the sites of intimal breaches was prevented by the depletion of Ly6G+ leucocytes, suggesting that the local injury driven by haemodynamic stress-induced breaches triggers atherogenic inflammation. Haemodynamic-driven breaches of the arterial intima drive atherogenic inflammation by triggering the recruitment of leucocyte at sites of disturbed arterial flow.

Dyslipidemia in pregnancy and maternal-fetal outcome.

Hyperlipidemia is a known cause of atherosclerosis and directly contributes to the current epidemic in cardio-vascular disease. Pregnancy is typified by an increase in serum levels of total cholesterol and triglycerides pushed by the rise in estrogen, progesterone and lactogen. Mobilization of stored fat depots in late pregnancy may provide a reservoir of fatty acids for fetal growth and placental tissue steroid synthesis. This physiologic increase in lipids performs an essential role during pregnancy; however, elevated levels of lipids in predisposed women or with familiar forms of hyperlipidemia can carry increased risk for maternal-fetal complications. The present treatment of pregnant women with hyperlipidemia is the suspension of medications. However, hyperlipidemia during pregnancy is associated with preeclampsia, preterm birth and gestational diabetes and offspring of these mothers show a propensity to enhanced fatty streak formation and an increased risk of progressive atherosclerosis. This current evidence may motivate the further study on the potential benefits of treatment of hyperlipidemia in pregnancy and its effects on maternal-fetal outcomes.

Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia.

A murine genetic model of LDL-cholesterol- (LDL-C-) driven atherosclerosis, based on complete deficiencies of both the LDL-receptor (Ldlr−/−) and key catalytic component of an apolipoprotein B-edisome complex (Apobec1−/−), which converts apoB-100 to apoB-48, has been extensively characterized. These gene deficiencies allow high levels of apoB-100 to be present and inefficiently cleared, thus leading to very high levels of LDL-C in mice on a normal diet. Many key features of atherosclerotic plaques observed in human familial hypercholesterolemia are found in these mice as they are allowed to age through 72 weeks. The general characteristics include the presence of high levels of LDL-C in plasma and macrophage-related fatty streak formation in the aortic tree, which progressively worsens with age. More specifically, plaque found in the aortic sinuses contains a lipid core with relatively high numbers of macrophages and a smooth muscle cell α-actin- and collagen-containing cap, which thins with age. These critical features of plaque progression suggest that the Ldlr−/−/Apobec1−/− mouse line presents a superior model of LDL-C-driven atherosclerosis.

Abstract 222: Translocator Protein as Novel Marker for Early Atherosclerosis

Atherosclerosis is characterized by lipid deposition, monocyte infiltration and foam cell formation in the artery wall. Translocator protein (TSPO) is abundantly expressed in lipid rich tissues. Recently, TSPO has been identified as a potential diagnostic tool in cardiovascular disease. Here, we aimed to determine if (i) the TSPO radioligand, 18 F-PBR111, can identify fatty streak formation that precedes atherosclerotic lesion development and (ii) TSPO expression can be used to identify distinct macrophage populations during different stages of lesion progression. Atherosclerosis-prone apoE -/- mice were maintained on a high-fat diet for 3, 9 and 12 weeks. C57BL6 mice maintained on chow diet served as controls. Mice were anesthetized, injected with 18 F-PBR111 (8-18 MBq, 0.1 mL, 0.2 nM) via the lateral tail vein and imaged using an Inveon PET/CT Scanner over 60 min. After euthanasia, aortas were isolated, fixed and optically cleared. Cleared aortas were immunostained with DAPI, fluorescently labelled anti-TSPO antibody and the macrophage markers F4/80 and CD11b. Tissues were visualized on a Lightsheet Z.1 microscope and analysed with 3D imaging software. A 3-fold increase in the uptake of 18 F-PBR111 was observed by PET/CT in the aortas of atherosclerotic mice relative to controls. Increased 18 F-PBR111 uptake was observed in the aortic arch and thoracic aorta, corresponding with sites of atherosclerotic lesion development. Light sheet microscopy revealed that TSPO expression increased correspondingly to atherosclerosis progression. The expression pattern of macrophage populations in early lesions differed from that in mature plaques. While F4/80-positive macrophages were evident uniformly throughout the aortas, CD11b-positive macrophages were increased in atherosclerotic areas. In conclusion, imaging TSPO expression is a new approach for studying atherosclerotic lesion progression and is associated with specific inflammatory cell infiltration. The TSPO ligand 18 F-PBR111 is a potential clinical diagnostic tool for the detection and quantification of atherosclerotic lesion progression in humans.

Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion.

Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme's role in atherothrombosis remains scant. This study tested the hypothesis that PAD4 and NETs influence experimental atherogenesis and in processes implicated in superficial erosion, a form of plaque complication we previously associated with NETs. Bone marrow chimeric Ldlr deficient mice reconstituted with either wild-type or PAD4-deficient cells underwent studies that assessed atheroma formation or procedures designed to probe mechanisms related to superficial erosion. PAD4 deficiency neither retarded fatty streak formation nor reduced plaque size or inflammation in bone marrow chimeric mice that consumed an atherogenic diet. In contrast, either a PAD4 deficiency in bone marrow-derived cells or administration of DNaseI to disrupt NETs decreased the extent of arterial intimal injury in mice with arterial lesions tailored to recapitulate characteristics of human atheroma complicated by erosion. These results indicate that PAD4 from bone marrow-derived cells and NETs do not influence chronic experimental atherogenesis, but participate causally in acute thrombotic complications of intimal lesions that recapitulate features of superficial erosion.

Biological markers of oxidative stress and allopurinol therapy: A meta-analysis of randomized controlled trials

Aim: Oxidative stress contributes to the development of atherosclerosis via production of reactive oxygen species (ROS). Xanthine oxidase is an important enzyme that generates ROS and mediates oxidative modification of low-density lipoprotein (LDL) which is a key step in fatty streak and subsequent atheroma formation. Allopurinol is a xanthine oxidase inhibitor that has been shown to reduce the concentrations of the biological markers of oxidative stress. This meta-analysis was designed to summarize the effect of allopurinol treatment on markers of oxidative stress. Methods: Medline, PubMed, Pro Quest Health & Medical Complete, Clinical Key, Wiley Online Library, and Cochrane Central Register of Controlled Trials were searched till 29th July, 2017. Meta-analysis was planned for randomized controlled trials (RCTs) that investigated allopurinol effects on oxidative stress. A random-effect model was used to calculate the raw mean difference or the standardized mean difference (with 95% confidence intervals: CI) as an estimate of effect size. Heterogeneity was quantified by four types of information; Q-statistic, I2 statistic, T2, and T. Results: 37 eligible studies were identified; 14 were included in the final analysis and subdivided between two oxidative stress markers: there were 8 Malondialdehyde (MDA)-based studies (198 subjects) and 6 oxidized Low-density lipoprotein (Ox-LDL)-based studies (347 subjects). Allopurinol treatment was associated with a statistically significant reduction in mean MDA serum concentration, by 0.403 nmol/ml (95% CI; -0.618, -0.189) (P<0.001) and a non-significant reduction in Ox-LDL serum concentration assessed by the standardized mean difference, by 0.409 (95% CI; -1.332, 0.515) (P=0.386). Conclusion: The antioxidant potential of allopurinol has been confirmed by a significant reduction of the serum concentration of MDA in a heterogeneous group of patients and healthy adults. The non-significant reduction in Ox-LDL may reflect methodological differences. To confirm whether or not allopurinol has clinically relevant antioxidant properties, future studies require reproducible measurement techniques and clearer characterization and quantification in different patient groups.

Pu-erh Tea Ameliorates Atherosclerosis Associated with Promoting Macrophage Apoptosis by Reducing NF-κB Activation in ApoE Knockout Mice.

We explored whether pu-erh tea consumption ameliorates atherosclerosis and the possible mechanism for its effects in apolipoprotein E-deficient (ApoE−/−) mice. Our data showed that pu-erh tea consumption markedly reduced early fatty streak formation and the advanced fibrofatty plaque sizes. Additionally, the mean proportion of inflammatory macrophages in the plaque decreased, and the number of apoptotic macrophages increased significantly. NF-κB activity in peritoneal macrophages decreased by 75.6% compared to the controls, similar with the levels of IL-6, IL-12, and TNF-α expression. The tea extract increased the apoptosis of RAW264.7 cells by decreasing NF-κB activation and reducing the inflammatory cytokine expression. In conclusion, pu-erh tea ameliorates atherosclerosis progress by alleviating the chronic inflammatory state by reducing NF-κB activation and promoting macrophage apoptosis in atherosclerotic plaques.

