Inflammatory Process Of Atherosclerosis Research Articles

Stilbene glycosides alleviate atherosclerosis partly by promoting lipophagy of dendritic cells

Atherosclerosis (AS) is a chronic inflammatory disease resulting from lipid metabolism disorders and immune imbalances. Dendritic cells (DCs) are key cells that regulate adaptive and adaptive immunity. When DCs engulf excessive amounts lipids, their function is altered, thereby, accelerating the inflammatory process of AS. Cellular lipophagy serves to reduce lipid accumulation and maintain cellular lipid metabolism balance. In this study, we investigated the effectiveness of 2,3,5,4′-tetrahydroxystilbene 2-O-β-D-glucoside (TSG) in intervening in the promotion of DCs lipid accumulation by ox-LDL, as well as its role in downregulating lipophagy. Our findings indicate that TSG reduces the maturity of DCs and promotes the differentiation of T cells towards Treg, thereby correcting the imbalanced Treg/Th17. These effects of TSG are closely associated with its inhibition of the PI3K-AKT-mTOR signaling pathway. After administering TSG to ApoE-/- mice that were fed a high-fat diet, there was a noticeable decrease in harmful blood lipids found in the serum. Additionally, the imbalanced Treg/Th17 levels in the spleen were restored, and the levels of pro-inflammatory factor IL-6 and IL-17A in the serum decreased, while the level of anti-inflammatory factor IL-10 increased. Furthermore, the arterial DCs showed a decrease in P62 content. Ultimately, these changes resulted in a reduction in plaque area. It is worth noting that the autophagy inhibitor chloroquine significantly altered the effects of TSG on ApoE-/- mice. In conclusion, this study reveals that TSG can alleviate AS. This is partly achieved through the activation of autophagy in DCs. By intervening in the lipophagy of DCs, it is possible to regulate the immune function of these cells, which in turn helps control the inflammation associated with AS. This presents a potential method for intervening in AS.

Actinidia arguta Extract Containing Myo-Inositol Suppresses TNF-α-Induced VCAM-1 Expression and Monocyte Adhesion to Endothelial Cells via Inhibition of the PTEN/Akt/GSK-3β and NF-κB Signaling Pathways.

The primary inflammatory process in atherosclerosis, a major contributor to cardiovascular disease, begins with monocyte adhering to vascular endothelial cells. Actinidia arguta (kiwiberry) is an edible fruit that contains various bioactive components. While A. arguta extract (AAE) has been recognized for its anti-inflammatory characteristics, its specific inhibitory effect on early atherogenic events has not been clarified. We used tumor necrosis factor-α (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs) for an in vitro model. AAE effectively hindered the attachment of THP-1 monocytes and reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Transcriptome analysis revealed that AAE treatment upregulated phosphatase and tensin homolog (PTEN), subsequently inhibiting phosphorylation of AKT and glycogen synthase kinase 3β (GSK3β) in HUVECs. AAE further hindered phosphorylation of AKT downstream of the nuclear factor kappa B (NF-κB) signaling pathway, leading to suppression of target gene expression. Oral administration of AAE suppressed TNF-α-stimulated VCAM-1 expression, monocyte-derived macrophage infiltration, and proinflammatory cytokine expression in C57BL/6 mouse aortas. Myo-inositol, identified as the major compound in AAE, played a key role in suppressing THP-1 monocyte adhesion in HUVECs. These findings suggest that AAE could serve as a nutraceutical for preventing atherosclerosis by inhibiting its initial pathogenesis.

ApoB100 and Atherosclerosis: What's New in the 21st Century?

ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.

Exercise-based cardiac rehabilitation in stable angina pectoris: anarrative review on current evidence and underlying physiological mechanisms.

