Abstract:Atherosclerosis is a lipid-driven chronic inflammatory disease characterized by the accumulation of apolipoprotein B-rich lipoproteins, immune cells, and extracellular matrix under the arterial endothelium to form atherosclerotic plaques. The modified lipoproteins acquire damage-related molecular patterning characteristics, first triggering an innate immune response dominated by monocytes-macrophages, followed by an adaptive immune response. These inflammatory responses are often chronic and irreversible, and can lead to arterial damage and thrombus-induced organ infarction. This article mainly reviews the role of the immune system in the occurrence and development of atherosclerosis and the current main immune prevention strategies for atherosclerosis.

Abstract:Aim To explore the effect of metformin (Met) regulating macrophage phenotype through adenosine monophosphate-activated protein kinase (AMPK)/signal transducer and activator of transcription 3 (STAT3) signal pathway on the formation of atherosclerosis (As) in mice. Methods RAW264.7 macrophages were cultured in vitro, lipopolysaccharide was used to promote macrophage differentiation, and Met was used to stimulate cells. The proportion of macrophages with different phenotypes (CD86, CD206) was detected by flow cytometry. The protein expression levels of inducible nitric oxide synthase (iNOS), arginase-1 (Arg-1), AMPK, phosphorylated AMPK (pAMPK), STAT3 and phosphorylated STAT3 (pSTAT3) were detected by Western blot. ApoE－/－ mice were fed with high-fat diet to construct As model. Mice in the experimental group (Met group) were given Met intragastric intervention, and mice in the control group (CTL group) were given the same volume of normal saline intragastric intervention. After 3 months, the whole length of the mouse aorta (from the brachiocephalic trunk to the bilateral iliac arteries) and the aortic root were extracted and stained with oil red O and immunofluorescence respectively to evaluate the lipid deposition of the aorta and the different phenotypic proportion of macrophages in the lipid plaque. The large artery proteins were extracted, and the expression levels of AMPK, pAMPK, STAT3 and pSTAT3 in related signal pathways were verified by Western blot. Results Cell experiments showed that after Met stimulation, the proportion of M1 macrophages decreased significantly, the proportion of M2 macrophages increased significantly (P＜0.05), AMPK activity increased significantly, and STAT3 activity decreased significantly. Animal experiments showed that three months after modeling, oil red O staining showed that the lipid depositions in the whole length of large artery and aortic valve in Met group were significantly lower than those in CTL group (P＜0.05); immunofluorescence staining showed that the proportion of M1 macrophages in lipid plaque in Met group was significantly lower than that in CTL group, while the proportion of M2 macrophages was significantly higher than that in CTL group (P＜0.05). Western blot experiment showed that AMPK activity increased significantly and STAT3 activity decreased significantly in Met group compared with the CTL group (P＜0.05). Conclusion Met inhibits the activity of STAT3 by activating AMPK, regulates the phenotypic differentiation of macrophages in plaque and inhibits the formation of As in mice.

Abstract:Aim Single nucleotide polymorphisms (SNP) occurring in the precursor or mature sequences of microRNA or in their binding sites on 3′ untranslated region of target genes may participate in the occurrence and development of many diseases, such as tumor, nervous system diseases, muscle hypertrophy, cardiovascular diseases and so on. In this study, bioinformatics technology was used to analyze the biological processes and signal pathways that may be affected by SNP rs386585341 A＞G located at the fourth position of miR-499a-3p seed sequence. Methods RNAfold database was used to predict whether rs386585341 A＞G would affect the secondary structure of pre-miR-499a. Pre-miR-499a-A and pre-miR-499a-G overexpression plasmids were constructed respectively to detect whether rs386585341 A＞G would affect the expression of mature miR-499a. Gene expression microarray and bioinformatics were used to analyze the effect of rs386585341 A＞G on the function of miR-499a-3p, then take the intersection of differential gene expression profile and TargetScan target gene, and analyze the divergence of target genes of miR-499a-3p with different alleles of rs386585341A＞G.Results rs386585341 A＞G did not affect the secondary structure of pre-miR-499a, nor the expression levels of mature miR-499a-5p and miR-499a-3p, but affected the target gene network regulated by mature miR-499a-3p. The results of GO and pathway analysis of differentially expressed genes (DEG) showed that miR-499a-3p-A and miR-499a-3p-G showed different biological functions. The downstream gene network of miR-499a-3p-A was mainly enriched in immune regulation, while the downstream gene network of miR-499a-3p-G was mainly enriched in angiogenesis. The 4 target genes of miR-499a-3p-A including Spry2, Pcnx, Ndufa5 and Tcf7l2, were obtained by intersect analysis of down-regulated genes and TargetScan target genes, but the direct target genes of miR-499a-3p-G were not obtained. It indicated that after the miR-499a-3p seed region fourth was converted from A to G by rs386585341, the target gene formula of miR-499a-3p could be transformed from the degradation of target gene mRNA to the protein translation that only inhibits target genes.Conclusion rs386585341 A＞G may play important roles in immune differentiation and angiogenesis by affecting the downstream network of miR-499a-3p.

