Rosuvastatin Enhances Lymphangiogenesis after Myocardial Infarction by Regulating the miRNAs/Vascular Endothelial Growth Factor Receptor 3 (miRNAs/VEGFR3) Pathway.

BACKGROUND: Several clinical studies have suggested that the early administration of statins could reduce the risk of in-hospital mortality in acute myocardial infarction (AMI) patients. Recently, some studies have identified that stimulating lymphangiogenesis after AMI could improve cardiac function by reducing myocardial edema and inflammation. This study aimed to identify the effect of rosuvastatin on postinfarct lymphangiogenesis and to identify the underlying mechanism of this effect. METHOD: Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in mice orally administered rosuvastatin for 7 days. The changes in cardiac function, pathology, and lymphangiogenesis following MI were measured by echocardiography and immunostaining. EdU, Matrigel tube formation, and scratch wound assays were used to evaluate the effect of rosuvastatin on the proliferation, tube formation, and migration of the lymphatic endothelial cell line SVEC4-10. The expression of miR-107-3p, miR-491-5p, and VEGFR3 was measured by polymerase chain reaction (PCR) and Western blotting. A gain-of-function study was performed using miR-107-3p and miR-491-5p mimics. RESULTS: The rosuvastatin-treated mice had a significantly improved ejection fraction and increased lymphatic plexus density 7 days after MI. Rosuvastatin also reduced myocardial edema and inflammatory response after MI. We used a VEGFR3 inhibitor to partially reverse these effects. Rosuvastatin promoted the proliferation, migration, and tube formation of SVEC4-10 cells. PCR and Western blot analyses revealed that rosuvastatin intervention downregulated miR-107-3p and miR-491-5p and promoted VEGFR3 expression. The gain-of-function study showed that miR-107-3p and miR-491-5p could inhibit the proliferation, migration, and tube formation of SVEC4-10 cells. CONCLUSION: Rosuvastatin could improve heart function by promoting lymphangiogenesis after MI by regulating the miRNAs/VEGFR3 pathway.

Unusual course of congenital complete heart block in an adult: A case report.

BACKGROUND: Congenital complete heart block (CCHB) with normal cardiac structure and negativity for anti-Ro/La antibody is rare. Additionally, CCHB is much less frequently diagnosed in adults, and its natural history in adults is less well known. CASE SUMMARY: A 23-year-old woman was admitted to our hospital for frequent syncopal episodes. She had bradycardia at the age of 1 year but had never had impaired exercise capacity or a syncopal episode before admission. The possible diagnosis of acquired complete atrioventricular block was carefully ruled out, and then the diagnosis of CCHB was made. According to existing guidelines, permanent pacemaker implantation was recommended, but the patient declined. With regular follow-up for 28 years, the patient had an unusually good outcome without any invasive intervention or medicine. She had an uneventful pregnancy and led a normally active life without any symptoms of low cardiac output or syncopal recurrence. CONCLUSION: This case implies that CCHB in adulthood may have good clinical outcomes and does not always require permanent pacemaker implantation.

Endothelial Microparticle-Mediated Transfer of microRNA-19b Inhibits the Function and Distribution of Lymphatic Vessels in Atherosclerotic Mice.

In recent years, the function of the lymphatic system in atherosclerosis has attracted attention due to its role in immune cell trafficking, cholesterol removal from the periphery, and regulation of the inflammatory response. However, knowledge of the mechanisms regulating lymphangiogenesis and lymphatic function in the pathogenesis of atherosclerosis is limited. Endothelial microparticles carrying circulating microRNA (miRNA)s are known to mediate cell-cell communication, and our previous research showed that miRNA-19b in EMPs (EMPmiR-19b) was significantly increased in circulation and atherosclerotic vessels, and this increase in EMPmiR-19b promoted atherosclerosis. The present study investigated whether atherogenic EMPmiR-19b influences pathological changes of the lymphatic system in atherosclerosis. We first verified increased miR-19b levels and loss of lymphatic system function in atherosclerotic mice. Atherogenic western diet-fed ApoE-/- mice were injected with phosphate-buffered saline, EMPs carrying control miRNA (EMPcontrol), or EMPmiR-19b intravenously. The function and distribution of the lymphatic system was assessed via confocal microscopy, Evans blue staining, and pathological analysis. The results showed that lymphatic system dysfunction existed in the early stage of atherosclerosis, and the observed pathological changes persisted at the later stage, companied by an increased microRNA-19b level. In ApoE-/- mice systemically treated with EMPmiR-19b, the distribution, transport function, and permeability of the lymphatic system were significantly inhibited. In vitro experiments showed that miRNA-19b may damage the lymphatic system by inhibiting lymphatic endothelial cell migration and tube formation, and a possible mechanism is the inhibition of transforming growth factor beta receptor type II (TGF-ßRII) expression in lymphatic endothelial cells by miRNA-19b. Together, our findings demonstrate that atherogenic EMPmiR-19b may destroy lymphatic system function in atherosclerotic mice by downregulating TGF-ßRII expression.

