High-Throughput Sequencing to Investigate the Expression and Potential Role of Differentially Expressed microRNAs in Myocardial Cells after Ischemia-Reperfusion Injury.

BACKGROUND: microRNAs (miRNAs) are closely associated with the pathogenesis of various diseases, but the relationship between miRNAs and myocardial ischemia-reperfusion (I/R) injury remains unclear. Therefore, we aimed to explore the role and function of miRNAs and identify target genes regulating I/R. METHODS: We established a hypoxia/reoxygenation (H/R) model to detect differentially expressed miRNAs using high-throughput sequencing in rat myocardial cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the potential functions and signaling pathways of target genes. RESULTS: We identified 113 differentially expressed miRNAs, comprising 76 and 37 upregulated and downregulated genes, respectively. Database predictions suggested that miR-200a-3p may act through the ferroptosis pathway, and we assessed the expression of miR-200a-3p, iron ions, and ferroptosis markers. The expression of miR-200a-3p significantly increased in the H/R group, along with increased production of reactive oxygen species (ROS) and iron ions. When the expression of miR-200a-3p was inhibited, iron ions and ROS levels decreased significantly. Western blotting showed that transferrin receptor (TFRC) and Acyl-coA synthetase long-chain family member 4 (ACSL4) levels were decreased and Glutathione peroxidase 4 (GPX4) expression was increased. CONCLUSIONS: These findings offer a novel perspective on I/R regulation, and the specific mechanisms underlying the actions of miR-200a-3p merit further investigation.

The clinical utility of circulating cell division control 42 in small-vessel coronary artery disease patients undergoing drug-coated balloon treatment.

BACKGROUND: Cell division control 42 (CDC42) regulates atherosclerosis, blood lipids, and inflammation and thus affects coronary artery disease (CAD), but its utility in drug-coated balloon (DCB)-treated small-vessel CAD (SV-CAD) patients is unclear. This study intended to evaluate the change and prognostic role of CDC42 in SV-CAD patients underwent DCB. METHODS: Serum CDC42 was measured by enzyme-linked immunosorbent assay in 211 SV-CAD patients underwent DCB at baseline, day (D) 1, D3, and D7, as well as in 50 healthy controls (HCs). RESULTS: CDC42 was decreased in SV-CAD patients compared to HCs (P < 0.001), and it was negatively associated with total cholesterol (P = 0.015), low-density lipoprotein cholesterol (P = 0.003), C-reactive protein (P = 0.001), multivessel disease (P = 0.020), and American college of cardiology/American heart association type B2/C lesions (P = 0.039) in SV-CAD patients. Longitudinally, CDC42 decreased from baseline to D1 and then gradually increased to D7 (P < 0.001) in SV-CAD patients after DCB. Interestingly, high CDC42 (cut-off value = 500 pg/mL) at baseline (P = 0.047), D3 (P = 0.046), and D7 (P = 0.008) was associated with a lower accumulating target lesion failure (TLF) rate; high CDC42 at D3 (P = 0.037) and D7 (P = 0.041) was related to a lower accumulating major adverse cardiovascular event (MACE) rate in SV-CAD patients underwent DCB. Importantly, CDC42 at D7 (high vs. low) independently predicted lower accumulating TLF (hazard ratio (HR) = 0.145, P = 0.021) and MACE (HR = 0.295, P = 0.023) risks in SV-CAD patients underwent DCB. CONCLUSIONS: Circulating CDC42 level relates to milder disease conditions and independently estimates lower risks of TLF and MACE in SV-CAD patients underwent DCB, but further validation is still needed.

A review on the current literature regarding the value of exosome miRNAs in various diseases.