Abstract:Atherosclerosis is the common pathological basis of various cardiovascular diseases. A large number of evidences indicate that inflammation plays an important role in the pathophysiological process of atherosclerosis. The development of atherosclerosis is regulated by innate and adaptive immune cells, and is closely related to the level of systemic inflammation. A variety of inflammatory factors can be used as predictors of atherosclerosis related cardiovascular diseases, meanwhile, some clinical trials for anti-inflammatory therapy have shown that the risk of cardiovascular events are decreased by reducing the level of systemic inflammatory factors. This article focuses on the role of inflammation, the characteristics of immune response in the development of atherosclerosis, as well as the current progress of clinical research on anti-inflammatory therapy of atherosclerosis, aiming to provide new therapeutic strategies and targets for atherosclerosis.

Abstract:Scholars often focus on the formation of vascular intimal atherosclerosis (As) plaque, but pay little attention to the immune response of vascular adventitia and its impact on the course of the disease. Previous studies have found that there are orderly aggregate of immune cells in the adventitia of aged ApoE－/－ mice, forming ectopic lymphoid tissue similar to lymph node, which is called artery tertiary lymphoid organs (ATLO), and its formation has an obvious regulatory effect on intimal As. The discovery and study of ATLO point out a new direction for the study of As and provide a good example for the study of tertiary lymphoid organ (TLO) in other diseases. Therefore, clarifying the characteristics and formation mechanism of TLO is of great significance for the prevention and treatment of As, and provides a solid foundation for its clinical application in other diseases.

Abstract:Recently, the American Heart Association (AHA) published the 2021 dietary guidelines for promoting cardiovascular health in the American Journal circulation, proposing to control energy balance, maintain healthy weight, increase the intake of fruits and vegetables, prefer whole grain food, reduce refined food, avoid over processed food, use vegetable oil reasonably, and minimize sugary food dietary guidelines such as choosing low salt diet and reasonably controlling drinking have important protective rolein promoting cardiovascular health. This paper interprets this latest dietary guide, and puts forward healthy dietary guidance suitable for Chinese people in combination with oriental eating habits and the changes of Chinese people's eating habits in recent years.

Abstract:Aim To investigate the effect of microRNA miR-25-3p on fibrosis-related gene expression in cardiac fibroblasts and mechanism involved. Methods A mouse model of cardiac fibrosis induced by angiotensin Ⅱ (AngⅡ) infusion was constructed, and the differentially expressed miRNAs in the fibrotic mouse myocardium were detected by miRNA chip array. Primary isolation and culture of C57BL/6 mouse cardiac fibroblasts (mCF) were performed, and a cell model of myocardial fibrosis was established based on AngⅡ-treated mCF. The effect of miR-25-3p mimic on the expression of fibrosis-related genes in mCF was studied. The dual luciferase reporter gene assay was performed to verify the binding of miR-25-3p on the 3′-untranslated region (3′UTR) of the B-cell translocation gene 2 (BTG2) gene. Actinomycin D experiment was performed to detect the effect of BTG2 on the stability of superoxide dismutase 2 (SOD2) mRNA in mCF. Results Expression of miR-25-3p was increased in the myocardium of AngⅡ-infused mice and AngⅡ-treated mCF. miR-25-3p could enhance the expression of fibrosis-related genes, including collagen type Ⅰ alpha 1 chain (COL1A1), collagen type Ⅲ alpha 1 chain(COL3A1) and α-smooth muscle actin(α-SMA) in mCF. BTG2 was confirmed to be a target gene of miR-25-3p, and BTG2 mediated the effect of miR-25-3p on promoting fibrosis-related gene expression in mCF. In addition, BTG2 could enhance the expression of SOD2 by increasing the stability of SOD2 mRNA in mCF. Conclusion MiR-25-3p inhibited the level of SOD2 through targeting BTG2 in mCF, resulting in enhancing fibrosis-related gene expression and promoting myocardial fibrosis.