Stable angina pectoris (SAP) is aprevalent condition characterised by ahigh disease burden. Based on recent evidence, the need for revascularisation in addition to optimal medical treatment to reduce mortality and re-events is heavily debated. These observations may be explained by the fact that revascularisation is targeted at the local flow-limiting coronary artery lesion, while the aetiology of SAP relates to the systemic, inflammatory process of atherosclerosis, causing generalised vascular dysfunction throughout the entire vascular system. Moreover, cardiovascular events are not solely caused by obstructive plaques but are also associated with plaque burden and high-risk plaque features. Therefore, to reduce the risk of cardiovascular events and angina, and thereby improve quality of life, alternative therapeutic approaches to revascularisation should be considered, preferably targeting the cardiovascular system as awhole with aphysiological approach. Exercise-based cardiac rehabilitation fits this description and is apromising strategy as afirst-line treatment in addition to optimal medical treatment. In this review, we discuss the role of exercise-based cardiac rehabilitation in SAP in relation to the underlying physiological mechanisms, we summarise the existing evidence and highlight future directions.

Sustained inflammation and high cortisol reactivity following an coronary event

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Heart and lung foundation Sweden. Background Over the last decades, significant improvements have been made in medical and lifestyle managements of patients with coronary artery disease (CAD). Nonetheless, "residual inflammatory risk" for recurrent cardiovascular events is high in this patient group and remains a diagnostic and therapeutic challenge. Activation of the NLRP3 inflammasome, involving release of interleukin (IL)-1β and IL-18 followed by their downstream target IL-6, is considered a major component of the inflammatory process in atherosclerosis. One major immunomodulator is the hypothalamic–pituitary–adrenal (HPA) axis. Interestingly, there is increasing evidence that cortisol exerts proinflammatory effects through the induction of NLRP3 expression. Purpose We investigated whether sustained inflammation was associated with altered HPA stress reactivity in patients with CAD. From 4 weeks up to 6 months after a coronary event, we measured systemic inflammation, with focus on inflammasome-related cytokines, and HPA axis hormones (ACTH and cortisol) before and after acute physical stress. Method We included 81 patients (mean age 62 years, 77 % males) and 30 controls (mean age 69 years, 67 % males). Patients underwent a standardized submaximal exercise stress test at 4 weeks (visit A) and 3-6 months after the coronary event (visit B) while controls performed one test only. Free cortisol was measured in saliva before, directly and 30 min after exercise. IL-18, IL-Ra (as a surrogate for IL-1 β), IL-6, ACTH and total cortisol were measured in plasma before and 30 min after exercise. Results At visit A, plasma levels of CRP (baseline only) and IL-6 did not differ between patients and controls while IL-18 and IL-1Ra were significantly higher in patients both before and after exercise, 500 (391-632) vs 386 (295-493), p=0.002; and 179 (141-267) vs 147 (117- 182), p=0.005, respectively(table 1). At visit B, CRP decreased while IL-18 and IL-1Ra levels remained at higher levels than controls. At both visits, patients showed a heightened cortisol reactivity (i.e. significant increase directly after exercise) while this did not occur in controls (Figure 1). At visit B, the relative increase in cortisol directly after exercise was even higher than at visit A (p=0.024). At both visits, ACTH decreased significantly after exercise in patients (p<0.01), probably due to negative feedback, while no change in ACTH was observed in controls. Conclusion Sustained elevations in IL-18 and IL-1Ra in CAD patients following a coronary event may indicate enhanced activity of NLRP3 inflammasome. Furthermore, patients exhibited a heightened cortisol stress reactivity, a phenomenon which has been associated with atherosclerosis progression and sedentary lifestyle in the population. It may be speculated that HPA axis alteration is directly associated with NLRP3 inflammasome activation in CAD, thus opening doors to new insights in prevention. However, this remains to be further investigated.

Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes.

Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis).