Potentially Inappropriate Medication and Associated Factors Among Older Patients with Chronic Coronary Syndrome at Hospital Discharge in Beijing, China.

PURPOSE: Medication therapy is crucial in the management of chronic coronary syndrome (CCS). The use of potentially inappropriate medications (PIMs) contributes to poor outcomes in older patients, making it a major public health concern. However, few studies are available on PIMs use in older Chinese CCS patients. To investigate the frequency of prescribed PIMs at discharge and explore risk factors in older adults with CCS. PATIENTS AND METHODS: The cross-sectional study was conducted in a tertiary hospital in China over three months, from 1st October to 31st December, 2019. CCS patients aged over 60 years who were discharged alive were recruited. Information on demographics and medications at discharge was collected. Clinical data including diagnoses, frailty status, New York Heart Association (NYHA) class and age-adjusted Charlson Comorbidity Index (ACCI) were evaluated in each patient. PIMs were identified using the 2019 Beers criteria. Binary logistic regression was performed to recognize variables related to PIMs. RESULTS: A total of 447 eligible patients with 2947 medications were included. The prevalence of PIMs use was 38%. Medications to be avoided, to be used with caution, and with drug-drug interactions were 38.4%, 48.9% and 12.7% of the PIMs, respectively. Medications with drug-disease/syndrome interactions and those adjusted for kidney function were not identified. The common PIMs were diuretics (37.1%), benzodiazepines and benzodiazepine receptor agonist hypnotics (15.2%), glimepiride (13.1%), and co-prescription of potassium-sparing diuretics and renin-angiotensin system (RAS) inhibitors (9.7%). Individuals with frailty syndrome, polypharmacy, multiple comorbidities, atrial fibrillation, psychiatric disorders and greater NYHA class severity were more likely to receive PIMs. CONCLUSION: Prescription of PIMs was a common burden in older adults. A CCS multidisciplinary team is needed to control PIMs, especially in vulnerable older patients.

An Hypothesis: Disproportion Between Cardiac Troponin and B-Type Natriuretic Peptide Levels-A High Risk and Poor Prognostic Biomarker in Patients With Fulminant Myocarditis?

In our clinical practice, we recently found some patients with severe fulminant myocarditis (FM) who showed persistently elevated cardiac troponin (cTn) levels and "seemingly normal" B-type natriuretic peptide (BNP) level, and who subsequently progressed to poor outcomes. Indeed, this sounds contrary to conventional wisdom, but it is not an accidental phenomenon. Fulminant myocarditis is a rapidly progressive disease associated with high mortality. Recent studies have shown that patients with FM are significantly more likely to require heart transplantation than those without FM. Prompt diagnosis of FM and the institution of advanced cardiac life support will save more lives. Cardiac troponin and BNP are widely used diagnostic markers. Cardiac troponin is a specific marker of cardiac injury and its level correlates with the severity of cardiac injury. However, plasma BNP has a dual identity; it is not only a marker of cardiac pressure/volume overload, but it is also a cardioprotective factor that provides effective neurohormonal compensation to maintain homeostasis. Similar to fulminant hepatitis (characterised by diffuse inflammation and massive parenchymal cell necrosis) sometimes showing disproportion between transaminase level and bilirubin level, the disproportion between cTn and BNP levels in FM seems to be consistent with its severe histopathological changes, including diffuse infiltration of the myocardium by inflammatory cells, as well as severe cardiomyocyte injury and necrosis. Moreover, in previous studies, a lower BNP level was found to be an adverse prognostic marker in end-stage heart failure. All these findings indicate that in patients with FM with a persistently high cTn level and ominous clinical presentation, a "seemingly normal" BNP level is not a friendly signal. We hypothesise that the combination of a persistently elevated cTn level and low BNP level in patients with FM indicates worse myocardial injury and poor prognosis.

