Atherosclerosis Formation Research Articles

Shenlian extract improves atherosclerosis by relieving adventitial inflammation

Ethnopharmacological relevanceShenlian (SL) extract, a Chinese medicinal compound mainly pointing at inflammation response of atherosclerosis, is composed of Salvia miltiorrhizae Bunge and Andrographis paniculata (Burm.f.) Nees. Salvia miltiorrhizae Bunge has been reported to activate blood to remove stasis, while another herb, Andrographis paniculata (Burm.f.) Nees, has been revealed to clear endogenous heat toxins. The anti-atherosclerotic effects of these two herbs have been reported closely relating to inflammation. However, from the point of view of adventitial inflammation, the in-depth study of SL extract in anti-atherosclerotic effects by relieving adventitial inflammation is still unknown. Aim of the studyTo explore the effects of adventitial inflammation in atherosclerosis progression and if SL extract could reverse the process. Materials and methodsA novel atherosclerosis model based on adventitial inflammation was established. High-fat diet-fed ApoE-/- mice were implanted a cotton thread soaked with LPS on the right common carotid artery (RCCA). Meanwhile, three time points were set (week 2, 4, and 12) to accurately evaluate the effect of SL extract on the whole process of atherosclerosis with adventitial inflammation. The pathological changes of phenotype transformation of VAFs, vascular cell proliferation and collagen synthesis were observed dynamically by immunohistochemistry (IHC), BrdU method and sirius red staining. Then primary VAFs were stimulated by LPS to mirror the process of adventitial inflammation in vitro. The VAFS phenotype conversion and its function alterations including proliferation, migration, inflammatory secretion was assessed. Finally, we established a co-culture model of activated VAFs and vascular smooth muscle cells (VSMCs) to observe the impacts of activated VAFs on phenotype transformation and migration of VSMCs. ResultsSL extract improved atherosclerosis progression by reducing lipid content, adventitial inflammation and plaque formation. HE results showed sham-operated group (Sham) appeared light infiltrated inflammation only in adventitia at week 2, and the degree of inflammation infiltrated in model was more severe than that in Sham at week 2, 4, and 12. At week 12, the sham and model group showed evidently thickened media and intima. The phenotypic transformation, proliferation and migration of vascular adventitial fibroblasts (VAFs) as well as inflammatory secretion enhanced remarkably in vivo and vitro, but SL extract reversed these changes. Moreover, SL extract downregulated JAK2-STAT3-MMP2 signal pathway. The VSMCs transformed from contractile phenotype into synthetic phenotype and the migration of VSMCs increased after co-culture with activated VAFs. In contrast, SL extract could suppress theses effects. ConclusionsTaken together, atherosclerotic inflammation could be a “outside-in” signaling. Adventitial inflammation not only accelerated intimal plaque formation in atherosclerosis, but also worsened the degree of vascular lesion. And SL extract improved atherosclerosis by relieving adventitial inflammation, and the underlying mechanisms could be associated with curbing phenotypic transformation, proliferation and migration of VAFs and VSMCs.

LITAF Promotes Atherosclerotic Plaque Formation by Stimulating the NF-κB Inflammatory Pathway.

Lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF) protein is a newly discovered inflammatory protein. This study aims to study the role of LITAF in the formation of atherosclerosis. A total of 10 C57BL/6J mice and 10 C57BL/6J mice with knockout of LITAF gene (C57BL/6J-LITAF-) were divided into two groups: the control group and the LITAF-/- group. The animals were accommodated for 16 weeks and then euthanized with their hearts and aortas isolated thereafter. Next, the roots of the mouse aorta were cryosectioned and stained with Oil Red O staining and immunohistochemical staining (CD68, α-SMA, and Masson), respectively. The area of Oil Red O staining and the proportion of positive expression after immunohistochemical staining were then compared between the control and LITAF-/- groups. At the same time, the blood of mice was collected for the extraction of proteins and RNA. The proteins and RNA were used to detect the expression of major molecules of the NF-κB inflammatory pathway in mice in the control group and the LITAF-/- group by Western blotting and RT-PCR. Oil Red O staining of the aortic root sections of the mice in each group revealed that the area of atherosclerotic plaques in the LITAF-/- group was substantially lower than that in the control group (P<0.05). Moreover, immunohistochemical staining determined that the expression level of α-SMA and CD68 in the LITAF-/- group was significantly lower than that in the control group, whereas the results were reversed following Masson staining (P<0.05). The expression levels of P65 and caspase 3 were significantly lower in the LITAF-/- group than in the control group (P<0.05), whereas the expression level of IκB was higher in the LITAF-/- group. LITAF might participate in the formation of atherosclerotic plaque through the NF-κB pathway and play a promoting role in the formation of atherosclerosis.