A free boundary mathematical model of atherosclerosis

This paper is devoted to the study of a mathematical model of atherosclerosis in one-dimensional geometry with a free boundary. The motion of the boundary is attributable to the concentration of cells in the intima and their interaction in the subendothelial space in addition to their influx through the boundary. A mathematical model that describes the main inflammatory processes in atherosclerosis is proposed, then, by considering some simplifications, a reduced model is obtained. Using a change of variables, the reduced model is converted to a fixed boundary model with space- and time-dependent coefficients and nonlinear terms. We study the existence of solution for the fixed boundary model starting with a model with linear terms then by applying the fixed point theorem. The wave solution is as well investigated along with numerical simulations. Then, we return to the reduced model, prove the existence of solution and present numerical results. Finally, we generalize the results to the complete model initially proposed.

Lnc-MRGPRF-6:1 Promotes M1 Polarization of Macrophage and Inflammatory Response through the TLR4-MyD88-MAPK Pathway.

Background Macrophage-mediated inflammation plays an essential role in the development of atherosclerosis (AS). Long noncoding RNAs (lncRNAs), as crucial regulators, participate in this process. We identified that lnc-MRGPRF-6:1 was significantly upregulated in the plasma exosomes of coronary atherosclerotic disease (CAD) patients in a preliminary work. In the present study, we aim to assess the role of lnc-MRGPRF-6:1 in macrophage-mediated inflammatory process of AS. Methods The correlation between lnc-MRGPRF-6:1 and inflammatory factors was estimated firstly in plasma exosomes of CAD patients. Subsequently, we established lnc-MRGPRF-6:1 knockout macrophage model via the CRISPR/Cas9 system. We then investigated the regulatory effects of lnc-MRGPRF-6:1 on macrophage polarization and foam cell formation. Eventually, transcriptome analysis by RNA sequencing was carried out to explore the contribution of differential genes and signaling pathways in this process. Results lnc-MRGPRF-6:1 was highly expressed in the plasma exosomes of CAD patients and was positively correlated with the expression of inflammatory cytokines in plasma. lnc-MRGPRF-6:1 inhibition significantly reduced the formation of foam cells. The expression of lnc-MRGPRF-6:1 was upregulated in M1 macrophage, and lnc-MRGPRF-6:1 knockout decreased the polarization of M1 macrophage. lnc-MRGPRF-6:1 regulates macrophage polarization via the TLR4-MyD88-MAPK signaling pathway. Conclusions lnc-MRGPRF-6:1 knockdown can inhibit M1 polarization of macrophage and inflammatory response through the TLR4-MyD88-MAPK signaling pathway. lnc-MRGPRF-6:1 is a vital regulator in macrophage-mediated inflammatory process of AS.

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.

Degradable co-delivery nanoplatforms for inflammation-targeted therapy against atherosclerosis

Atherosclerosis is characterized by chronic inflammation of the arterial wall. Activated macrophages play a significant role in the inflammatory process of atherosclerosis by secreting inflammatory factors such as interleukin-1 (IL-1) and interleukin-6 (IL-6). Among all the several methods to treat atherosclerosis, anti-inflammatory therapy with copper ions and IL-1 receptor antagonist (IL-1Ra) are the most promising approaches, but they are limited by side effects on liver damage and the short in vivo half-life of IL-1Ra, respectively. Herein, we developed an inflammation-targeted nanoplatform, i.e. IL-1Ra-loaded copper-doped mesoporous silica nanoparticles (IL-1Ra@Cu-MSNs), for co-delivery of IL-1Ra and copper ions. The nanoplatform showed outstanding drug-loading efficiency, sustained release property and biodegradability. Released copper ions specifically induced macrophage apoptosis by triggering ROS production. The loaded IL-1Ra conferred IL-1R-targeting and anti-inflammatory properties to the nanoplatform. In vivo study revealed that the IL-1Ra@Cu-MSNs significantly reduced arterial stenosis, plaque burden and macrophage infiltration due to the combined action of copper ions and IL-1Ra. Our work demonstrates that integration of targeted modulation of cellular function and inhibition of inflammation based on MSNs significantly alleviates arterial inflammation, which provides a novel strategy for the inflammation-targeted therapy against atherosclerosis.