Therapeutic targets of rosuvastatin on heart failure and associated biological mechanisms: A study of network pharmacology and experimental validation.

To explore the potential targets underlying the effect of rosuvastatin on heart failure (HF) by utilizing a network pharmacology approach and experiments to identify the results. PharmMapper and other databases were mined for information relevant to the prediction of rosuvastatin targets and HF-related targets. Then, the rosuvastatin-HF target gene networks were created in Cytoscape software. Eventually, the targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, we constructed an HF animal model and used rosuvastatin to treat them, identifying the changes in heart function and related protein expression. We further used different cells to explore the mechanisms of rosuvastatin. Thirty-five intersection targets indicated the therapeutic targets linked to HF. GO analysis showed that 481 biological processes, 4 cellular components and 23 molecular functions were identified. KEGG analysis showed 13 significant treatment pathways. In animal experiments, rosuvastatin significantly improved the cardiac function of post-myocardial infarction mice and prevented the development of HF after myocardial infarction by inhibiting IL-1Β expression. Cell experiments showed that rosuvastatin could reduce the expression of IL-1B in HUVEC and THP-1 cells. The therapeutic mechanism of rosuvastatin against HF may be closely related to the inhibition of the expression of apoptosis-related proteins, inflammatory factors, and fibrosis-related genes. However, IL-1Β is one of the most important target genes.

Efficacy and safety of catheter-based renal denervation for heart failure with reduced ejection fraction: a systematic review and meta-analysis.

PURPOSE: To perform a comprehensive meta-analysis of all available evidence on the efficacy and safety of catheter-based renal denervation for heart failure with reduced ejection fraction. METHODS: We searched English and Chinese databases and calculated the weighted mean difference or standardized mean difference and 95% confidence intervals to estimate the efficacy and safety of renal denervation for heart failure. All relevant studies were screened and a meta-analysis was conducted using Review Manager 5.4. RESULTS: A total of 11 studies were identified for the meta-analysis. For the primary outcomes, the results showed that renal denervation significantly improved ejection fraction (weighted mean difference 6.42), left ventricular end-systolic diameter (weighted mean difference -3.95), left ventricular end-diastolic diameter (weighted mean difference -4.17) and left atrial diameter (weighted mean difference -4.09). For the secondary outcomes, renal denervation reduced the B-type natriuretic peptide level, heart rate, systolic blood pressure and diastolic blood pressure. However, further analysis revealed that renal denervation improved heart function but did not further reduce the heart rate and blood pressure compared with the control group. CONCLUSION: Treatment with renal denervation can significantly improve heart function and structure in patients with heart failure. In addition, the level of B-type natriuretic peptide can be reduced after renal denervation treatment. Renal denervation did not further reduce heart rate and blood pressure compared with the control group. Therefore, the treatment of heart failure with renal denervation is effective and safe.

Effect of Endothelial Microparticles Induced by Hypoxia on Migration and Angiogenesis of Human Umbilical Vein Endothelial Cells by Delivering MicroRNA-19b.