Stenting for Severe C7 Stenosis of Internal Carotid Artery (ICA) and Related Literature Review

Intracranial Atherosclerosis (ICAS) is a common cerebrovascular lesion worldwide and an important cause of stroke [1]. Non-modifiable risk factors include age, gender, and genetics, with age being a key factor and atherosclerosis usually progressive, with no clinical manifestations until middle age. Ischemic Heart Disease (IHD) has increased fivefold among people aged 40 to 60. Before menopause, women are less prone to atherosclerosis than men, and the incidence of atherosclerosis is increased in postmenopausal women [2,3]. The inheritance of various genetic polymorphisms and the accumulation of family risk factors (such as diabetes and hypertension) create multiple conditions for the formation of atherosclerosis [4]. On the other hand, modifiable risk factors, such as smoking, hyperlipidemia, diabetes, and high blood pressure, can be improved by adjusting daily life. Studies have analyzed that white people are prone to extracranial arterial occlusive disease, while Asian, black and Hispanic people have a higher risk of intracranial atherosclerotic disease [1]. Therefore, the prevention of atherosclerotic disease, has been very urgent, to increase publicity, from the source to solve the problem.

Finding small molecular compounds to decrease trimethylamine oxide levels in atherosclerosis by virtual screening

Abstract The intestinal microbial metabolite trimethylamine oxide (TMAO) affects the formation and development of atherosclerosis (AS). The design and development of an effective targeted drug to reduce serum TMAO levels may provide new avenues for inhibiting AS morbidity. Target genes that may elevate TMAO levels in patients with AS were explored using bioinformatics, virtual screening, and molecular dynamics (MD). We expected these genes to indicate potential TMAO inhibitors. Of these genes, hFMO3 was responsible for increasing TMAO levels. Four small-molecule compounds (SMC-1, SMC-2, SMC-3, and SMC-4) with the lowest binding energy and CGenFF penalty &lt; 10 were connected to the main binding pocket of hFMO3 by hydrogen and/or cation–pi interactions. A 100 ns MD simulation showed that the four systems quickly reached equilibrium. The root mean square deviation of all four small-molecule compounds was less than 0.35 nm, that of the four ligand complexes was less than 0.40 nm, and the average deviations of each amino acid residue from the reference position over time did not differ. Molecular mechanics Poisson–Boltzmann surface area analyses showed that SMC-2, SMC-3, and SMC-4 bound very well to hFMO3, and the energy contribution of the key residues LEU40 and GLU32 was more remarkable in SMC-2, SMC-3, and SMC-4. These four small-molecule compounds may be useful as targeted drugs to reduce serum TMAO levels, inhibiting atherosclerosis formation.

Hyperlipidemia in immune thrombocytopenia: a retrospective study

BackgroundImmune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease characterized by low platelet count and bleeding manifestations. However, some patients also suffered from atherosclerosis or even infarction. Apart from activated platelets, lipid metabolism takes a large part in the formation of atherosclerosis and metabolic syndrome. The lipid metabolic state in ITP patients is still unknown.MethodsWe retrospectively reviewed 302 hospitalized ITP patients in our cohort, comparing their blood lipids, bleeding symptoms, metabolic diseases and treatment responses.ResultsWe found a high proportion of ITP patients suffered from hyperlipidemia, and other metabolic diseases including cardiovascular or cerebral atherosclerosis or infarction, hypertension, and type 2 diabetes. Hyperlipidemia was associated with severe bleeding and treatment refractoriness in ITP. Statins could alleviate thrombocytopenia and bleeding severity, and facilitate ITP treatment, while improving hyperlipidemia in ITP patients.ConclusionsOur present study demonstrated that lipid metabolism might play an indispensable role in ITP pathogenesis and development.