Association of elevated lipoprotein(a) level with expansion of non-classical monocytes.

Background and Aims: Chronic inflammation plays a key role in atherosclerosis progression. Blood monocytes form a heterogeneous populations differently contributing to the inflammatory process in atherosclerosis. High level of lipoprotein(a) [Lp(a)] is a proven ASCVD risk factor. We compared the number of classical, intermediate and non-classical monocytes in blood of patients with coronary atherosclerosis and different Lp(a) levels.

Blood monocyte populations in coronary atherosclerosis.

Background and Aims: Blood monocytes form a heterogeneous populations differently contributing to the inflammatory process in atherosclerosis. We compared the number of classical, intermediate and non-classical monocytes in blood of patients with the severity of coronary atherosclerosis.

The impacts of C1q/TNF-related protein-15 and adiponectin on Interleukin-6 and tumor necrosis factor-α in primary macrophages of patients with coronary artery diseases

Atherosclerosis is a progressive inflammatory disease characterized by the accumulation of lipids in the arterial wall. Inflammation plays a key role in the pathogenesis of atherosclerosis and some previous studies have shown the role of adipokines during the inflammatory process of atherosclerosis. Therefore, the present study aimed to evaluate the impacts of adiponectin and CTRP15 on inflammatory cytokines secretions from THP1 and primary macrophages. MethodsTHP1 monocytes were differentiated to macrophages and primary monocytes were then isolated from patients with coronary artery disease and controls who were differentiated to macrophages. Macrophages were treated with LPS, LPS+adiponectin, and LPS+CTRP15. ResultsAdiponectin and CTRP15 have reduced IL-6 and TNF-α secretions from LPS-induced THP1 macrophages, and the CTRP15 indicated a more potent anti-inflammatory property compared to adiponectin. In addition, adiponectin reduced cytokines’ expressions and secretions in primary macrophages of both patient and control groups. However, CTRP15 has only reduced cytokines’ expressions and secretions in controls and it was not able to ameliorate inflammation in macrophages of CAD patients. ConclusionThe results of the present study indicate anti-inflammatory impact of adiponectin and CTRP15, while this property was stronger for CTRP15. In addition, it seems likely that anti-inflammatory CTRP15′s impact on macrophages in the CAD patients was weaker than macrophages from the controls.

Systemic immune-inflammation index and incident cardiovascular diseases among middle-aged and elderly Chinese adults: The Dongfeng-Tongji cohort study

Background and aimsSystemic immune-inflammation index (SII) has been recently investigated as a novel inflammatory and prognostic marker. SII may be used as an indicator reflecting the progressive inflammatory process in atherosclerosis, although its link to incident cardiovascular disease (CVD) has not been examined in previous studies. This study aims to prospectively assess the association of SII with incident CVD and its main subtypes in Chinese adults. MethodsUsing data from the Dongfeng-Tongji cohort study, 13,929 middle-aged and older adults with a mean age of 62.56 years (range 35–91 years), who were free of CVD and cancer, were included for analysis. The baseline study was conducted in Shiyan city, Hubei province from 2008 to 2009. The SII was calculated as platelet count (/L) × neutrophil count (/L)/lymphocyte count (/L). Cox regression models were used to examine the associations of SII with incident CVD, including stroke and coronary heart disease (CHD). ResultsOver a median 8.28 years (maximum 8.98 years) of follow-up, 3386 total CVD cases, including 801 stroke cases and 2585 total CHD cases, were identified. In multivariable Cox regression analyses, higher levels of log-transformed SII were significantly associated with total stroke (HR 1.224, 95% CI 1.065–1.407) and ischemic stroke (HR 1.234, 95% CI 1.055–1.442). For those participants with the highest quartiles of SII versus the lowest quartiles of SII, the HRs were 1.358 (95% CI 1.112–1.658) for total stroke, 1.302 (95% CI 1.041–1.629) for ischemic stroke, and 1.600 (95% CI 1.029–2.490) for hemorrhagic stroke. ConclusionsSII may serve as a useful marker to elucidate the role of the interaction of thrombocytosis, inflammation, and immunity in the development of cerebrovascular diseases in the middle-aged and elderly population.

