Process Of Atherosclerosis Research Articles

DNA Methyltransferase 3b Accelerates the Process of Atherosclerosis.

Background DNA methylation plays a key role in establishing cell type–specific gene expression profiles and patterns in atherosclerosis. The underlying mechanism remains unclear. Previous studies have shown that DNA methyltransferase 3b (DNMT3b) may play an important role in atherosclerosis. This study aimed to establish the regulatory role of DNMT3b in the development of atherosclerosis. Methods We constructed a viral vector carrying Dnmt3b shRNA to transduce ApoE−/− mice. Meanwhile, healthy human peripheral blood Treg cells were treated with inhibitor of DNMT3b (AZA and EGCG) or transduced with DNMT3b shRNA. Results It showed that Dnmt3b silencing attenuated atherosclerosis, including decreased lesion size and macrophage content and increased collagen and smooth muscle cells content in ApoE−/− mice. To further investigate the possible mechanisms, combined with previous studies by our group, we showed that Foxp3-TSDR methylation level was significantly reduced Foxp3 expression and peripheral blood Treg levels were significantly increased by Dnmt3b shRNA vector transduction in animals committed to western diet for 12 and 18 weeks. Consistently, inhibition of DNMT3b (AZA and EGCG) decreased the expression levels of DNMT3b, which can increase the expression levels of FOXP3, and increase the levels of TGF-β and IL-10 and decrease the levels of IL-β and IFN-γ. After transduction with DNMT3b shRNA, the effect was more obvious. Conclusions DNMT3b accelerated atherosclerosis, and may be associated with FOXP3 hypermethylation status in regulatory T cells.

Elevated serum uric acid was associated with pre-inflammatory state and impacted the role of HDL-C on carotid atherosclerosis

Background and aimsUric acid (UA) and high-density lipoprotein cholesterol (HDL-C) are positively and negatively associated with atherosclerosis, respectively. UA and HDL-C are involved in the balance of proinflammatory and anti-inflammatory processes in atherosclerosis. However, it is still unclear whether UA affects the effect of HDL-C on atherosclerosis. Methods and resultsIn this retrospective study, we enrolled 1437 patients with multiple risk factors for atherosclerosis. Patients were categorized into two groups according to their baseline UA level. Multivariate logistic regression analysis and restricted cubic spline curves were used to assess the relationship between HDL-C and carotid atherosclerosis (abnormal carotid intima–media thickness [cIMT] and carotid artery plaque) at different UA levels. Compared to patients with normouricemia, patients with hyperuricemia were older and had a more extensive history of disease and unhealthy behavior. In the normouricemia group, multivariate-adjusted odds ratios (95% CIs) for HDL-C were 0.55 (0.33–0.92) for abnormal mean cIMT, 0.59 (0.35–1.00) for abnormal maximum cIMT, and 0.53 (0.29–0.94) for the occurrence of carotid artery plaque, while the correlation between each of these three indicators with HDL-C were not significant in those with hyperuricemia. Spline regression models yielded similar results. The effect of UA on the association between HDL-C and carotid atherosclerosis remained in the subset of patients with optimal low-density lipoprotein cholesterol. ConclusionElevated UA marks a pre-inflammatory state and impacts the role of HDL-C on carotid atherosclerosis.

Immune system and atherosclerosis: Hostile or friendly relationship.

Coronary artery disease has remained a major health challenge despite enormous progress in prevention, diagnosis, and treatment strategies. Formation of atherosclerotic plaque is a chronic process that is developmentally influenced by intrinsic and extrinsic determinants. Inflammation triggers atherosclerosis, and the fundamental element of inflammation is the immune system. The immune system involves in the atherosclerosis process by a variety of immune cells and a cocktail of mediators. It is believed that almost all main components of this system possess a profound contribution to the atherosclerosis. However, they play contradictory roles, either protective or progressive, in different stages of atherosclerosis progression. It is evident that monocytes are the first immune cells appeared in the atherosclerotic lesion. With the plaque growth, other types of the immune cells such as mast cells, and T lymphocytes are gradually involved. Each cell releases several cytokines which cause the recruitment of other immune cells to the lesion site. This is followed by affecting the expression of other cytokines as well as altering certain signaling pathways. All in all, a mix of intertwined interactions determine the final outcome in terms of mild or severe manifestations, either clinical or subclinical. Therefore, it is of utmost importance to precisely understand the kind and degree of contribution which is made by each immune component in order to stop the growing burden of cardiovascular morbidity and mortality. In this review, we present a comprehensive appraisal on the role of immune cells in the atherosclerosis initiation and development.