The Prophylactic Effect of Eucheuma spinosum on Total Blood Cholesterol Levels in Rattus norvegicus Dexamethasone-Induced

Hyperlipidemia is one of the main risk factors for heart disease caused by the formation of atherosclerosis. Eucheuma spinosum contains a natural antioxidant flavonoid, which has an antiatherogenic effect that can inhibit the formation of cholesterol in the liver so that it can prevent the development of atherosclerosis. This study aims to determine the effect of prophylactic administration of Eucheuma spinosum on the total cholesterol levels of Rattus novergicus induced by dexamethasone. This study was an experimental design with a post-test-only control group design. This study would use 24 white male Rattus norvegicus divided into three groups; a negative control group (K-) without treatment, a positive control group (K+) induced dexamethasone 8 mg/Kg BW on day 14 until day 20, treatment group (KP) given Eucheuma spinosum extract 200 mg/Kg BW on day 8 until day 20 as Prophylactic and on day 14 until day 20 induced dexamethasone 8 mg/Kg BW. After completing the treatment period, all groups were terminated and taken total calculation of cholesterol levels through the aorta of rats. Data was analyzed statistically computerized. The results of the study of total cholesterol levels that used Kruskal-Wallis test showed differences between groups (p&lt;0.001). There was a decrease in total cholesterol levels in the treatment group (p&lt;0.024) compared with the positive control group. The administration of Eucheuma spinosum extract as a prophylactic dose of 200 mg/Kg BW for 14 days could reduce the total cholesterol level of Rattus norvegicus induced by dexamethasone compared to those not given Eucheuma spinosum extract.

Reactive Oxygen Species-Responsive Sequentially Targeted AIE Fluorescent Probe for Precisely Identifying the Atherosclerotic Plaques.

The formation of atherosclerosis is the root cause of various cardiovascular diseases (CVDs). Therefore, effective CVD interventions call for precise identification of the plaques to aid in clinical treatment of such diseases. Herein, a reactive oxygen species (ROS)-responsive sequentially targeted fluorescent probe is developed for atherosclerotic plaque recognition. An aggregation-induced emission active fluorophore is linked to maleimide (polyethylene glycol) hydroxyl with a ROS-responsive cleavable bond, which is further functionalized with CLIKKPF peptide (TPAMCF) for specifically binding to phosphatidylserine of the foam cells. After being assembled in aqueous medium, TPAMCF nanoparticles can efficiently accumulate in the plaques through the high affinity of CLIKKPF to the externalized phosphatidylserine of the foam cells. Activated by the locally accumulated ROS in foam cells, the nanoparticles are interrupted, and then TPA can be released and subsequently identify the lipid droplets inside the foam cells to achieve fluorescence imaging of the plaques. Such nanoprobes have the favorable ROS response performance and exhibit a special target binding to the foam cells in vitro. In addition, nanoprobe-based fluorescence imaging permitted the high-contrast and precise detection of atherosclerosis specimens ex vivo. Therefore, as a promising fluorescent probe, TPAMCF is capable of being a potential candidate for the detection of atherosclerotic plaque.

PPARγ in Atherosclerotic Endothelial Dysfunction: Regulatory Compounds and PTMs.

The formation of atherosclerotic plaques is one of the main sources of cardiovascular disease. In addition to known risk factors such as dyslipidemia, diabetes, obesity, and hypertension, endothelial dysfunction has been shown to play a key role in the formation and progression of atherosclerosis. Peroxisome proliferator-activated receptor-gamma (PPARγ), a transcription factor belonging to the steroid superfamily, is expressed in the aorta and plays a critical role in protecting endothelial function. It thereby serves as a target for treating both diabetes and atherosclerosis. Although many studies have examined endothelial cell disorders in atherosclerosis, the role of PPARγ in endothelial dysfunction is still not well understood. In this review, we summarize the possible mechanisms of action behind PPARγ regulatory compounds and post-translational modifications (PTMs) of PPARγ in the control of endothelial function. We also explore the potential use of endothelial PPARγ-targeted agents in the prevention and treatment of atherosclerosis.