The expression levels of miRNAs- 27a and 23a in the peripheral blood mononuclear cells (PBMCs) and their correlation with FOXO1 and some inflammatory and anti-inflammatory cytokines in the patients with coronary artery disease (CAD)

BackgroundAtherosclerosis as a progressive inflammatory disease is the main cause of Coronary Artery Disease (CAD). Multiple genetic and environmental factors are involved in susceptibility to atherosclerotic vascular diseases. FOXO1 gene acts as a key molecular proinflammatory transcription factor and the FBOX32 gene as an F-box protein plays pivotal roles in regulation of muscle atrophy and inhibition of the pathologic cardiac hypertrophy. MiR-27a has been reported to contribute to atherosclerosis prevention and the inflammatory processes of atherosclerosis. MicroRNA-23a has been found to promote atherosclerotic plaque progression and vulnerability. Hence, given the importance of these subjects, the present study was carried out to investigate the expression levels of the desired genes. MethodologyIn this case-control study, 82 patients with CAD and 80 healthy controls were investigated. Expression levels of miRNAs -27a and 23a, FOXO1, Sirtuin 1 (SIRT1) in the Peripheral Blood Mononuclear Cells (PBMCs), serum concentration of IL6 and TNF-α of the studied subjects were evaluated using the real-time Polymerase Chain Reaction (PCR) technique. The correlation between the variables was also investigated. ResultsResults of the study demonstrated that expression of FOXO1, IL-6, TNF-α, miR-27a, and miR-23a increased in the PBMCs of the patients with CAD and their expression levels were significantly correlated with the severity of stenosis. A significant decrease was observed in the expression of SIRT1 in the patients with CAD compared to the healthy controls. Furthermore, the Receiver Operating Characteristic (ROC) curve was plotted to find the effectiveness of FOXO1 and miRNA-27a gene expression as a diagnostic marker for CAD. ConclusionsFindings of the study suggested that miRs-27a and FOXO1 genes have a potential role in the progression of atherosclerosis and mediate the molecular and genetic disturbances of the intracellular communication in the atherosclerosis.

NLRP3 Inflammasome: A Potential Alternative Therapy Target for Atherosclerosis.

Atherosclerosis (AS) is a complex and chronic inflammatory disease that occurs in multiple systems of the human body. It is an important pathological basis for a variety of diseases and a serious threat to human health. So far, many theories have been formed to explain the pathogenesis of atherosclerosis, among which “inflammation theory” has gradually become a research focus. This theory presents that inflammatory response runs through the whole progress of AS, inflammatory cells play as the main executors of AS, and inflammatory mediators are the key molecules of AS. In the inflammatory process of atherosclerosis, the role of NLRP3 in the atherosclerosis has gradually got the attention of researchers. NLRP3 is a kind of signal-transductional pattern recognition receptors (PRRs). After recognizing and binding to the damage factors, NLRP3 inflammasome will be assembled to activate IL-1β and caspase-1 pathways, resulting in promoting the inflammation process of AS, reducing the stability of the plaques, and finally increasing the incidence of adverse cardiovascular events. Taken above, the article will review the potential benefits of drugs targeting the NLRP3 inflammasome in the therapy of AS.

Inflammasome Activation in Human Macrophages Induced by a LDL (-) Mimetic Peptide.