Exosome microRNAs (miRNAs) have great research outlook in clinical therapy and biomarkers, they have been found to have a close to multiple diseases. A growing number of studies have attempted to alleviate or treat diseases through exosomes. It indicates that miRNAs in exosomes have great significance in preventing and controlling diseases in clinical research. We summarise these studies below to better understand their implications.We screened and analyzed more than 100 articles from PubMed, Web of Science, and other databases from 1987 to 2022. Data of the clinical trials are collected from clinicaltrials.gov.In this review, we introduce the source, type, and characteristics of several exosomes, summarising current research on their role in cardiovascular, nervous system disease, tumour, and other diseases. Further, we discuss their mechanism of action and future directions for development of treatments in several diseases, and highlight the significant research value and potential use of exosomes in clinical diagnosis and treatment.An increasing number of researchers have begun to explore the link between exosomal miRNAs and diseases. More exosome therapeutics will be used in future clinical trials, which may bring new hope for the diagnosis and treatment of several diseases.KEY MESSAGESExosomes have unique advantages in molecular transport and cell signal transduction.miRNAs play an essential role in the formation of multiple diseases.Research on the clinical application and potential value of exosomes is growing.

Comparison of insulin resistance-associated parameters in US adults: a cross-sectional study.

BACKGROUND: Triglyceride-glucose (TyG) is correlated with cardiovascular events caused by insulin resistance (IR). The aim of this study was to analyze the relationship between TyG and its related indicators and IR among US adults from 2007 to 2018 in the National Health and Nutrition Examination Survey (NHANES) database so as to identify more accurate and reliable predictors of IR. METHODS: This is a cross-sectional study including 9884 participants (2255 with IR and 7629 without IR). TyG, TyG-body mass index (TyG-BMI), TyG waist circumference (TyG-WC), and TyG waist-to-height ratio (TyG-WtHR) were measured using standard formulas. RESULTS: TyG, TyG-BMI, TyG-WC, and TyG-WtHR were significantly correlated with IR in the general population, with TyG-WC being the most strongly correlated, with an odds ratio of 8.00 (95% confidence interval 5.05-12.67) for the fourth quartile of TyG-WC compared with the first quartile in the adjusted model. Receiver operating characteristic (ROC) analysis of the participants showed that the maximum area under the TyG-WC curve was 0.8491, which was significantly higher than that of the other three indicators. Moreover, this trend was stable both among people of both genders and among patients with coronary heart disease (CHD), hypertension, and diabetes. CONCLUSIONS: The present study confirms that the TyG-WC index is more successful than TyG alone in identifying IR. In addition, our findings demonstrate that TyG-WC is a simple and effective marker for screening the general US adult population and those with CHD, hypertension, and diabetes and can be effectively used in clinical practice.

Association between monocyte to high-density lipoprotein ratio and coronary heart disease in US adults in the National Health and Nutrition Examination Surveys 2009-2018.

BACKGROUND: Monocyte to high-density lipoprotein ratio (MHR) is associated with coronary heart disease (CHD) events. The purpose of this study was to analyze the correlation between MHR and CHD in American adults from 2009 to 2018 in the National Health and Nutrition Examination Surveys (NHANES) database. METHODS: A total of 25 862 persons in the NHANES from 2009 to 2018 were included in the cross-sectional analysis. The independent variable was MHR and the outcome variable was CHD. MHR was obtained by dividing the number of monocytes by the high-density lipoprotein concentration, and whether it is CHD is obtained through a questionnaire. Univariate analysis, stratified analysis, and a multivariate linear regression model were used to study the correlation between MHR and CHD. RESULTS: In each multivariate linear regression model, MHR was positively correlated with CHD, and this positive correlation was stable in both men and women [man odds ratio (OR): 1.54; 95% confidence interval (CI), 1.17-2.03; woman OR: 2.21; 95% CI, 1.40-3.50]. Our results show that the association between MHR and CHD was significant until MHR was less than 0.6 (OR: 7.2; 95% CI, 4.0-13.0); however, in cases where MHR was greater than 0.6, the results were negative but not significantly different (OR: 0.6; 95% CI, 0.3-1.2). CONCLUSION: MHR has a clear association with CHD. Our prediction model and validation model show that MHR is highly predictive and robust as a predictor of CHD, therefore it can play an important role in the prediction of CHD.