Helicobacter pylori infection increases the risk of carotid plaque formation: Clinical samples combined with bioinformatics analysis

ObjectiveInfection with Helicobacter pylori (H. pylori) may increase atherosclerosis, which can lead to carotid plaque formation. Our study examined the relationship between H. pylori infection and carotid plaque formation, and its underlying mechanisms. MethodsA total of 36,470 people who underwent physical examination in Taizhou Hospital Health Examination Center from June 2017 to June 2022 were included in this study. All people participated in the urease test, neck ultrasound, blood pressure detection, anthropometric measurement and biochemical laboratory examination. In addition, the GSE27411 and GSE28829 datasets in the Gene Expression Omnibus (GEO) database were used to analyze the mechanism of H. pylori infection and atherosclerosis progression. ResultsH. pylori infection, sex, age, blood lipids, blood pressure, fasting blood glucose, glycated hemoglobin and body mass index were risk factors for carotid plaque formation. An independent risk factor was still evident in the multivariate logistic regression analysis, indicating H. pylori infection. Furthermore, after weighted gene coexpression network analysis (WGCNA), we discovered 555 genes linked to both H. pylori infection and the advancement of atherosclerosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed a strong correlation between these genes and immunity, infection, and immune disorders. SsGSEA analysis showed that H. pylori infection and atherosclerosis included changes in the immune microenvironment. Finally, three genes MS4A6A, ADAMDEC1 and AQP9 were identified to be involved in the formation of atherosclerosis after H. pylori infection. Conclusion: Our research affirms that H. pylori is a unique contributor to the formation of carotid plaque, examines the immune microenvironment associated with H. pylori infection and advanced carotid atherosclerosis, and offers fresh perspectives on how H. pylori infection leads to atherosclerosis.

Multivessel Coronary Artery Disease Complicated by Diabetes Mellitus Has a Relatively Small Effect on Endothelial and Lipoprotein Lipases Expression in the Human Atrial Myocardium and Coronary Perivascular Adipose Tissue.

Endothelial (EL) and lipoprotein (LPL) lipases are enzymes involved in lipoproteins metabolism and formation of atherosclerosis, a pathological feature of coronary artery disease (CAD). This paper examines the role of the lipases in the right atrial appendage (RAA) and coronary perivascular adipose tissue (PVAT) of patients with CAD alone or with accompanying diabetes. Additionally, correlation analysis for plasma concentration of the lipases, apolipoproteins (ApoA-ApoJ) and blood lipids (Chol, HDL-C, LDL-C, TAG) was performed. We observed that CAD had little effect on the lipases gene/protein levels in the RAA, while their transcript content was elevated in the PVAT of diabetic CAD patients. Interestingly, the RAA was characterized by higher expression of EL/LPL (EL: +1-fold for mRNA, +5-fold for protein; LPL: +2.8-fold for mRNA, +12-fold for protein) compared to PVAT. Furthermore, ApoA1 plasma concentration was decreased, whereas ApoC1 and ApoH were increased in the patients with CAD and/or diabetes. The concentrations of ApoC3 and ApoD were strongly positively correlated with TAG content in the blood, and the same was true for ApoB with respect to LDL-C and total cholesterol. Although plasma concentrations of EL/LPL were elevated in the patients with diabetes, CAD alone had little effect on blood, myocardial and perivascular fat expression of the lipases.

Correlation between renal metabolism and cardiovascular disease

Cardiovascular disease is the main medical burden in the world, and coronary heart disease and heart failure are the main reasons for the increase of all-cause mortality and cardiovascular mortality year by year. There is a synergistic effect between cardiovascular and kidney diseases. Under pathological conditions, there is a significant correlation between various cardiovascular diseases and kidney diseases. In this review, we discussed the effects of metabolite accumulation caused by kidney disease on multiple mechanisms of atherosclerosis from the whole process of the formation and development of atherosclerosis. These metabolites can be mainly divided into uremic toxins, intestinal metabolites, fibroblast growth factor 23, and advanced glycosylation end products. Then we summarized the effects of metabolites related to renal metabolism on heart failure according to the biological changes of patients with heart failure at three different levels.

