Abstract:Selective autophagy is specific to degraded substrate proteins, including mitophagy, lipophagy, inflammasomophagy, reticulophagy, pexophagy, aggrephagy and ribophagy, etc. Atherosclerosis (As) is a chronic inflammatory disease mainly characterized by lipid accumulation, foam cell formation, endothelial cell dysfunction, abnormal proliferation of vascular smooth muscle cell, and local inflammation. In recent years, a large number of studies have suggested that selective autophagy is involved in the development of As. This paper reviewed the regulatory mechanisms of selective autophagy, and the potential roles of mitophagy, lipophagy, inflammasomophagy, reticulophagy and pexophagy in As, which can provide new ideas for the treatment of As.

Abstract:Aim To explore the role of silent information regulator 1(SIRT1)/forkhead transcription factor O1 (FOXO1) in H₂S antagonism of H₂O₂-induced endothelial cell senescence. Methods The positive cell rate was calculated by the number of blue-stained cells (senescent cells) observed under the light microscope by senescence-associated β-gal (SA-β-gal) staining. Western blot was used to detect the expression levels of P21, P53, plasminogen activator inhibitor-1 (PAI-1), FOXO1, acetylated FOXO1 (ac-FOXO1), manganese superoxide dismutase (MnSOD) and catalase proteins, and biotin-switch assay was used to measure the expression of S-sulfhydration of SIRT1, and ROS detection was used to quantitatively evaluate intracellular reactive oxygen species (ROS) level. Results Treatment with 100 μmol/L H₂O₂ significantly increased the SA-β-gal staining-positive cell rate and the expression of P21, P53 and PAI-1 proteins, suggesting that the senescent cell model was successfully established, whereas 100 μmol/L NaHS significantly antagonized this effect, and the number of SA-β-gal staining-positive cells decreased significantly (P＜0.01), and the expression of P21, P53 and PAI-1 proteins significantly reduced (P＜0.01). Compared with the control group, the expression of SIRT1, FOXO1, ac-FOXO1, MnSOD and catalase proteins in the H₂O₂ group significantly decreased (P＜0.05 or P＜0.01), the ac-FOXO1/FOXO1 ratio significantly increased (P＜0.01), and the ROS level significantly increased (P＜0.01). Compared with H₂O₂ group, the expression of SIRT1, S-sulfhydration of SIRT1, FOXO1, ac-FOXO1, MnSOD and catalase proteins in the NaHS+H₂O₂ group was significantly increased (P＜0.05 or P＜0.01), and the ac-FOXO1/FOXO1 ratio was significantly decreased (P＜0.01), while the ROS level was significantly reduced (P＜0.01). Conclusion H₂S can antagonize H₂O₂-induced senescence of HUVEC by a mechanism related to promoting SIRT1 sulfhydrylation and reducing FOXO1 acetylation.

Abstract:Aim To investigate the mechanism of Danggui Buxuetang in treating atherosclerosis (As) by using network pharmacology and molecular docking technology. Methods The active ingredients of Danggui Buxuetang were obtained with the help of TCMSP database, and their potential targets were predicted using the Swiss Target Prediction platform. GeneCards and DisGeNET databases were used to screen As targets, and the intersection of active ingredient prediction targets and disease targets was used to obtain key intersection targets. The STRING platform was used to construct the intersection target PPI interaction network, and the Cytoscape software network topology analysis screened potential key targets. Cytoscape software was used to construct drug-ingredient-target and find the core active ingredient. GO function enrichment analysis and KEGG pathway enrichment analysis were carried out through the Metascape database, and finally, through molecular docking, the components and target mechanism of its therapeutic effect were further clarified. Results A total of 19 active ingredients of Danggui Buxue tang were screened, 204 predicted targets, 5 213 disease targets, and 176 intersection targets for the treatment of As were screened. The top five core targets were Akt1, JUN, TP53, TNF, IL-6. GO and KEGG enrichment analysis mainly pointed to functions such as oxidative stress response and transcriptional regulatory complex, and the signal transduction involved mainly included FoxO signaling pathway, JAK-STAT signaling pathway and IL-17 signaling pathway, etc. Molecular docking results showed that the docking binding energies of the five active ingredients and five important core targets were all less than －5 kJ/mol, suggesting that the binding between the receptor protein and the ligand small molecule was stable, and the lower the value, the higher the binding stability, and the top five active ingredients in terms of binding energy included β-sitosterol and quercetin, among which the active ingredient β-sitosterol had the lowest binding energy to TNF, which was －10.52 kJ/mol, indicating that β-sitosterol alcohol and quercetin, two active ingredients of traditional Chinese medicine, may play an important role in the treatment of atherosclerotic diseases. Conclusion The core active ingredients such as quercetin and β-sitosterol in Danggui Buxuetang may regulate inflammatory response, lipid metabolism and other related pathways by acting on core targets such as Akt1, JUN, TP53, TNF and IL-6, thereby exerting role in the treatment of atherosclerosis.