The inflammasome is responsible for maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) contributing to the inflammatory process in atherosclerosis. It is shown here that an electronegative low-density lipoprotein [LDL (-)] apoB-100 mimetic peptide can activate the transcriptional and posttranslational signs needed for complete inflammasome activation. This peptide, named p2C7, can activate the Toll-like receptor 4 (TLR4) that induces NF-κB activation and the transcription of inflammasome components. After blocking TLR4 with a neutralizing antibody, inflammasome component (NLRP3, CASP1, and ASC) and IL1b and IL18 gene downregulation occurred in human-derived macrophages stimulated with p2C7 or LDL (-). Moreover, the posttranslational signal was activated by the interaction between p2C7 and the lectin-type oxidized LDL receptor 1 (LOX-1), as demonstrated by the induction of caspase-1 cleavage in macrophages. The blockage of either TLR4 or LOX-1 decreased IL-1β and IL-18 secretion by human-derived macrophages as both pathways are necessary for complete inflammasome activation. These findings suggest a mechanism by which macrophages transduce the pro-inflammatory signal provided by LDL (-) ApoB-100 and its mimetic peptides to activate the inflammasome protein complex what may be relevant for the inflammatory process in atherosclerosis.

Increased Expression of miR-146a in Valvular Tissue From Patients With Aortic Valve Stenosis.

miR-146a has been implicated in the regulation of the immune response as well as in inflammatory process of atherosclerosis. In the present study, we have investigated the expression of miR-146a and its targets, TLR4 a IRAK1, in aortic valve stenosis. A total of 58 patients with aortic stenosis (non- and atherosclerotic; tissue obtained during standard aortic valve replacement) were enrolled. The relative expression of mir-146a was higher in valvular tissue from patients with atherosclerosis compared to those without atherosclerosis (p = 0.01). Number of the IRAK1 and TLR4 transcripts did not differ between the investigated groups. There was a trend toward elevation of miR-146a expression in context of inflammatory infiltrate observed in the valvular tissue from patients with atherosclerosis (p = 0.06). In conclusion, in line with the acknowledged role of miR-146a in atherosclerotic inflammation, our data suggest it may be extended to the specific location of aortic valves in aortic stenosis.

G-Protein Coupled Receptor Targeting on Myeloid Cells in Atherosclerosis.

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. Gold standard therapy with statins and the more recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have improved health conditions among CVD patients by lowering low density lipoprotein (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that ‘just’ lipid lowering is insufficient. The results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes – such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD.

PTPN22 Gene Polymorphisms Are Associated with Susceptibility to Large Artery Atherosclerotic Stroke and Microembolic Signals

Large artery atherosclerotic stroke (LAAS) is the most common ischemic stroke (IS) subtype, and microemboli may be clinically important for indicating increased risk of IS. The inflammatory process of atherosclerosis is well known, and lymphoid phosphatase (Lyp), which is encoded by the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene, plays an important role in the inflammatory response. Our study was intended to evaluate the relationship between PTPN22 gene and LAAS and microembolic signals (MES). Three loci of the PTPN22 gene (rs2476599, rs1217414, and rs2488457) were analyzed in 364 LAAS patients and 369 control subjects. A genotyping determination was performed using the TaqMan assay. The G allele of rs2488457 might be related to a higher risk for developing LAAS and MES (odds ratio (OR) = 1.456, 95% confidence interval (CI) 1.156-1.833, P = 0.001; OR = 1.652, 95% CI 1.177-2.319, P = 0.004, respectively). In the LAAS group, the prevalence of the GTG haplotype was higher (P < 0.001) and the prevalence of the GCC haplotype was lower (P = 0.001). An interaction analysis of rs2488457 with smoking showed that smokers with the CG/GG genotypes had a higher risk of LAAS, compared to nonsmokers with the rs2488457 CC genotype (OR = 2.492, 95% CI 1.510–4.114, P < 0.001). Our research indicated that the PTPN22 rs2488457 might be related to the occurrence of LAAS and MES in the Han Chinese population. In addition, the rs2488457 polymorphism and the environmental factor of smoking jointly influenced the susceptibility of LAAS.