Blockade of CXCR4 promotes macrophage autophagy through the PI3K/AKT/mTOR pathway to alleviate coronary heart disease

ObjectiveAutophagy is important in regulating inflammation and cholesterol efflux, suggesting that targeting autophagy may slow down atherosclerosis (AS). Since the pathological basis of coronary artery disease (CAD) is atherosclerosis, it is crucial to investigate the role of autophagy in atherosclerosis. This study aimed to investigate the role of the chemokine CXC chemokine receptor 4 (CXCR4) in promoting macrophage autophagy through the phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway to alleviate coronary artery disease. MethodsThe human left coronary artery and myocardium were collected to detect CXCR4, MAP1LC3(LC3) and SQSTM1(p62) expression. ApoE−/− mice were used to establish an atherosclerosis mice model, while human monocytes (THP-1) were used to establish a foam cell model and co-cultured with foam cells using siRNACXCR4. Western blotting was conducted to quantify CXCR4, PI3K/AKT/mTOR pathway protein, LC3, Beclin1 and p62 protein levels. The left coronary artery from humans and mouse aorta and myocardium were stained with Hematoxylin and Eosin (H&E), macrophages with Oil Red O staining and foam cells were assessed by Movat's staining. CXCR4 levels, PI3K/AKT/mTOR pathway protein, LC3 and p62 were detected by immunohistochemistry (IHC) and immunofluorescence assays. Detection of autophagosomes in macrophages using transmission electron microscopy. We further assessed whether the effect of CXCR4-mediated macrophage autophagy on the formation of atherosclerosis and structural changes in the myocardium was mediated via the PI3K/AKT/mTOR signaling pathway. ResultsCXCR4 and p62 proteins were upregulated in human coronary lesions, mouse aorta, myocardial tissue, and foam cells, while LC3II/LC3I was downregulated. p85 (P-PI3K), Ser473 (P-AKT), and Ser2448 (P-mTOR) phosphorylated proteins associated with the PI3K/AKT/mTOR pathway were detected in AS and foam cell models. Upregulated CXCR4 inhibited autophagy of macrophages and increased the severity of atherosclerotic lesions. After specific knockdown of CXCR4 by adeno-associated virus (AAV9-CXCR4-RNAi) and siRNACXCR4, the above indicators were reversed, macrophage autophagy was promoted, the severity of atherosclerotic lesions was reduced, and the disorganized arrangement of myocardial architecture was improved. ConclusionKnockdown of CXCR4 reduces the extent of coronary artery disease by promoting macrophage autophagy through the PI3K/AKT/mTOR pathway to attenuate atherosclerosis.

Mechanisms of fibrous cap formation in atherosclerosis.

The fibrous cap is formed by smooth muscle cells that accumulate beneath the plaque endothelium. Cap rupture is the main cause of coronary thrombosis, leading to infarction and sudden cardiac death. Therefore, the qualities of the cap are primary determinants of the clinical outcome of coronary and carotid atherosclerosis. In this mini-review, we discuss current knowledge about the formation of the fibrous cap, including cell recruitment, clonal expansion, and central molecular signaling pathways. We also examine the differences between mouse and human fibrous caps and explore the impact of anti-atherosclerotic therapies on the state of the fibrous cap. We propose that the cap should be understood as a neo-media to substitute for the original media that becomes separated from the surface endothelium during atherogenesis and that embryonic pathways involved in the development of the arteria media contribute to cap formation.

Endocytosis of red blood cell extracellular vesicles by macrophages leads to cytoplasmic heme release and prevents foam cell formation in atherosclerosis.

Extracellular vesicles (EVs) can be produced from red blood cells (RBCs) on a large scale and used to deliver therapeutic payloads efficiently. However, not much is known about the native biological properties of RBCEVs. Here, we demonstrate that RBCEVs are primarily taken up by macrophages and monocytes. This uptake is an active process, mediated mainly by endocytosis. Incubation of CD14+ monocytes with RBCEVs induces their differentiation into macrophages with an Mheme-like phenotype, characterized by upregulation of heme oxygenase-1 (HO-1) and the ATP-binding cassette transporter ABCG1. Moreover, macrophages that take up RBCEVs exhibit a reduction in surface CD86 and decreased secretion of TNF-α under inflammatory stimulation. The upregulation of HO-1 is attributed to heme derived from haemoglobin in RBCEVs. Heme is released from internalized RBCEVs in late endosomes and lysosomes via the heme transporter, HRG1. Consequently, RBCEVs exhibit the ability to attenuate foam cell formation from oxidized low-density lipoproteins (oxLDL)-treated macrophages in vitro and reduce atherosclerotic lesions in ApoE knockout mice on a high-fat diet. In summary, our study reveals the uptake mechanism of RBCEVs and their delivery of heme to macrophages, suggesting the potential application of RBCEVs in the treatment of atherosclerosis.