Mid-Term Clinical Outcomes Following Drug-Coated Balloons in Coronary Artery Disease.

Objective: The aim of this study was to evaluate the mid-term efficacy of drug-coated balloons (DCB) in percutaneous coronary intervention (PCI) in two different pathophysiologic scenarios. Background: There are different underlying pathological processes in coronary artery disease. Mid-term safety and efficacy of DCB approach is still limited. Methods: Medical records of all consecutive patients undergoing DCB were evaluated. The primary endpoint was the rate of clinically driven target lesion revascularization (TLR) after 24 months. Results: Between January 2011 and December 2017, 442 patients were included, representing 4.4% of all PCIs in our institution. A total of 460 DCB lesions were treated, of which 328 (71.3%) were de novo and 132 (28.7%) were combined bare metal or drug-eluting stents with in-stent restenosis (ISR). The patients’ mean age was 66.2 ± 11.7 years with a diabetes prevalence of 45.3%. The TLR rate was lower in the de novo group (5.3%) compared to the ISR group (9.4%) (p = 0.04). No differences were observed in major adverse cardiovascular events (MACE) between the de novo group (38.9%) and ISR group (42.5%) (p = 0.47). No significant differences were detected in the TLR occurrence in the subgroup analysis. Conclusion: Our extended experience demonstrates that the mid-term DCB approach in these two pathophysiologic settings represent a reasonable option, with low TLR rate.

Comparison between Traditional Chinese Medicine Constitution and Blood Biochemical Markers Associated with Left and Right Mammary Hyperplasia in Rural Areas of Southwest China.

Background Hyperplasia of mammary glands (HMG) is the breast disease with the highest clinical incidence. Many traditional Chinese medicine (TCM) doctors suggest that the treatment of HMG should be based on the left and right breast pain difference. However, these views are based on case reports, and an objective basis has not been established for treatment according to left-side and right-side differences. Methods We enrolled 150 patients who met the clinical diagnostic criteria of HMG. The incidence bias was determined according to the score difference between bilateral breast pain and mass in patients with HMG. A left group, right group, and bilateral group were included, and TCM constitution was investigated in each group. Blood biochemical indicators were measured for 120 fasting patients. We conducted a network pharmacology study of the key herb qingpi and chenpi, which are used by TCM doctors to treat different lateral HMG. Results In patients with biased onset of HMG, the results showed that the frequency and constitution score of stagnant blood in the L group were higher than those of the R group, and the frequency and constitution score of phlegm-dampness in the R group were higher than those of the L group. Both the L and R groups had high proportion of stagnant Qi. The results indicated that the concentration of coagulation factor VIII (FVIII) was higher in the L group than that in the R group, and the concentration of lipoprotein a (Lp-α) was higher in the R group than that in the L group. The results showed that sinensetin and neohesperidin contained in qingpi might interfere with platelet activation, thrombogenesis, prolactin signaling pathway, and atherosclerosis process, in removing “blood stasis” and eventually treating the left-leaning group of HMG patients. Sitosterol and citromitin contained in chenpi could regulate lipid metabolism by interfering with regulation of lipolysis in adipocytes, salivary secretion, estrogen signaling pathway, and thyroid hormone signaling pathway. Chenpi could eliminate “phlegm turbidity” and treat HMG patients in the right-leaning group. Conclusions We preliminarily confirmed that the clinical pathogenesis of HMG is not a left-right equilibrium and TCM constitution, coagulation function, and lipid metabolism may be used as the objective basis for the difference between the left and right in HMG pathogenesis. For left-sided HMG patients, the doctor can consider qingpi, herb of activating blood and removing stasis, to treat HMG. However, for right-sided HMG, we think doctors should apply herb of activating Qi and eliminating phlegm, such as chenpi.

Hsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis

Endothelial dysfunction is the initial process of atherosclerosis. Heat shock protein 90 (Hsp90), as a molecular chaperone, plays a crucial role in various cardiovascular diseases. Hsp90 function is regulated by S-nitrosylation (SNO). However, the precise role of SNO-Hsp90 in endothelial dysfunction during atherosclerosis remains unclear. We here identified Hsp90 as a highly S-nitrosylated target in endothelial cells (ECs) by biotin switch assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The elevation of SNO-Hsp90 was observed in atherosclerotic human and rodent aortas as well as in oxidized LDL (oxLDL)-treated ECs. Inhibition of inducible nitric oxide synthase (iNOS) or transfection with Hsp90 cysteine 521 (Cys521) mutation plasmid decreased the level of SNO-Hsp90 in oxLDL-cultured ECs. Coimmunoprecipitation and proximity ligation assay demonstrated that SNO-Hsp90 at Cys521 suppressed the interaction between Hsp90 and activator of Hsp90 ATPase activity 1 (AHA1), but promoted the association of Hsp90 and cell division cycle 37 (CDC37). Hsp90 Cys521 mutation increased endothelial nitric oxide synthase (eNOS) activity and inhibited nuclear factor kappa-B (NF-κB) signaling, thereby increasing nitric oxide (NO) bioavailability and alleviating endothelial adhesion, inflammation and oxidative stress in oxLDL-treated ECs. Also, administration of endothelial-specific adeno-associated viruses of Cys521-mutated Hsp90 significantly mitigated vascular oxidative stress, macrophage infiltration and atherosclerosis lesion areas in high fat diet-fed ApoE-/- mice. In conclusion, SNO-Hsp90 at Cys521, that serves as a conformational switch, disrupts Hsp90/AHA1 interaction but promotes recruitment of CDC37 to exacerbate atherosclerosis.

Imbalance of NK cell subpopulations and polymorphisms of proinflammatory cytokine genes in the pathogenesis of atherosclerosis

Understanding the pathogenetic mechanism of development and identifying trigger markers of the disease will significantly increase the efficiency of pre-nosological diagnosis and medical follow-up of patients. In this case, one should take into account the role of mutations in cytokine genes, which affect their biochemical activity and production level. The objective of the study was to investigate the role of mediators of acute and chronic inflammation (IL-17A, IL-1â, TNFá and IL-4), the ratio of natural killer cell subpopulations (CD56hiCD16-/CD56loCD16+) in pathogenesis of coronary atherosclerosis resulting into coronary heart disease.To analyze the results, an integrated approach was used, including molecular genetic methods such as polymerase chain reaction, typing of single-nucleotide substitutions in cytokine genes, isolation and cultivation of peripheral blood mononuclear cells, assessment of spontaneous and in vitro-induced production of immune system mediators, enzyme-linked immunosorbent assay, cytotoxic test, flow cytometry with monoclonal antibodies (Beckman Coulter, USA) to CD16, CD56 NK markers.The study included 130 residents of the North Caucasus, including the patients (n = 62) treated at the Cardiology Department of the Adyghe Republican Clinical Hospital (ARCB) with a verified diagnosis of ischemic heart disease (IHD), and a control group (n = 68), represented by unrelated healthy donors.Overexpression of cytokines in IHD patients was associated with distinct single nucleotide substitutions in certain genes. Studying a group of residents from the Republic of Adygeya, the authors experimentally established that harboring the 511C allele of the IL-1â gene (p < 0.0004; OR = 4.67), A197A of the IL-17A gene genotype (p < 0.04; OR = 3.88), G308 SNP of TNFá gene (p < 0.01; OR = 3.41), and 589T variant of IL-4 gene (p < 0.04; OR = 2.45) are associated with hyperproduction of the first-wave inflammatory mediators that increase the risk of developing ischemic heart disease. In atherosclerosis and associated cardiovascular diseases, we have noted a significant decrease in spontaneous and induced activity of natural killer cells involved in the utilization of “foamy cells”. The NK activity of peripheral blood mononuclear cell in patients with coronary heart disease is significantly reduced. In the IHD patients, an imbalance of phenotypically and functionally different CD56hiCD16-/CD56loCD16+ NK subpopulations with a predominance of CD56hiCD16- phenotype were revealed. Conclusions: Immuno-inflammatory mechanisms of evolving coronary atherosclerosis are associated with single-nucleotide substitutions, i.e., polymorphisms in the promoter regions of the IL-17A (G197A), IL-1 â (T511C), and TNFá (G308A), the known mediators of acute and chronic inflammation.Genetically determined overexpression of IL-17A, IL-1â, and TNFá, confirmed in experiments on evaluation of spontaneous and stimulated cytokine production in patients with CHD, together with reduced NK activity of РВМС, due to predominance of CD56hiCD16-, a subpopulation with high cytokine production, manifested by an increased pro-inflammatory component that triggers and provides long-term support to pathophysiological processes of atherosclerosis.