Abstract:Aim To investigate the effect and possible mechanism of oxymatrine injection (OMT) on cardiac function and ventricular remodeling in doxorubicin-induced chronic heart failure (CHF) rats. Methods The rat model with CHF was established by intraperitoneal injection (ip) of adriamycin (1.5 mg/kg, twice a week for 6 weeks).The model group, captopril injection (CTP, 6.5 mg/kg) group and OMT low (25 mg/kg), medium (50 mg/kg), high (100 mg/kg) dose group were set up, and the control group was set up, with 10 rats in each group. The rats in each group were treated by intraperitoneal injection once a day. 4 weeks later, the cardiac function indexes (left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left ventricular fractional shortening (LVFS), stroke volume (SV)) were measured through animal ultrasound; the content of cardiac troponin I (cTnI), brain natriuretic peptide (BNP), stromelysin-2 (ST2) in serum were detected by enzyme-linked immunosorbent assay (ELISA); the left ventricular hypertrophy index (LVHI) was calculated; the morphological changes and fibrosis of myocardial tissue were observed by HE staining and Masson staining; the expression of collagen I (Coll-1), α smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), Smad2, p-Smad2, Smad3, p-Smad3, Smad7 were detected by Western blot. Results Compared with the model group, the LVESD and LVEDD were decreased in CTP group and OMT low, medium, high dose groups; the LVFS, LVEF and SV were increased (all P＜0.05). The contents of cTnI, BNP and ST2 were decreased (all P＜0.05). The pathological changes and fibrosis of myocardial tissue were significantly improved, and the collagen volume fraction (CVF) were decreased (P＜0.05). The expressions of Coll-1, α-SMA and TGF-β1 were decreased; the ratio of p-Smad2/Smad2 and p-Smad3/Smad3 were decreased; the expression of Smad7 were increased (all P＜0.05). The effect of OMT on various indexes of CHF rats were dose-dependent, and the effect of OMT high-dose group on various indexes were significantly better than those of CTP group. Conclusion OMT can improve cardiac function and inhibit ventricular remodeling in CHF rats, which mechanism may be related to the inhibition of TGF-β1/Smads signaling pathway.

Abstract:Aim To investigate the effect of antagomiR-21 on endothelium-dependent relaxation of coronary artery in type 2 diabetes mellitus (T2DM) rats by regulating silent information regulator 1 (SIRT1) and its mechanism. Methods T2DM rat model was established by intraperitoneal injection of streptozotocin and fed with high-fat diet. 28 adult rats were randomly divided into model group, antagomiR-NC group, antagomiR-21 group, and antagomiR-21＋SIRT1 inhibitor EX527 group, with 7 rats in each group; in addition, 7 normal rats fed with common diet were used as control group. The changes of coronary artery flow in rats were observed, and the diastolic effect of coronary artery in rats was observed by isolated vascular ring perfusion technique. Human coronary artery endothelial cells (HCAEC) were divided into mannitol group, high glucose group, high glucose＋antagomiR-NC group, high glucose＋antagomiR-21 group, high glucose＋antagomiR-21＋EX527 group. The expression of miR-21 and SIRT1 mRNA was detected by qRT-PCR, and the expression of SIRT1, phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), endothelial nitric oxide synthase (eNOS) and its phosphorylated protein was detected by Western blot. Results Compared with the control group, the levels of miR-21 in the coronary arteries of T2DM model rats increased by 96.88%, while the expression levels of SIRT1 protein and mRNA, and coronary artery flow decreased by 40.85%, 64.29% and 22.15%, respectively (P＜0.05); compared with the mannitol group, in vitro high glucose treatment caused an increase of 285.71% in miR-21 expression in HCAEC, while the expression levels of SIRT1 protein and mRNA decreased by 44.78% and 74.51%, respectively (P＜0.05). The intervention of antagomiR-21 resulted in a decrease of 77.42% and 58.66% in both in vivo and in vitro miR-21 levels, an increase of 55.56% and 91.43% in SIRT1 protein levels, and an increase of 88.57% and 97.30% in SIRT1 mRNA levels, respectively (P＜0.05). Compared with the model group, the intervention of antagomiR-21 resulted in a 19.23% increase in coronary artery flow in rats, and a 111.89%, 41.88%, 41.98%, and 30.01% increase in coronary artery relaxation rate induced by 10－8 mol/L, 10－7 mol/L, 10－6 mol/L and 10－5 mol/L acetylcholine (Ach), respectively (P＜0.05), and the coronary artery contraction rate in rats decreased by 36.71%, 47.90%, 49.19% and 45.27% induced by 10－8 mol/L, 10－7 mol/L, 10－6 mol/L and 10－5 mol/L phenylephrine (Phe) (P＜0.05). After the intervention of antagomiR-21, the phosphorylation levels of PI3K, Akt and eNOS in HCAEC increased by 48.48%, 81.40% and 134.29%, respectively, compared to the high glucose group (P＜0.05). EX527 treatment can significantly reverse the above changes caused by antagomiR-21 in vitro and in vivo (P＜0.05). Conclusion AntagoniR-21 can activate the PI3K/Akt/eNOS signaling pathway by upregulating SIRT1 expression, thereby improving endothelium-dependent relaxation of coronary artery in T2DM rats.