Oxidative Stress in Cardiovascular Diseases: Involvement of Nrf2 Antioxidant Redox Signaling in Macrophage Foam Cells Formation.

Oxidative stress is an important risk factor contributing to the pathogenesis of cardiovascular diseases. Oxidative stress that results from excessive reactive oxygen species (ROS) production accounts for impaired endothelial function, a process which promotes atherosclerotic lesion or fatty streaks formation (foam cells). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in cellular redox homeostasis. Upon exposure to oxidative stress, Nrf2 is dissociated from its inhibitor Keap-1 and translocated into the nucleus, where it results in the transcriptional activation of cell defense genes. Nrf2 has been demonstrated to be involved in the protection against foam cells formation by regulating the expression of antioxidant proteins (HO-1, Prxs, and GPx1), ATP-binding cassette (ABC) efflux transporters (ABCA1 and ABCG1) and scavenger receptors (scavenger receptor class B (CD36), scavenger receptor class A (SR-A) and lectin-type oxidized LDL receptor (LOX-1)). However, Nrf2 has also been reported to exhibit pro-atherogenic effects. A better understanding on the mechanism of Nrf2 in oxidative stress-induced cardiac injury, as well as the regulation of cholesterol uptake and efflux, are required before it can serve as a novel therapeutic target for cardiovascular diseases prevention and treatment.

Vascular Calcification, Vitamin K and Warfarin Therapy - Possible or Plausible Connection?

Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast-like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone. The elevated stiffness of the arteries leads to severe vascular complications in brain, heart and kidneys. Recently, evidence from animal experiments as well as clinical and epidemiological results suggests that long-term treatment with warfarin, but not with the novel direct anticoagulants, can increase the risk or even induce vascular calcification in some individuals. Gamma-carboxylation is an enzymatic process not only needed for activation of vitamin K but also other proteins which participate in bone formation and vascular calcification. Thus, reduced expression of the vitamin K-dependent proteins which physiologically inhibit calcification of cellular matrix could be postulated to lead to vascular calcification. Published clinical data, describing at present a few thousand patients, need to be supplemented with controlled studies to confirm this interesting hypothesis.

Kimchi attenuates fatty streak formation in the aorta of low-density lipoprotein receptor knockout mice via inhibition of endoplasmic reticulum stress and apoptosis.

BACKGROUND/OBJECTIVESEndoplasmic reticulum (ER) stress is positively associated with atherosclerosis via elevating macrophage cell death and plaque formation, in which oxidative stress plays a pivotal role. Antioxidative, lipid-lowering, and anti-atherogenic effects of kimchi, a Korean fermented vegetable, have been established, wherein capsaicin, ascorbic acid, quercetin, 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid, and lactic acids were identified. In this study, mechanisms of action of kimchi methanol extracts (KME) on fatty streak formation via suppression of ER stress and apoptosis in aorta were examined in low-density lipoprotein receptor knockout mice.MATERIALS AND METHODSMice fed a high cholesterol diet with an oral administration of KME (KME group, 200 mg·kg-bw−1·day−1) or distilled water (control group) for 8 weeks (n = 20 for group). Plasma lipid and oxidative stress levels were evaluated. Protein expression was measured by western blot assay. Fatty streak lesion size and the degree of apoptosis were examined in the aorta.RESULTSCompared to the control group, in the KME group, plasma lipids levels were decreased and oxidative stress was alleviated (P < 0.05). Protein expression levels of nuclear factor (erythroid-derived 2)-like 2-mediated antioxidants in aorta were increased whereas those for ER stress markers, glucose regulated protein 78, phospho-protein kinase RNA-like ER kinase, phospho-eukaryotic initiation factor 2 subunit α, X-box binding protein 1, and C/EBP homologous protein were decreased in the KME group (P < 0.05). Moreover, apoptosis was suppressed via downregulation of phospho-c-Jun N-terminal kinase, bcl-2-associated X protein, caspases-9, and -3 with a concomitant upregulation of anti-apoptotic protein, B-cell lymphoma 2 (P < 0.05). Fatty streak lesion size was reduced and the degree of apoptosis was less severe in the KME group (P < 0.05).CONCLUSIONSIn conclusion, antioxidant activity of KME might prevent fatty streak formation through, in part, inhibition of ER stress and apoptosis in aortic sinus where macrophages are harbored.