Abstract:Aim To evaluate whether remnant cholesterol combined with traditional blood lipid parameters can improve the predictive efficacy for major adverse cardiovascular and cerebrovascular events (MACCE) in prehypertensive patients. Methods The clinical data of 421 prehypertensive patients who underwent coronary angiography for coronary heart disease or suspected coronary heart disease in General Hospital of Northern Theater Command from 2004 to 2014 were retrospectively analyzed, and various types of data before coronary angiography were recorded during hospitalization, including basic clinical baseline data such as age, gender, height, weight, blood lipids, and blood glucose. A total of 95 patients were included in the case group when they were readmitted due to MACCE during long-term follow-up (follow-up methods included but not limited to telephone, SMS, etc.); 200 patients with prehypertension but without MACCE in the concurrent cohort were selected as the control group. The differences in clinical baseline data between the two groups were analyzed and compared, multivariate Logistic regression analysis was performed for various lipid parameters to determine their OR, receiver operating characteristic (ROC) curves were used to analyze the predictive value of various lipid parameters and combined predictors for MACCE in prehypertensive patients, and MEDCALC software was used to compare the area under the curve of traditional lipid parameters and combined predictors. Results The levels of remnant cholesterol, low density lipoprotein cholesterol (LDLC), triglyceride (TG), total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDLC), remnant cholesterol/HDLC, and LDLC/HDLC in the case group were significantly higher than those in the control group, and the number of patients with high-salt diet and diabetes in the case group were also higher than those in the control group, and the above differences were statistically significant (P＜0.05). The results of multivariate Logistic regression analysis showed that remnant cholesterol, non-HDLC, TG, TC, remnant cholesterol/HDLC, and LDLC/HDLC were all independent predictors of prehypertension patients after adjusting for gender and age factors (P＜0.01). ROC curve analysis showed that the AUC of remnant cholesterol combined with other lipid parameters in predicting the occurrence of MACCE in prehypertensive patients was 0.704, while the AUC of remnant cholesterol or other lipid parameters in predicting the occurrence of MACCE in prehypertensive patients was less than that of the combined predictor; comparison of the AUC of the combined predictor with the AUC of lipid parameters alone using the DELONG method revealed significant differences in other AUC except for non-HDLC (P＝0.054), which showed borderline positivity (P＜0.05). Conclusions In prehypertensive patients, remnant cholesterol, LDLC, non-HDLC, TG, TC remnant cholesterol/HD-C, and LDLC/HDLC are independent risk factors for MACCE in such patients. The combined predictive value constructed by remnant cholesterol combined with other lipid parameters has a better predictive value for MACCE in prehypertensive patients.

Abstract:Aim To investigate the relationship between complement-C1q/TNF-related protein 13 (CTRP13), urinary microalbumin/creatinine ratio (UACR) and unstable angina pectoris (UAP) with type 2 diabetes (T2DM). Methods From October 2019 to October 0,0 patients who were hospitalized in the Department of Cardiology and Endocrinology of the Affiliated Hospital of Chengde Medical College were divided into UAP+T2DM group (n＝50), UAP group (n＝50) and T2DM group (n＝50) according to whether they were diagnosed with UAP and T2DM. Healthy people who underwent physical examination at the same time were selected as the control group (n＝50). Serum CTRP13 concentration and morning urine UACR level were measured in four groups. The general data and the differences of CTRP13 and UACR levels were compared among groups, and the correlation between CTRP13, UACR and various indexes was analyzed in UAP+T2DM group; The reciprocal f(CTRP13(ng/L))＝1/(CTRP13(ng/L)) was used to convert CTRP13. The predictive efficacy of f(CTRP13) and UACR on UAP+T2DM was analyzed by ROC curve. Results The level of serum CTRP13 was the lowest in UAP+T2DM group, followed by T2DM group and UAP group, and the highest in control group(P＜0.05). The level of UACR was the highest in UAP+T2DM group, followed by UAP group and T2DM group, and the lowest in control group(P＜0.05). The Gensini score of UAP+T2DM group was higher than that of UAP group. Correlation analysis showed that in UAP+T2DM group, the level of serum CTRP13 was negatively correlated with fasting blood glucose (FPG), high sensitivity C-reactive protein (hs-CRP) and Gensini score, and positively correlated with high density lipoprotein cholesterol (HDLC) (all P＜0.05); UACR was positively correlated with waist circumference, low density lipoprotein cholesterol (LDLC), hs-CRP and Gensini score (all P＜0.05). The ROC curve showed that the areas under the curve (AUC) of f(CTRP13) and UACR single detection and combined detection of UAP combined with T2DM were 0.820 (95%CI:0.759～0.882), 0.846 (95%CI:0.786～0.905) and 0.876 (95%CI:0.820～0.931) respectively; their sensitivities were 88%, 82% and 86%, respectively; and their specificity were 64%, 80% and 77.3%, respectively (all P＜0.05). Conclusions CTRP13 and UACR may not only be used as auxiliary indicators for clinical diagnosis of UAP complicated with T2DM, but also can be used to evaluate the severity of coronary artery disease. The combined detection of both of them is of higher value in the diagnosis of UAP with T2DM.