Abstract:Aim To investigate clinical characteristics, outcome analysis and related factors of early left ventricular thrombosis (LVT) in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods With a retrospective study, from January 2019 to December 1,7 patients with acute anterior wall myocardial infarction were enrolled in the Cardiovascular Department of Shenzhen Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences.Among them, 53 patients with early LVT were selected as the STEMI＋LVT group, and 244 patients without LVT were selected as the STEMI group. Collect and compare basic clinical data, occurrence of embolic events, echocardiography and cardiac magnetic resonance imaging data, ventricular morphological characteristics of LVT, coronary angiography, interventional therapy, and medication plans between two groups of patients. Multivariate Logistic regression analysis was used to investigate the related factors of early LVT formation in acute STEMI patients. Results There was no significant difference between the two groups in age, hypertension, diabetes, smoking, multi vessel disease, high sensitivity C-reactive protein (hs-CRP), serum creatinine (SCr), total cholesterol (TC), triglyceride (TG), N-terminal pro-brain natriuretic peptide (NT-proBNP), and the proportion of patients receiving antiplatelet therapy (P＞0.05). The STEMI＋LVT group had a history of previous myocardial infarction, early ventricular aneurysm formation, concomitant shock (SCAI classification), and higher support rates for intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO) compared to the STEMI group (P＜0.05). Left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) in the STEMI＋LVT group were higher than those in the STEMI group, LVEF in the STEMI＋LVT group was obviously lower than that in the STEMI group (P＜0.05). Multivariate Logistic regression analysis showed that a history of previous myocardial infarction (OR＝3.6,5%CI:1.069～10.592, P＝0.036), early ventricular aneurysm formation (OR＝3.0,5%CI:1.025～8.864, P＝0.047), and concomitant shock (OR＝3.1,5%CI:1.215～9.031, P＝0.017) were associated with an increased risk of early LVT formation in acute STEMI, while LVEF＞40% (OR＝0.3,5%CI:0.054～0.669, P＝0.011) and emergency PCI (OR＝0.4,5%CI:0.089～0.678, P＝0.008) were associated with a reduced risk of early LVT formation in STEMI. Conclusion Early LVT formation in acute STEMI patients is more common in the left ventricular apex, the combination of shock, previous history of myocardial infarction, early ventricular aneurysm, emergency PCI and baseline LVEF＞40% may be independent influencing factors for early LVT formation in acute STEMI patients.

Abstract:Aim To explore the correlation between ultrasound evaluation of epicardial adipose thickness (EAT) and right common carotid artery elasticity and carotid intima-media thickness (CIMT) in middle-aged and elderly coronary heart disease (CHD) patients. Methods The middle-aged and elderly patients (100 cases) who visited Nanyang Central Hospital from February 2018 to June 2021 and were diagnosed with CHD by coronary angiography(CAG) were selected as the research subjects. According to the number of diseased branches, they were divided into single (31 cases), double (36 cases) and triple (33 cases) vessel lesions groups. In addition, physical examination population without coronary heart disease (50 cases) at Nanyang Central Hospital during the same period were selected as the control group. The general information and ultrasonic testing parameters of the four groups of subjects were compared and analyzed. Pearson was used to analyze the correlation between EAT and the elasticity of the right common carotid artery, CIMT. The receiver operating characteristic (ROC) curve was used to analyze the value of EAT, right common carotid artery elasticity and CIMT in predicting CHD. Results Compared with the control group, vascular stiffness (β), elastic modulus (Ep), pulse wave velocity (PWV-β), CIMT, and EAT were increased in the single vessel lesion group, double vessel lesions group, and triple vessel lesions group (all P＜0.05), aortic compliance (AC) were decreased (all P＜0.05). Pearson analysis showed that EAT was positively correlated with β, Ep, PWV-β and CIMT (P＜0.05), and negatively correlated with AC (P＜0.05). The results of ROC curve analysis showed that the sensitivity, specificity and Youden index of the three combined detection (EAT, CIMT and right common carotid artery elasticity) were 89%, 82% and 71%in predicting the occurrence of CHD, respectively. Conclusion EAT in middle-aged and elderly patients with CHD has a good correlation with the elastic changes of the right common carotid artery, CIMT. The combined detection of EAT, right common carotid artery elasticity changes, and CIMT can provide a good basis for clinical prediction of CHD.