Enhancer promoter interactome and Mendelian randomization identify network of druggable vascular genes in coronary artery disease

Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.

Aggressive lipid-lowering therapy after percutaneous coronary intervention - for whom and how?: Aggressive lipid-lowering therapy after PCI.

Percutaneous coronary intervention (PCI) has been established as a definitive method to treat obstructive coronary artery disease. The procedure on its own, however, is insufficient to ensure optimal long-term patient outcomes as it is also necessary to achieve good control of relevant risk factors. The process of atherosclerosis as a result of dyslipidaemia is a risk continuum and secondary preventive measures for patients who have undergone PCI are of paramount importance to mitigate the risk of procedural failure and further cardiovascular events. This review aims to provide an overview of the landscape of lipid-lowering therapy for the purpose of secondary prevention by summarising recommendations derived from contemporary guidelines and highlighting the rationale and evidence behind the three main lipid-lowering therapies, namely statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. It also provides insights into real-world challenges and issues surrounding secondary prevention of dyslipidaemia such as suboptimal lipid goal attainment and nonadherence, and assesses the possible methods to overcome them.

Transcriptomic modulation in response to high-intensity interval training in monocytes of older women with type 2 diabetes.

Type 2 diabetes is associated with a higher risk of cardiovascular diseases, lowering the quality of life and increasing mortality rates of affected individuals. Circulating monocytes are tightly involved in the atherosclerosis process leading to cardiovascular diseases (CVD), and their inflammatory profile can be modified by exercise. The objective was to exploratory identify genes associated with CVD that could be regulated by high-intensity interval training (HIIT) in monocytes of type 2 diabetes patients. Next-generation RNA sequencing (RNA-seq) analyses were conducted on isolated circulating monocytes (CD14+) of six women aged 60 and over with type 2 diabetes who completed a 12-week supervised HIIT intervention on a treadmill. Following the intervention, a reduction of resting diastolic blood pressure was observed. Concomitant with this result, 56 genes were found to be downregulated following HIIT intervention in isolated monocytes. A large proportion of the regulated genes was involved in cellular adhesion, migration and differentiation into an "atherosclerosis-specific" macrophage phenotype. The downregulation of transcripts in monocytes globally suggests a favorable cardiovascular effect of the HIIT in older women with type 2 diabetes. In the context of precision medicine and personalized exercise prescription, shedding light on the fundamental mechanisms underlying HIIT effects on the gene profile of immune cells is essential to develop efficient nonpharmacological strategies to prevent CVD in high-risk population.

Cathepsin S are involved in human carotid atherosclerotic disease progression, mainly by mediating phagosomes: bioinformatics and in vivo and vitro experiments.