Abstract:Aim To investigate the correlation between serum endothelial cell specific molecule-1 (ESM-1), hypoxia-inducible factor-1α (HIF-1α) levels and in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) in patients with unstable angina pectoris (UAP). Methods 202 patients with UAP who underwent PCI in our hospital from March 2018 to April 2019 were selected as the research objects. According to whether ISR occurred within 1 year of postoperative follow-up, the patients were divided into two groups:56 cases in ISR group and 146 cases in non-ISR group. Enzyme-linked immunosorbent assay was used to detect serum ESM-1 and HIF-1α levels in patients 24 h after PCI. The predictive value of serum ESM-1 and HIF-1α levels on ISR and the factors affecting ISR were analyzed. Results The proportion of smoking history, blood glucose, LDLC level, serum ESM-1 and HIF-1α levels in the ISR group were higher than those in the non-ISR group, and the difference was statistically significant (P＜0.05). Serum ESM-1 levels were positively correlated with HIF-1α levels in ISR patients after UAP PCI (r＝0.545, P＜0.05). The area under the ROC curve (AUC) of serum ESM-1 and HIF-1α predicting ISR in UAP patients after PCI were 0.913 and 0.851, respectively, the specificities were 87.0% and 74.0%, and the sensitivities were 82.1% and 85.7%, respectively; the AUC of the joint prediction of the two was 0.936, the specificity was 91.8%, and the sensitivity was 78.6%. ESM-1 (≥2.42 μg/L) and smoking were the independent risk factors affecting ISR in UAP patients after PCI (P＜0.05). Conclusion Increased serum ESM-1 and HIF-1α levels are closely related to the occurrence of ISR after PCI in UAP patients.

Abstract:Krüppel-like factor 15 (KLF15) is a critical member of Krüppel-like factor (KLF) family containing zinc finger. Studies have shown that KLF15 plays an important role in regulating various signal transduction pathways and energy metabolism. KLF15 can play an anti-myocardial remodeling role by affecting myocyte enhancer factor 2 (MEF2), transforming growth factor β (TGF-β) and so on. In addition, KLF15 is the key factor to maintain ventricular arrhythmia and circadian rhythm. This paper reviews the physiological and pathological role of KLF15 in the heart and the latest research progress in cardiovascular diseases.

Abstract:Atherosclerosis is a chronic vascular inflammation caused by lipid deposition. The onset and progression of atherosclerotic lesions are closely related to the disturbance of cellular cholesterol homeostasis. ATP-binding cassette transporter A1 (ABCA1) mediates active cholesterol efflux to apolipoprotein AⅠ, preβ high density lipoprotein (HDL), and HDL₃. The impairment of this cholesterol efflux pathway leads to the intracellular accumulation of cholesterol esters. Importantly, loss-of-function mutations of ABCA1 influence the growth of atherosclerotic plaques and the incidence of coronary heart diseases. Recent studies using transgenic animals have shown that effects of ABCA1 on atherosclerosis are tissue/cell-specific. This paper focuses on the role of tissue/cell-specific ABCA1 in atherosclerosis and underlying mechanisms after briefly introducing reverse cholesterol transport and atherosclerosis.

Abstract:Macrophages are a type of phagocytes, which play a crucial role in the occurrence and development of atherosclerosis. Studies have shown that different phenotypes of macrophages play different roles in the progression of atherosclerosis. Reducing the local proliferation of pro-inflammatory macrophages and inducing macrophages to transform into an anti-inflammatory phenotype are crucial to the treatmenent of atherosclerosis in the future. This article reviews the macrophage phenotype, phenotypic regulation related signaling pathways, and therapeutic strategies targeting the regulation of macrophage phenotypes, hoping to provide new targets or avenues for the prevention and treatment of atherosclerosis.