Abstract:Aim To develop and validate a risk prediction model for fundus arteriosclerosis. Methods Patients without fundus arteriosclerosis who underwent physical examination in Huadong Sanatorium from 2006 to 2013 were selected as the derivation cohort. Lasso method was used to screen the predictors, and Cox regression method was used to establish the prediction model. The model was presented as an online calculator. The Bootstrap method was used for internal validation, and the physical examination subjects in the hospital from 2015 to 2021 were selected for temporal validation. The concordance (C) statistic was used to quantify discrimination, and the calibration of the model was evaluated by comparing the predicted survival probability with the observed survival probability using calibration plots and the Kaplan-Meier method. Results The derivation cohort included 33 218 participants and external validation cohort included 53 863 participants. The final model included nine predictors:age, body mass index, alcohol consumption, diastolic blood pressure, hypertension, fasting blood glucose, diabetes, triglyceride, and serum uric acid. Online calculator site at:https://rui2022.shinyapps.io/DynNomapp/. The C statistic of internal validation was 0.841, and the C statistic of external validation was 0.856. Calibration performed well in both the derivation and external validation cohorts. Conclusion The established risk prediction model of fundus arteriosclerosis has a good predictive ability in the physical examination population. The model only needs the variables routinely obtained by the hospital, so it can be applied to the individualized management of physical examination population and the decision support of the management of high-risk people.

Abstract:Chylomicrons, as the main source of intestinal triglyceride-rich lipoproteins and their remnants, can promote the occurrence and development of atherosclerosis. Therefore, reducing chylomicrons and their remnants are expected to be one of the effective methods to reduce the residual risk of cardiovascular disease. This review describes the key proteins in the production of chylomicrons and their molecular mechanisms, as well as the progress of Chinese and Western medicine therapy systematically in order to provide reliable new ideas for the prevention and treatment of atherosclerosis.

Abstract:According to statistics, 67% women and 33% men with angina and 10% of patients with acute myocardial infarction have no significant stenosis in the epicardial coronary lumen during coronary angiography (CAG). After excluding coronary spasm, thrombosis autolysis, mental and other factors, no significant stenosis was found in CAG but the patients still had symptoms of myocardial ischemia, suggesting the existence of coronary artery microcirculation disorder (CMD). The CMD mechanism is still unclear, and it is generally believed that the main mechanisms leading to CMD are coronary microembolization (CME), endothelial dysfunction (ED), myocardial ischemia/reperfusion injury (MIRI) and autonomic dysfunction (AD). A large number of non-coding RNA (ncRNA) are involved in the development of CMD through these mechanisms. This review focuses on the regulatory role of microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) in the development and treatment of CMD.

Abstract:The hypoxia inducible factor-1α (HIF-1α) is a major regulator of the cellular response to hypoxia, and its high expression is induced in the hypoxic environment of atherosclerosis (As) plaques. It is a key protein to promote the progression of As and widely involved in the occurrence and development of As. This article reviews the structure and function of HIF-1α and its role in endothelial cells, vascular smooth muscle cells, mononuclear macrophages and the differentiation of CD4＋T cells, in order to provide new ideas for the prevention and treatment of As based on HIF-1α.

Abstract:CD147 is a member of the immunoglobulin super family, which can be highly expressed in inflammatory tissues and has a pro-inflammatory effect. Atherosclerosis is well known as a chronic inflammatory disease, and the mechanism of high expression of CD147 promoting atherosclerosis has been confirmed by a large number of studies. Understanding how CD147 promotes the occurrence and development of atherosclerosis can provide new ideas for the prevention and treatment of this disease. At the same time, a large number of compounds have been proved to be able to downregulate CD147 to have anti-atherosclerosis effect, which also provides a direction for drug design targeting CD147 in the future. This article reviews the mechanism of atherosclerosis induced by CD147 and the research progress of compounds that downregulate CD147.