Integrated Cascade Nanozymes with Antisenescence Activities for Atherosclerosis Therapy

AbstractSenescent cells are the critical drivers of atherosclerosis formation and maturation. Mitigating senescent cells holds promise for the treatment of atherosclerosis. In an atherosclerotic plaque microenvironment, senescent cells interact with reactive oxygen species (ROS), promoting the disease development. Here, we hypothesize that a cascade nanozyme with antisenescence and antioxidant activities can serve as an effective therapeutic for atherosclerosis. An integrated cascade nanozyme with superoxide dismutase‐ and glutathione peroxidase‐like activities, named MSe1, is developed in this work. The obtained cascade nanozyme can attenuate human umbilical vein endothelial cell (HUVEC) senescence by protecting DNA from damage. It significantly weakens inflammation in macrophages and HUVECs by eliminating overproduced intracellular ROS. Additionally, the MSe1 nanozyme effectively inhibits foam cell formation in macrophages and HUVECs by decreasing the internalization of oxidized low‐density lipoprotein. After intravenous administration, the MSe1 nanozyme significantly inhibits the formation of atherosclerosis in apolipoprotein E‐deficient (ApoE−/−) mice by reducing oxidative stress and inflammation and then decreases the infiltration of inflammatory cells and senescent cells in atherosclerotic plaques. This study not only provides a cascade nanozyme but also suggests that the combination of antisenescence and antioxidative stress holds considerable promise for treating atherosclerosis.

Integrated Cascade Nanozymes with Antisenescence Activities for Atherosclerosis Therapy.

Senescent cells are the critical drivers of atherosclerosis formation and maturation. Mitigating senescent cells holds promise for the treatment of atherosclerosis. In an atherosclerotic plaque microenvironment, senescent cells interact with reactive oxygen species (ROS), promoting the disease development. Here, we hypothesize that a cascade nanozyme with antisenescence and antioxidant activities can serve as an effective therapeutic for atherosclerosis. An integrated cascade nanozyme with superoxide dismutase- and glutathione peroxidase-like activities, named MSe1 , is developed in this work. The obtained cascade nanozyme can attenuate human umbilical vein endothelial cell (HUVEC) senescence by protecting DNA from damage. It significantly weakens inflammation in macrophages and HUVECs by eliminating overproduced intracellular ROS. Additionally, the MSe1 nanozyme effectively inhibits foam cell formation in macrophages and HUVECs by decreasing the internalization of oxidized low-density lipoprotein. After intravenous administration, the MSe1 nanozyme significantly inhibits the formation of atherosclerosis in apolipoprotein E-deficient (ApoE-/- ) mice by reducing oxidative stress and inflammation and then decreases the infiltration of inflammatory cells and senescent cells in atherosclerotic plaques. This study not only provides a cascade nanozyme but also suggests that the combination of antisenescence and antioxidative stress holds considerable promise for treating atherosclerosis.

Dickkopf-1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1.

Vascular smooth muscle cells (VSMCs) are considered to be a crucial source of foam cells in atherosclerosis due to their low expression level of cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) intrinsically. While the definite regulatory mechanisms are complicated and have not yet been fully elucidated, we previously reported that Dickkopf-1 (DKK1) mediates endothelial cell (EC) dysfunction, thereby aggravating atherosclerosis. However, the role of smooth muscle cell (SMC) DKK1 in atherosclerosis and foam cell formation remains unknown. In this study, we established SMC-specific DKK1-knockout (DKK1SMKO ) mice by crossbreeding DKK1flox/flox mice with TAGLN-Cre mice. Then, DKK1SMKO mice were crossed with APOE-/- mice to generate DKK1SMKO /APOE-/- mice, which exhibited milder atherosclerotic burden and fewer SMC foam cells. In vitro loss- and gain-of-function studies of DKK1 in primary human aortic smooth muscle cells (HASMCs) have proven that DKK1 prevented oxidized lipid-induced ABCA1 upregulation and cholesterol efflux and promoted SMC foam cell formation. Mechanistically, RNA-sequencing (RNA-seq) analysis of HASMCs as well as chromatin immunoprecipitation (ChIP) experiments showed that DKK1 mediates the binding of transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ) to the promoter of cytochrome P450 epoxygenase 4A11 (CYP4A11) to regulate its expression. In addition, CYP4A11 as well as its metabolite 20-HETE-promoted activation of transcription factor sterol regulatory element-binding protein 2 (SREBP2) mediated the DKK1 regulation of ABCA1 in SMC. Furthermore, HET0016, the antagonist of CYP4A11, has also shown an alleviating effect on atherosclerosis. In conclusion, our results demonstrate that DKK1 promotes SMC foam cell formation during atherosclerosis via a reduction in CYP4A11-20-HETE/SREBP2-mediated ABCA1 expression.