Association between hypertension and stroke in US adults in the National Health and Nutrition Examination Surveys (NHANES) 2007 to 2018.

BACKGROUND: Hypertension is associated with stroke events. The purpose of this study was to analyze the correlation between hypertension and stroke in American adults from 2007 to 2018 in National health and Nutrition Examination Survey (NHANES) database. METHODS: 28528 individuals in the NHANES from 2007 to 2018 were included in the cross-sectional analysis. The independent variable was blood pressure (BP) and the outcome variable was stroke. Multivariate linear regression model was used to study the correlation between BP and stroke. RESULTS: In each multivariate linear regression model, BP level was positively correlated with stroke, and this positive correlation was stable in both men and women (man OR: 1.36, 95% CI: 0.95 to 1.69; woman OR: 1.45, 95% CI: 1.12 to 1.78). CONCLUSION: Our results show that there is a significant positive correlation between BP and stroke. When the systolic blood pressure (SBP) is about 140 mmHg, the risk of stroke is the lowest; Male patients with diastolic blood pressure (DBP) of about 80 mmHg have a lower risk of stroke.

Development and validation using NHANES data of a predictive model for depression risk in myocardial infarction survivors.

BACKGROUND: Depression after myocardial infarction (MI) is associated with poor prognosis. This study aimed to develop and validate a nomogram to predict the risk of depression in patients with MI. METHODS: This retrospective study included 1615 survivors of MI aged >20 years who were selected from the 2005-2018 National Health and Nutrition Examination Survey database. The 899 subjects from the 2005-2012 survey comprised the development group, and the remaining 716 subjects comprised the validation group. Univariate and multivariate analyses identified variables significantly associated with depression. The least absolute shrinkage and selection operator (LASSO) binomial regression model was used to select the best predictive variables. RESULTS: A full predictive model and a simplified model were developed using multivariate analysis and LASSO binomial regression results, respectively, and validated using data from the validation group. The receiver operator characteristic curve and Hosmer-Lemeshow goodness of fit test were used to assess the nomogram's performance. The full nomogram model included 8 items: age, BMI, smoking, drinking, diabetes, exercise, insomnia, and PIR. The area under the curve for the development group was 0.799 and for the validation group was 0.731, indicating that our model has good stability and predictive accuracy. The goodness of fit test showed a good model calibration for both groups. The simplified model includes age, smoking, PIR, and insomnia. The AUC of the simplified model was 0.772 and 0.711 in the development and validation groups, respectively, indicating that the simplified model still possessed good predictive accuracy. CONCLUSION: Our nomogram helped assess the individual probability of depression after MI and can be used as a complement to existing depression screening scales to help physicians make better treatment decisions.

Myocardial protective effect of sacubitril-valsartan on rats with acute myocardial infarction.

OBJECTIVE: The purpose of this study was to explore the effect of sacubitril-valsartan on rats with acute myocardial infarction. METHODS: Sprague-dawley rats were randomly divided into six groups. Rats in Group A and B were threaded without deligation and treated with valsartan (34 mg/kg) or sacubitril-valsartan (68 mg/kg) after operation. Rats in Group C and D were given the two drugs (34 mg/kg, 68 mg/kg) after ligation of the left anterior descending branch for 40 minutes. Rats in Group E and F were restored the blood of the coronary artery after ligation, and given the two drugs (34 mg/kg, 68 mg/kg) at the same time. N-terminal pro-brain natriuretic peptide, high sensitivity troponin T, aldosterone and Cyclic guanosine monophosphate were measured and Color Doppler echocardiography was performed. Six weeks later, the rats were killed, the hearts were weighed and stained with Masson staining. RESULTS: Compared with Group A and B, the levels of N-terminal pro-brain natriuretic peptide, high sensitivity troponin T, aldosterone and Cyclic guanosine monophosphate in other groups were significantly increased (p < 0.05). Before treatment, the left ventricular end diastolic diameter and left ventricular end systolic diameter were similar in each group. After treatment, the levels of left ventricular end diastolic diameter and left ventricular end systolic diameter, and collagen fiber range stained with blue in other groups were significantly increased in comparison with Group A and B (p < 0.05). In addition, the left ventricular volume and collagen fiber range stained with blue were notably decreased, the levels of ejection fraction (EF) were increased in sacubitril-valsartan groups in comparison with valsartan groups (p < 0.05). CONCLUSION: Early application of sacubitril-valsartan has a protective effect on rats with acute myocardial infarction.