The role of cholesterol-enriched diet and paraoxonase 1 inhibition in atherosclerosis progression.

Introduction: Atherosclerosis could be deemed as a chronic, progressive, and inflammatory disease. It has been well-documented that high-density lipoprotein (HDL) can reduce the risk of the atherosclerosis occurrence through exerting some anti-atherogenic mechanisms. In recent years, the strong evidence has suggested that paraoxonase 1 (PON1) may contribute to antioxidant properties of HDL. In the present study, the impact of a diet enriched with cholesterol and also the PON1 inhibition on atheroma formation and lipid profile has been investigated. Methods: In this study, 24 New Zealand rabbits were randomly assigned to three groups receiving standard diet, atherogenic diet, and atherogenic diet plus once daily intramuscular injection of nandrolone decanoate as the PON1 inhibitor. Triglyceride, cholesterol, HDL, and low-density lipoprotein (LDL) were determined and both cholesterol accumulation in aorta and fatty streak formation were evaluated. Results: The comparison of the results in three groups reveals that cholesterol level in the group received cholesterol-enriched diet plus once daily injection of PON1 inhibitor was higher than the groups received standard diet or atherogenic diet without PON1 inhibitor (P < 0.05). Furthermore, the percentage of atheroma with type-I lesions was equal to 75% compared with the group received atherogenic diet plus nandrolone at 30%. Additionally, the differences in fatty streak formation in aorta, as well as the right and left coronary arteries in three groups given show that the difference between groups receiving atherogenic diet and standard diet was significantly lower (P < 0.05) than the difference between groups receiving atherogenic diet plus PON1 inhibitor and standard diet. Conclusion: It can be concluded that lack of paraoxanase1 or even reduced the activity of this enzyme could accelerate the progression of fatty streak lesions toward advanced atherosclerotic lesions.

A Cure for Coronary Artery Disease

To cure coronary artery disease, complete removal of atheroma from coronary arteries is necessary and may be achieved using pharmacological intervention. This hypothesis requires verification by a trial. The conditions that lead to the formation of atheroma are as follows: Insulin resistance and vascular endothelial dysfunction, Atherogenic dyslipidemia, Risk factors for coronary artery disease, Inflammation of coronary arteries, Drugs that increase insulin resistance. Atheroma formation begins with the formation of fatty streaks on the endothelium, which progress into stable or unstable atheromatous plaques. The unstable plaque has a thin fibrous cap that is prone to rupture. Unstable plaques contain a large lipid pool consisting of oxidized low-density lipoprotein (LDL), apoB and cholesterol that can grow; they are also have heavy inflammatory cell infiltration, including monocytes, macrophages and T cell lymphocytes. Moreover, debris from ruptured macrophages that were overloaded with lipids attracts more macrophages. The plaque can grow and protrude into the coronary artery lumen. Plaques exhibit overgrowth of vasa vasorum and they can rupture, leading to the formation of a large thrombus that may severely or completely obstruct the coronary artery. Hemorrhage may also occur in the plaque. Carvedilol and metformin promote plaque stability. The supply of lipids to the lipid pool in the plaque is reduced by statins and evolocumab, and lipids are removed from the lipid pool by apoA-1 and high-density lipoprotein (HDL) as their levels in the blood are increased. Severe inflammation is treated with carvedilol, metformin, statins and apoA. Growth of vasa vasorum is attributed to insulin resistance and can be reversed by carvedilol and metformin, thereby preventing hemorrhage. The size of the thrombus on a ruptured plaque can also be reduced by carvedilol, metformin and apoA-1, as these three agents prevent platelet aggregation. Thrombi are removed by endothelial thrombolysis. A thrombus may also form in the plaque from intraplaque hemorrhage; if present, the size of this type of thrombus will be small, as vasa vasorum are atrophic. In both cases, thrombi are removed by endothelial thrombolysis. Subsequently, healthy macrophages infiltrate and remove debris, after which the plaque changes to a fibrous nodule that can be removed by endothelial fibrinolysis. The plaque is then completely removed.