BackgroundAtherosclerosis emerges as a result of multiple dynamic cell processes including endothelial damage, inflammatory and immune cell infiltration, foam cell formation, plaque rupture, and thrombosis. Animal experiments have indicated that cathepsins (CTSs) mediate the antigen transmission and inflammatory response involved in the atherosclerosis process, but the specific signal pathways and target cells of the CTSs involved in atherosclerosis are unknown.MethodsWe used the GEO query package to download the dataset GSE28829 from the Gene Expression Omnibus (GEO) and filtered the data to check the standardization of the samples through the box chart. We then used the ‘limma’ package to analyze between-group differences and selected the corresponding differentially expressed genes of CTSs from the protein-protein interaction (PPI) network constructed with the STRING database, and then visualized the CTS-target genes. The best matching pathway and target cells were verified by a male mouse ligation experiment, single-sample GSEA (ssGSEA) analysis, and vitro experiment.ResultsThere were 275 differentially expressed genes (DEGs) selected from the GSE28829 dataset, and the DEGs were identified mainly in the PPI network; 58 core genes (APOE, CD74, CP, AIF1, etc.) target three selected CTS family members (CTSS, CTSB, and CTSC). After the enriched analysis, 15 CTS-target genes were markedly enriched in the phagosome signaling pathway. The mouse experiment results revealed that the percentages and numbers of monocytes and neutrophils and the number of CD68+ cells in CTSS deficiency (CatS−/−) group were lower than those in the wildtype (CatS+/+) group. CTSS mediating phagosome via macrophage were further verified by ssGSEA analysis and vitro experiment.ConclusionsCTSS are the main target molecules in the CTS family that are involved in atherosclerosis. The molecule participate in the progression of atherosclerosis by mediating the phagosome via macrophage.

Expression ratio of circular to linear ANRIL in hypertensive patients with coronary artery disease

Atherosclerotic lesions of the coronary arteries are still in charge of significant annual morbidity and mortality despite intense therapeutic advancements. Genome-born elements contribute substantially to the atherosclerosis process. ANRIL is one of the long non-coding RNAs with outstanding functions particularly regulation of genes involved in atherosclerosis development. In this study, we measured ANRIL expression (circular-, linear-, and circular/linear ratio) in hypertensive patients with coronary artery disease (CAD) compared with peers without CAD. Among hypertensive patients who were candidates of angiography, 25 subjects with CAD and the equal number without CAD were considered as the case and control groups, respectively. Different categories of data were recorded through a predefined questionnaire. Before angiography, blood samples were obtained. After RNA extraction and cDNA synthesis, quantitative PCR was performed using specific primers for circular and linear ANRIL. Age and gender were not different between the groups. Most of the parameters of the lipid profile besides creatinine and blood urea nitrogen were remarkably worse in the case group. Circular ANRIL was significantly lower in the case group while linear counterparts were significantly higher in this group. Circular/linear ratio was also significantly lower in the case group. To overcome growing devastating trend of CAD, scrutinizing different factors involved in the initiation and development of atherosclerosis is a must. Atheroprotective role of circular ANRIL and atheroprogressive role of linear ANRIL were shown in our patients with hypertension.

The potential roles of RNA N6-methyladenosine in atherosclerosis.

Atherosclerosis, characterized by endothelial injury, multicellular involvement, chronic inflammation, and lipid deposition, can lead to acute cardiovascular events. N6-methyladenosine (m6A) is the most abundant, prevalent RNA modification in mammalian cells. m6A, a reversible modification, can be catalyzed by m6A methyltransferase complexes (writers), reverted by demethylases (erasers), and recognized by m6A-binding proteins (readers). Emerging evidence suggests that m6A modification plays a significant role in regulating many biological and cellular processes in atherosclerosis. In this review, we highlight the biological function of m6A modification and give a brief perspective on its future applications in atherosclerosis. This is a narrative review. The literature search strategy for indexed Scopus articles was performed randomly using PubMed and MEDLINE as the primary sources. No specific term was used. As the mechanism of the relationship between inflammatory response and atherosclerosis, m6A has become a new focus in the study of clinical treatment strategies for atherosclerosis. METTL14-dependent m6A modification may be a target for atherosclerosis therapy. A variety of m6A regulatory factors promote the progression of atherosclerosis by regulating polarization and inflammation of macrophages. WTAP and METTL14 can affect the phenotypic modulation of VSMCs through m6A modification. The existence of m6A in cardiovascular transcripts is necessary to maintain cardiac function, and the level of m6A modification is increased in a variety of atherosclerotic vascular cells, indicating that m6A modification is involved in the pathophysiological process of atherosclerosis. m6A modification plays an important character in atherosclerosis.