Angiotensin receptor-neprilysin inhibitor attenuates ischemia-hypoxia-induced myocardial injury via inhibition of autophagy.

OBJECTIVES: Angiotensin receptor-neprilysin inhibitor (ARNI) improves cardiac function and protects from an ischemic myocardium. However, the role and mechanism of ARNI on autophagy in cardiac ischemic injury are poorly understood. Here, we investigated the protective effect and underlying mechanisms of ARNI on autophagy in H9c2 cardiomyocytes induced through ischemia and hypoxia (IH) treatment. METHODS: The cytotoxicity of IH injury on H9C2 cells with and without ARNI were evaluated using cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. The effect of ARNI on apoptosis was detected using flow cytometry. The expression of autophagic proteins (LC3-II, Beclin 1, and p62) was detected using western blot. RESULTS: The viability of H9c2 cells was significantly decreased at different IH-treated time points; ARNI pretreatment increased cell viability and inhibited IH injury in a dose-dependent manner. H9c2 cells treated with IH (6 h) significantly increased LDH release, while ARNI dose-dependently improved LDH release, with 20 µmol/L ARNI having the most significant effect. ARNI also ameliorated IH-induced apoptosis. IH treatment increased the protein expression of LC3-II and Beclin 1 and decreased the expression of p62, which were reversed by ARNI pretreatment. Furthermore, autophagy was further increased after pretreatment with rapamycin in IH-induced H9c2 cells, which abrogated the protective effect of ARNI. CONCLUSIONS: Our study shows that ARNI has a protective effect on IH-induced cardiomyocyte injury, which may be related to the inhibition of autophagy.

Practicability of Bivalirudin plus Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Percutaneous Coronary Intervention: A Meta-Analysis.

A variety of antithrombotic drugs are used during percutaneous coronary interventions (PCIs). We aimed to investigate the practicability of the use of bivalirudin and GPIs in patients receiving PCI. We searched 7 of 629 relevant records from PubMed, the Cochrane Library, EMBASE, and Web of Science for randomised controlled trials. There were no significant differences in the rates of major adverse cardiac events (MACE) between bivalirudin plus GPI and heparin (all P  >  .05). Bivalirudin plus planned GPI was similar to bivalirudin monotherapy in terms of the risk of MACE (risk ratio [RR] = 1.07; 95% confidence interval [CI] = .91 - 1.27; P = .55). Bivalirudin plus provisional GPI was associated with lower bleeding risk (RR = .57; 95% CI = .47 - .69; P < .01) compared to using heparin plus GPI. Compared to bivalirudin alone, bivalirudin plus planned GPI evidently increased bleeding risk (RR = 2.20; 95% CI = 1.73 - 2.79; P < .01). Patients receiving bivalirudin or heparin therapy had semblable efficacy endpoints, but those receiving bivalirudin had a significantly lower bleeding risk. For high-risk bleeding patients, bivalirudin plus provisional GPI can have a better antithrombotic effect than heparin, without increasing the bleeding risk.

Distal Transradial Access in Anatomical Snuffbox for Coronary Angiography and Intervention: An Updated Meta-Analysis.