PREVENTIVE EFFECTS OF FIGS POWDER &amp; GARLIC POWDER IN MALE ALBINO RATS WITH INDUCED DYSLIPIDEMIA

Dyslipidemia is one of the predisposing factors for the development of cardiovascular diseases due to the formation of atherosclerosis. Statin drugs are commonly used for the management of dyslipidemia but due to different side effects, drug resistance and affordability issues now, researchers working on the different preventive and curative effects of different natural herbs, fruits, etc. this study aimed to evaluate &amp; compare the preventive effects of Ficus Carica &amp; Allium Sativum on serum lipid profile levels in albino rats on induction of dyslipidemia. This experimental study was conducted at the Department of Biochemistry Liaquat University of Medical &amp; Health Sciences (LUMHS) Jamshoro, Pakistan. Total of 24 male albino rats weighing of 170-190 grams were purchased from the Ojha campus of DUMHS Karachi Pakistan and caged at the Animal House of Agriculture University Tando Jam Pakistan. Twenty-four male albino rats were divided into four groups; each group contained 6 rats, group A as control group received a normal diet; group B rats received high fatty diet; group C rats received high fatty diet along with figs powder; group D rats received a high fatty diet with garlic powder with the calculated and proper dose for six weeks. After six weeks, orbital capillary blood samples were drawn to estimate lipid profile parameters. Lipid profile performed on Cobas chemical analyzer of Roche Hitachi at Diagnostic &amp; Research Laboratory LUMHS. The Statistical data was analyzed by SPSS version 21 by applying ANOVA test for significance. The serum cholesterol level was highly observed in group B rats, and serum cholesterol level was significantly (P &lt; .001) low in the group C &amp; D rats in comparison to group B male albino rats. The serum T.G. level is highly observed in group B rats, T.G.’s level is significantly (P &lt; .001) low in the group C &amp; D rats compared to group B male albino rats. The serum LDL level is highly observed in group B rats, with a significant serum LDL level (P = 0.05) low in the group C &amp; D rats compared to group B male albino rats. The serum HDL level more decline in group B rats serum HDL level was significantly (P = 0.05) high in the group C &amp; D rats with the comparison to group B male albino rats. Figs and garlic powder had a significant role in normal levels of different lipid profile parameters. This study concluded that figs powder and garlic powder could perform a preventive role in the development of dyslipidemia.

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Meet the First Authors.

NOX2 inhibition stabilizes vulnerable plaques by enhancing macrophage efferocytosis via MertK/PI3K/AKT pathway

NADPH oxidases 2 (NOX2) is the main source of ROS in macrophages, which plays a critical role in the formation of atherosclerosis. However, effects of NOX2 inhibition on established vulnerable plaques and the potential role involved remain unclear. The purpose of this study is to investigate the latent mechanism of NOX2-triggered vulnerable plaque development. We generated a vulnerable carotid plaque model induced by carotid branch ligation and renal artery constriction, combined with a high-fat diet in ApoE−/− mice. NOX2 specific inhibitor, GSK2795039 (10 mg/kg/day by intragastric administration for 8 weeks) significantly prevented vulnerable plaque, evaluated by micro-ultrasound imaging parameters. A profile of less intraplaque hemorrhage detection, increased collagen-lipid ratio, fibrous cap thickness and less necrotic core formation were also found in GSK2795039 treated group. Mechanistically, reduced 4-HNE, in situ lesional apoptosis and enhanced efferocytosis were involved in mice treated with NOX2 inhibitor. Further analysis in mouse macrophages confirmed the role of NOX2 inhibition in enhancing macrophage efferocytosis by regulating the MertK/PI3K/AKT pathway. In summary, our data defined previously few recognized roles of NOX2 in vulnerable plaque pathogenesis and an undescribed NOX2-ROS-MerTK axis acts involved in regulating macrophage efferocytosis in the formation of rupture-prone vulnerable plaques.