MiR-155 activates the NLRP3 inflammasome by regulating the MEK/ERK/NF-κB pathway in carotid atherosclerotic plaques in ApoE-/- mice.

Atherosclerosis is an inflammatory disease. The NLRP3 inflammasome and miR-155 are significant components of inflammation and atherosclerosis. The aim of this research was to explore the possible mechanism by which miR-155 mediates the formation of carotid atherosclerotic plaques via the NLRP3 inflammasome. Fifty 6-week-old male ApoE-/- mice were randomly divided into 5 groups. They are the blank group, the negative control (NC) group, the miR-155 mimic group, the miR-155 inhibitor group, and the miR-155 mimic and ERK inhibitor group. The blood lipid levels were measured by the enzyme method Oil red O, HE, and immunohistochemical staining were used to observe the degree of carotid plaque formation. PCR was used to measure the expression of miR-155. The blood lipid levels were measured by the enzyme method. Western blotting was used to measure the expression of NLRP3 inflammasome-related proteins, interleukin-1β, interleukin-18, and MEK/ERK/NF-κB signaling pathway-related proteins. Compared with those of the NC group, the expression of miR-155 in the miR-155 mimic group increased significantly (P < 0.05), the degree of carotid plaque formation increased, the plasma levels of TC and LDL also increased significantly (P < 0.05); the expression levels of NLRP3 inflammasome-related proteins, interleukin-1β, interleukin-18, and MEK/ERK/NF-κB signaling pathway-related proteins were also significantly increased. Injection of ERK inhibitors into miR-155 mimic mice reduced the expression levels of p-NF-κB, NLRP3 inflammasome-related proteins, and inflammatory cytokines. In conclusion, miR-155 can promote the formation of atherosclerotic plaque in ApoE-/- mice, which may be achieved by regulating the MEK/ERK/NF-κB pathway to activate the NLRP3 inflammasome. HIGHLIGHTS: • In ApoE-/- mice, miR-155 promotes atherosclerotic plaque formation. • The NLRP3 inflammasome has an important role in the inflammatory process of atherosclerosis. • miR-155 activates the NLRP3 inflammasome by regulating the MEK/ERK/NF-κB pathway in carotid atherosclerotic plaques of ApoE-/- mice.

Protein Phosphatase 2A Deficiency in Macrophages Increases Foam Cell Formation and Accelerates Atherosclerotic Lesion Development.

Protein phosphatase 2A (PP2A), a crucial serine/threonine phosphatase, has recently been reported to play an important role in cardiovascular disease. Previous studies have hinted that PP2A is involved in atherosclerosis formation, but the associated mechanisms remain poorly understood. In this study, we investigate the role of PP2A in the pathogenesis of atherosclerosis. In human atherosclerotic coronary arteries, we found that the expression and activity of PP2A decreased significantly when compared to non-atherosclerotic arteries. Additional experiments demonstrated that pharmacological inhibition of PP2A aggravated atherosclerosis of ApoE−/− mice. Considering the central role of macrophages in atherosclerosis, mice with conditional knockout of the PP2A-Cα subunit in myeloid cells were produced to investigate the function of PP2A in macrophages. Results showed that PP2A deficiency in myeloid cells aggravated atherosclerotic lesions in mice. in vitro experiments indicated that PP2A-deficient macrophages had an enhanced ability of lipid uptake and foam cell formation. Mechanistically, the deficiency of the PP2A in macrophages led to an increase in the phosphorylation level of p38, which contributed to the elevated expression of scavenger receptor CD36, a key factor involved in lipoprotein uptake. Our data suggest that PP2A participates in the pathophysiological process of atherosclerosis. The decrease of PP2A expression and activity in macrophages is a crucial determinant for foam cell formation and the initiation of atherosclerosis. Our study may provide a potential novel approach for the treatment of atherosclerosis.