OBJECTIVE: The previous meta-analysis has assessed that distal transradial access (dTRA) in anatomical snuffbox is safe and effective for coronary angiography and intervention and can reduce radial artery occlusion. However, since the publication of the previous meta-analysis, several observational studies have been added, so we performed an updated meta-analysis to include more eligible studies to compare distal transradial access in anatomical snuffbox with conventional transradial access (cTRA). METHOD: Pubmed, Embase, and Cochrane Library databases were searched for relevant studies from the literature published until 5 January 2021 to evaluate catheterization/puncture failure, hematoma, radial artery spasm, radial artery occlusion (RAO), access time, fluoroscopy time, radiation dose area product, total procedure time, and hemostatic device removal time. The pooled odds ratio (OR), weighted mean difference (WMD), and standardized mean difference (SMD) with 95% confidence interval (95% CI) were calculated for dichotomous and continuous variables, respectively. RESULTS: A total of 9,054 patients from 14 studies were included in the meta-analysis, and we found no significant difference in catheterization/puncture failure (OR = 1.94, 95CI [0.97, 3.86], P=0.06), hematoma (OR = 0.97, 95CI [0.55, 1.73], P=0.926), radial artery spasm (OR = 0.76, 95CI [0.43, 1.36], P=0.354), total procedure time (SMD = 0.23, 95CI [-0.21, 0.68], P=0.308), or radiation dose area product (WMD = 216.88 Gy/cm2, 95CI [-126.24, 560.00], P=0.215), but dTRA had a lower incidence of RAO (OR = 0.39, 95CI [0.23, 0.66], P < 0.001), shorter hemostatic device removal time (WMD = -66.62 min, 95CI [-76.68, -56.56], P < 0.001), longer access time (SMD = 0.32, 95CI [0.08, 0.56], P=0.008), and longer fluoroscopy time (SMD = 0.16, 95CI [-0.00, 0.33], P=0.05) than cTRA. CONCLUSION: Compared with the cTRA, the dTRA has a lower incidence of radial artery occlusion and shorter hemostatic device removal time, which is worthy of further evaluation in clinical practice.

Unitization facilitates familiarity-based cross-language associative recognition.

The unitization effect means a phenomenon in which familiarity can contribute to associative recognition judgments when pairs of items are treated as a single entity rather than two separate items. Cumulative evidences suggested that the unitization effect was not influenced by the type of language, and this effect could be generalized to bilinguals when they performed an associative recognition in their second language. In the present study, the influence of familiarity on cross-language associative retrieval under unitization and the underlying neurophysiological mechanism behind this effect were investigated. Participants completed two "study-test" tasks presented in intralinguistic (from Uygur to Uygur) or interlinguistic assignment (from Chinese to Uygur) respectively. The study showed that: (1) during intralinguistic assignments, both FN400 and LPC were found under unitization for balanced and unbalanced bilinguals, while an LPC but not FN400 was found under non-unitization. (2) During interlinguistic assignments, both FN400 and LPC were found under unitization for balanced bilinguals. However, an LPC but not FN400 was found under unitization for unbalanced bilinguals. Collectively, these results indicated that unitization facilitated familiarity to support cross-language retrieval. In particular, the effects of familiarity on cross-language retrieval were mediated by the second language proficiency.

The clinical effects of a new management mode for hypertensive patients: a randomized controlled trial.

BACKGROUND: The Internet, smartphones, and the application of health technology have great potential for hypertension management. We aim to evaluate a new mode of mobile health management with a social network application to guide blood pressure management in patients with hypertension. METHODS: Using a randomized controlled trial design, 120 hypertensive patients in the First Hospital of Shanxi Medical University who volunteered to participate in the study were randomly divided into an experimental group and a control group. The experimental group was divided into low, middle, or high-risk groups according to the cardiovascular risk stratification. The blood pressures of both the experimental group (the WeChat-guided new mode group) and the control group (the conventional mode group) were administered for three months. RESULTS: With intervention, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the experimental group were significantly lower than those in the control group (P=0.016). The SBP and DBP of the experimental group after intervention were lower than those before intervention (P<0.001), which was not observed in the control group (P=0.056). There was no difference in the SBP drops in the low-risk, middle-risk, and high-risk groups (P=0.402). Similarly, no difference in DBP drop was observed (P=0.628). There were no differences in Colorado Pretrial Assessment Tool (CPAT) scores between the experimental group and the control group before intervention (P=0.509). After intervention, CPAT scores in the experimental group were higher than those in the control group (P<0.001). Before intervention, there was no significant difference in the Hypertension Patients Self-Management Behavior Rating Scale (HPSMBRS) scores, blood lipid, body mass index (BMI), and urinary microalbumin between the experimental group and the control group (P>0.05). After intervention, the HPSMBRS score in the experimental group was significantly higher than that in the control group (P<0.05). The HPSMBRS score of the experimental group after intervention was higher than before intervention, and BMI, urinary microalbumin, TC, LDL-C were lower than before intervention (P<0.05). CONCLUSIONS: This new mode of mobile health management has a good effect on blood pressure control in patients with hypertension. It provides evidence for the application of mobile information technology for hypertension patients in clinical practice.

IFN regulatory Factor-1 induced macrophage pyroptosis by modulating m6A modification of circ_0029589 in patients with acute coronary syndrome.

BACKGROUND: Pyroptosis is identified as a novel form of inflammatory programmed cell death and has been recently found to be closely related to atherosclerosis (AS). We found that IFN regulatory factor-1(IRF-1) effectively promotes macrophage pyroptosis in patients with acute coronary syndrome (ACS). Subsequent studies have demonstrated that circRNAs are implicated in AS. However, the underlying mechanisms of circRNAs in macrophage pyroptosis remain elusive. METHODS: We detected the RNA expression of hsa_circ_0002984, hsa_circ_0010283 and hsa_circ_0029589 in human PBMC-derived macrophages from patients with coronary artery disease (CAD). The lentiviral recombinant vector for hsa_circ_0029589 overexpression (pLC5-GFP-circ_0029589) and small interference RNAs targeting hsa_circ_0029589 and METTL3 were constructed. Then, macrophages were transfected with pLC5-GFP-circ_0029589, si-circ_0029589 or si-METTL3 after IRF-1 was overexpressed and to explore the potential mechanism of hsa_circ_0029589 involved in IRF-1 induced macrophage pyroptosis. RESULTS: The relative RNA expression level of hsa_circ_0029589 in macrophages was decreased, whereas the N6-methyladenosine (m6A) level of hsa_circ_0029589 and the expression of m6A methyltransferase METTL3 were validated to be significantly elevated in macrophages in patients with ACS. Furthermore, overexpression of IRF-1 suppressed the expression of hsa_circ_0029589, but induced its m6A level along with the expression of METTL3 in macrophages. Additionally, either overexpression of hsa_circ_0029589 or inhibition of METTL3 significantly increased the expression of hsa_circ_0029589 and attenuated macrophage pyroptosis. CONCLUSION: Our observations suggest a novel mechanism by which IRF-1 facilitates macrophage pyroptosis and inflammation in ACS and AS by inhibiting circ_0029589 through promoting its m6A modification.

Implications of C1q/TNF-related protein superfamily in patients with coronary artery disease.

The C1q complement/TNF-related protein superfamily (CTRPs) displays differential effects on the regulation of metabolic homeostasis, governing cardiovascular function. However, whether and how they may serve as predictor/pro-diagnosis factors for assessing the risks of coronary artery disease (CAD) remains controversial. Therefore, we performed a clinical study to elaborate on the implication of CTRPs (CTRP1, CTRP5, CTRP7, and CTRP15) in CAD. CTRP1 were significantly increased, whereas CTRP7 and CTRP15 levels were decreased in CAD patients compared to the non-CAD group. Significant differences in CTRP1 levels were discovered between the single- and triple-vascular-vessel lesion groups. ROC analysis revealed that CTRP7 and CTRP15 may serve as CAD markers, while CTRP1 may serve as a marker for the single-vessel lesion of CAD. CTRP1 and CTRP5 can serve as markers for the triple-vessel lesion. CTRP1 may serve as an independent risk predictor for triple-vessel lesion, whereas CTRP15 alteration may serve for a single-vessel lesion of CAD. CTRP1 may serve as a novel superior biomarker for diagnosis of severity of vessel-lesion of CAD patients. CTRP7, CTRP15 may serve as more suitable biomarker for the diagnosis of CAD patients, whereas CTRP5 may serve as an independent predictor for CAD. These findings suggest CTRPs may be the superior predictive factors for the vascular lesion of CAD and represent novel therapeutic targets against CAD.