The Function, Regulation and Mechanism of Programmed Cell Death of Macrophages in Atherosclerosis.

Atherosclerosis is a chronic progressive inflammatory vascular disease, which is an important pathological basis for inducing a variety of cardio-cerebrovascular diseases. As a kind of inflammatory cells, macrophages are the most abundant immune cells in atherosclerotic plaques and participate in the whole process of atherosclerosis and are the most abundant immune cells in atherosclerotic plaques. Recent studies have shown that programmed cell death plays a critical role in the progression of many diseases. At present, it is generally believed that the programmed death of macrophages can affect the development and stability of atherosclerotic vulnerable plaques, and the intervention of macrophage death may become the target of atherosclerotic therapy. This article reviews the role of macrophage programmed cell death in the progression of atherosclerosis and the latest therapeutic strategies targeting macrophage death within plaques.

RISK FACTORS OF CORONARY HEART DISEASE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Highlight:1. One of the major causes of morbidity and mortality in diabetes mellitus patients is coronary heart disease (CHD).2. The risk factors for coronary heart disease in type 2 diabetes mellitus patients were observed.3. The risk factors of CHD more commonly found in T2DM patients were high-risk age, male sex, hypertension and dyslipidemia.Abstract:Background: Diabetes mellitus is a metabolic syndrome that becomes a concern in almost all countries in the world, particularly developing countries. Changes in lifestyle and genetic factors are causing the incidence of this disease to continue to increase every year. Nowadays, type 2 diabetes mellitus (T2DM) caused by insulin resistance is the most common kind. One of its complications known as a major cause of morbidity and mortality in patients with diabetes is coronary heart disease (CHD). Insulin resistance can lead to the atherosclerosis process that is the basis of coronary heart disease. It is said that conditions of hyperglycemia, hypercoagulable state, and high cholesterol can induce the process of atherosclerosis. Besides diabetes mellitus, the other risk factors that increase the incidence of CHD are sex, age, family history, dyslipidemia, smoking, hypertension, and obesity. Objective: The purpose of this study was to describe the risk factors for coronary heart disease in patients with type 2 diabetes mellitus in Dr. Soetomo General Academic Hospital, Surabaya, Indonesia. Materials and Methods: A cross-sectional study of diabetes mellitus patients with coronary heart disease was conducted in Dr. Soetomo General Academic Hospital from 1 January 2014 to 31 December 2014. Data were taken from medical records at the Department of Internal Medicine. Incomplete medical records were not included in this study. Risk factors analyzed were age, sex, history of hypertension and dyslipidemia. Results of this study were presented in a frequency distribution table. Results: Based on the data of 70 samples, risk factors of CHD in T2DM patients are found as follows: 44 (62.9%) samples were male, 56 (80%) high-risk aged group, 48 (68.6%) with dyslipidemia, and 50 (71.4%) with hypertension, while 24 (34.3%) samples had three risk factors at once. Conclusion: High-risk aged, male sex, hypertension, and dyslipidemia are more commonly found in T2DM patients with CHD. The more risk factors that one may have will increase the occurrence of cardiovascular disease within 10 years forward.