Recognition without Cued Recall across Chinese and English: Exploring the Role of Phonological, Orthographic, and Semantic Features.

Recognition without cued recall (RWCR) is a phenomenon that participants can effectively discriminate cues that resemble studied items from the ones that do not, even when they are not able to recall a studied item which is cued at test. It has been shown that a word's features could give rise to the RWCR effect. In the present study, by using this paradigm, we systematically investigated whether particular types of features alone, including orthographic, phonological, and semantic features, could evoke feelings of familiarity. By taking the advantage of a logographically scripted language (i.e., Chinese) to dissociate phonological from orthographic features in Experiment 1 and vice versa in Experiment 2, we examined whether phonological and orthographic features could induce a significant RWCR effect. In Experiment 3, by using a cross-language design to dissociate sematic features from orthographic and phonological features, we further explored whether separate semantic features could elicit the RWCR effect. A significant RWCR effect was found in all these experiments. These results have demonstrated that familiarity could be based on separate phonological, orthographic, and semantic features. The results are further discussed in relation to several theoretical explanations of familiarity.

IFN Regulatory Factor 1 Mediates Macrophage Pyroptosis Induced by Oxidized Low-Density Lipoprotein in Patients with Acute Coronary Syndrome.

BACKGROUND: Atherosclerosis (AS) is recognized as a chronic inflammatory disease. It is caused by the interaction between inflammatory cells such as macrophages, dendritic cells, and lipoproteins. Evidence has revealed that macrophage pyroptosis in lesion contributes to the formation of the necrotic core and thinning of the fibrous cap, which plays crucial roles in the onset of acute coronary syndrome (ACS). IFN regulatory factor 1 (IRF-1) is a pleiotropic transcription factor involved in various immune processes and cell death. We propose that IRF-1 may be implicated in macrophage pyroptosis in the pathogenesis of AS and ACS. METHODS: Patients with stable angina, unstable angina, acute myocardial infarction, and clinical presentation of chest pain were enrolled. The expression of IRF-1 in human PBMC-derived macrophages was analyzed. Then, overexpression and inhibition of IRF-1 was performed in macrophages from patients with ACS to explore the possible role and mechanism of IRF-1 involvement in macrophage pyroptosis. RESULTS: The expression of IRF-1 in macrophages was upregulated in ACS patients. The overexpression or inhibition of IRF-1 effectively modulated caspase-1 activation, as well as macrophage lysis, expression of gasdermin D-N (GSDMD-N), production of IL-1ß and IL-18, and activation of NLRP3-ASC inflammasome, which were all inhibited by caspase-1 inhibitor. Further experiments revealed that pyroptosis and the downstream inflammatory response in AS induced by IRF-1 is a process that is dependent on reactive oxygen species (ROS) generation. CONCLUSION: Our observations suggest that IRF-1 potently activates ox-LDL-induced macrophage pyroptosis and may play an important role in AS and ACS.

Adiponectin inhibits vascular smooth muscle cell calcification induced by beta-glycerophosphate through JAK2/STAT3 signaling pathway.

Vascular calcification is a common problem in the elderly with diabetes, heart failure and end-stage renal disease. The differentiation of vascular smooth muscle cells (VSMCs) into osteoblasts is the main feature, but the exact mechanism remains unclear. It is not clear whether adiponectin (APN) affects osteogenic differentiation of VSMCs. This study aims to explore the effect of APN on vascular calcification by using a cell model induced by beta-glycerophosphate (beta-GP). VSMCs were isolated and treated with beta-GP and APN in this study. The alkaline phosphatase (ALP) activity and expression levels of Runx2, BMP-2, collagen type I and osteocalcin were determined. The expression levels of STAT3 and p-STAT3 in nucleus and cytoplasm of VSMCs were analyzed. The results showed that APN significantly inhibited the expression of ALP, Runx2, BMP-2, collagen I, osteocalcin and the formation of the mineralized matrix in VSMCs induced by beta-GP. APN reduces the osteogenic differentiation of VSMCs induced by beta-GP and down-regulates the expression of the osteogenic transcription factor osterix by inhibiting STATS3 phosphorylation and nuclear transport. APN may be one of the potential candidates for clinical treatment of vascular calcification.

Plasma-derived exosomal miR-183 associates with protein kinase activity and may serve as a novel predictive biomarker of myocardial ischemic injury.

Myocardial infarction (MI) is primarily caused by ischemic heart or coronary artery disease and is a major cause of mortality worldwide. Thus, it is necessary to establish reliable biochemical markers for the early diagnosis of MI. MicroRNAs (miRNAs or miR) have been demonstrated to circulate in biological fluids and are enclosed in extracellular vesicles, including exosomes. The current study assessed the differential expression of exosomal miRNAs in the plasma of patients with MI and healthy individuals, and the possible mechanism involved. Plasma-derived exosomes were isolated from patients with MI and healthy control individuals, and vesicles with a membrane were observed using transmission electron microscopy. Furthermore, an exosomal miRNA expression profile was compared between patients with MI and healthy individuals using a miRNA microarray. Significantly differentially expressed miRNAs were validated using reverse transcription-quantitative polymerase chain reaction. To the best of our knowledge, the present study was the first to demonstrate that miR-183 was markedly upregulated in patients with MI compared with healthy individuals. In addition, the relative exosomal miR-183 level increased with the degree of myocardial ischemic injury. Additionally, GO and KEGG analyses demonstrated that miR-183 is primarily involved in cell communication, protein kinase activity regulation and adrenergic signaling in cardiomyocytes. Furthermore, a protein-protein interaction network of all the miR-183 target genes was constructed. The results demonstrated that five core genes (PPP2CB, PPP2CA, PRKCA, PPP2CA, PPP2R5C and PPP2R2A) in the PPI network were also associated with protein kinase activity regulation and adrenergic signaling in cardiomyocytes. Taken together, these data demonstrate that exosomal miR-183 derived from the serum of patients with MI may be a novel diagnostic biomarker involved in the regulation of protein kinase activity. miR-183 may therefore be further developed for clinical use to benefit patients with coronary artery diseases.

Adiponectin inhibits proliferation of vascular endothelial cells induced by Ox-LDL by promoting dephosphorylation of Caveolin-1 and depolymerization of eNOS and up-regulating release of NO.

Oxidized low density lipoprotein (ox-LDL) can induce the proliferation and differentiation of endothelial cells, which is one of the important mechanisms of ox-LDL atherosclerosis. Adiponectin is an endogenous bioactive polypeptide secreted by adipocytes, it participates in the metabolism of fat and glucose. It has the effect of reducing blood triglyceride and LDL content. Adiponectin also inhibits the abnormal proliferation and migration of endothelial cells, but its molecular mechanism is unclear. In this study, we used cell model of Ox-LDL-induced human aortic endothelial cells (HAECs) proliferation to analyze the molecular mechanism of APN inhibiting HAECs abnormal proliferation. The results showed that APN could inhibit the cell viability and DNA synthesis of HAECs after Ox-LDL treatment, up-regulate the apoptosis level and reduce the proportion of S + G2 phase cells. Further analysis showed that adiponectin could promote the dephosphorylation of Caveolin-1, which could dissociate eNOS and Caveolin-1, promote the phosphorylation of eNOS and enhance the synthesis of NO. NO increased expression levels of cleaved caspase 3 and p21 in the cells and inhibited the abnormal proliferation of HAECs. The regulation of phosphorylation and dephosphorylation of Caveolae-1 plays a key role in this process. Further study of the molecular mechanism of Caveolae-1 in the inhibition of HAECs abnormal proliferation by APN may reveal the potential of APN in the treatment of cardiovascular diseases.