Atherosclerosis and multiple sclerosis: An overview on the prevalence of risk factors

BackgroundAtherosclerosis is the leading cause of ischemic heart disease and coronary artery disease. The process of atherosclerosis develops over a period of years and is mainly immune-mediated. Data regarding the prevalence of vascular disease and atherosclerosis among people with multiple sclerosis (pwMS) is inconsistent, therefore, we aimed to provide an overview of the prevalence of atherosclerotic risk factors in pwMS. MethodsThis is a cross-sectional study over a period of one year among pwMS visiting the Isfahan MS center. Study data have been extracted using participants’ files and a checklist that was completed by the observers. Only people with relapsing-remitting (RRMS) and secondary progressive (SPMS) forms of MS were included in the study. Participants with primary progressive (PPMS) disease are only described and have been excluded from analyses. ResultsOf the 396 pwMS (343 with RRMS and 53 with SPMS), in descending order, the reported risk factors were tobacco smoking (18.4%), dyslipidemia (10%), hypertension (8.8%), and diabetes mellitus (4.5%). In people with RRMS, 17.4% were smokers, 9.9% had dyslipidemia, 8.1% had hypertension, and 4.3% had diabetes mellitus. In SPMS patients 24.5% reported a history of smoking, 13.2% had hypertension, 9.4% had dyslipidemia, and 3.7% had diabetes mellitus. Smoking was insignificantly associated with higher expanded disability status scale (Z: 1.70, p-value = 0.090). Male sex (RR [95%CI]: 1.628 [1.172, 2.261], p-value = 0.004) and increasing age (RR [95%CI]: 1.024 [1.008, 1.040], p-value = 0.003) were associated with a higher number of risk factors. ConclusionThe highest observed atherosclerosis risk factor among pwMS was smoking. Diabetes mellitus was the least reported risk factor in our population as a whole. Overall, and in participants with RRMS, dyslipidemia and hypertension were the second and third most commonly reported risk factors, however, hypertension exceeded dyslipidemia in participants with SPMS. Male sex and increasing age were associated with a higher number of atherosclerosis risk factors.

HDL and Oxidation.

In this chapter, we will focus on HDLs' activity of inhibiting LDL oxidation and neutralizing some other oxidants. ApoA-I was known as the main antioxidant component in HDLs. The regulation of antioxidant capacity of HDL is mainly exhibited in regulation of apoA-I and alterations at the level of the HDL lipidome and the modifications of the proteome, especially MPO and PON1. HDL oxidation will influence the processes of inflammation and cholesterol transport, which are important processes in atherosclerosis, metabolic diseases, and many other diseases. In a word, HDL oxidation might be an effective antioxidant target in treatment of many diseases.

Minimally Oxidized-LDL-Driven Alterations in the Level of Pathological Mediators and Biological Processes in Carotid Atherosclerosis.

The global burden of cerebrovascular disease, especially cerebral infarction has been increasing at an alarming rate with the atherosclerosis in carotid arteries as the primary risk factor. Despite the active involvement of minimally oxidized LDL (oxLDL) in atherosclerosis, limited information is available regarding the role of oxLDL in the pathogenesis of cerebrovascular diseases. The present study utilized the carotid bifurcation tissues and isolated carotid SMCs challenged with oxLDL from clinically relevant minimally invasive minimally-oxLDL-induced carotid atheroma microswine model to examine the levels of pro-atherogenic and pro-inflammatory mediators and cellular processes following immunostaining approaches. The immunopositivity of IL18, PDGFRA, IL17, LOX1, TLR4, MYF5, IL1B, and PDPN were increased in the carotid artery bifurcation tissues with a concomitant decrease in DAMPs, HMGB1 and S100B in oxLDL (600μg)-treated group compared to non-intervention control. Moreover, the cultured SMCs displayed increased level of IL18, LOX1, TLR4, MYF5, NLRP3, and PDPN upon challenging with oxLDL (100 mg/ml) compared to non-treatment control. In addition, the SMCs treated with oxLDL were resistant to the peroxidation of lipids as evident from lipid peroxidation staining. Also, the oxLDL displayed compromised mitochondrial membrane potential based on mitochondrial pore transition assay and increased hypertrophy due to decreased level of microtubules. Overall, oxLDL alters the expression status of pathological mediators and multiple biological processes in carotid SMCs aggravating carotid atherosclerosis. The understanding regarding the molecular mechanisms underlying oxLDL-driven pathological events would open novel translational avenues in the management of carotid atherosclerosis.