BACKGROUND: Microparticles (MPs) are small extracellular plasma membrane particles shed by activated and apoptotic cells, which are involved in the development of atherosclerosis. Our previous study found that microRNA (miR)-19b encapsulated within endothelial MPs (EMPs) may contribute to the upregulation of circulating miR-19b in unstable angina patients. Hypoxia is involved in atherosclerosis as a critical pathological stimulus. However, it still remains unclear whether the increase of miR-19b levels in EMPs is related to hypoxia and if the effect of miR-19b - wrapped within EMPs - stimulates hypoxia on vascular endothelial cells. This study aimed to explore the changes of miR-19b in EMPs induced by hypoxia as well as their effects on endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and arranged to harvest EMPs in two parts: the first part consisted of EMPcontrol and EMPhypoxia and the second part included EMPvehicle, EMPNC mimic, and EMPmiR-19b mimic. Cell migration was detected by scratch migration and transwell chamber migration. Angiogenesis was assessed by tube formation assays. Furthermore, we predicted the target gene of miR-19b by bioinformatics analysis, and luciferase assay was used to verify the targeted gene of miR-19b. Data were analyzed by one-way analysis of variance. Student's t-test was used when two groups were compared. RESULTS: Compared with EMPcontrol- and EMPhypoxia-inhibited migration of cells by scratch migration assay (80.77 ± 1.10 vs. 28.37 ± 1.40, P < 0. 001) and transwell chamber migration assay (83.00 ± 3.46 vs. 235.00 ± 16.52, P < 0.01), the number of tube formations was markedly reduced by 70% in the EMPhypoxia group (P < 0.001) in vitro analysis of HUVECs. Meanwhile, a strong inhibition of migration and tube formation of HUVECs in the presence of miR-19b-enriched EMPmiR-19b mimic was observed. This effect might be due to the delivery of miR-19b in EMPs. Transforming growth factor-ß2 (TGFß2) was predicted to be one of the target genes of miR-19b, and we further confirmed that TGFß2 was a direct target gene of miR-19b using the luciferase assay. The expression of TGFß2 in HUVECs was inhibited by treatment with EMPhypoxia and EMPmiR-19b mimic. CONCLUSIONS: MiR-19b in EMPs induced by hypoxia could reduce endothelial cell migration and angiogenesis by downregulating TGFß2 expression, which may have inhibited the progression of atherosclerosis.

Characteristics of elevated cardiac troponin I in patients with acute ischemic stroke.

OBJECTIVE: To study prognostic characteristics of cardiac troponin I (cTnI) elevation in acute ischemic stroke. METHODS: We retrospectively studied patients (n = 248) with acute ischemic stroke, acute ST-segment elevation myocardial infarction, and acute non-ST-elevation myocardial infarction who were treated between January 2013 and October 2015. Baseline demographic data and changes in cTnI levels among these three groups were compared. Patients with acute ischemic stroke were assigned to either the cTnI elevation group (cTnI > 0.034 ng/mL) or the no cTnI elevation group (cTnI ≤ 0.034 ng/mL). Logistic regression analysis was used to identify risk factors associated with elevated serum cTnI in patients with acute ischemic stroke. Moreover, the duration of hospital stay and incidence of major cardiovascular outcomes were compared in patients with acute ischemic stroke, with or without elevated cTnI. RESULTS: In this study population of patients with acute ischemic stroke (n = 178), acute ST-segment elevation myocardial infarction (n = 35), and acute non-ST-elevation myocardial infarction (n = 35), patients with acute ischemic stroke with elevated cTnI comprised 18.5% of subjects. Patients with elevated cTnI were older and more likely to have a history of hypertension. In addition, these patients had higher levels of inflammatory markers, reduced renal functions, increased D-dimer levels, higher NIH stroke scores, and lower left ventricular ejection fractions. Logistic regression analysis showed that both percentage of neutrophil and NIH stroke scores were elevated; estimated glomerular filtration rate and left ventricular ejection fraction were decreased in patients with acute ischemic stroke who had elevated cTnI, and they had more frequent major cardiovascular events during hospital stay. CONCLUSION: Elevated cTnI detected in patients with acute ischemic stroke, indicated a greater likelihood of poor short-term prognosis during hospital stay.

Dietary Capsaicin Improves Glucose Homeostasis and Alters the Gut Microbiota in Obese Diabetic ob/ob Mice.

Background: The effects of capsaicin on obesity and glucose homeostasis are still controversial and the mechanisms underlying these effects remain largely unknown. This study aimed to investigate the potential relationship between the regulation of obesity and glucose homeostasis by dietary capsaicin and the alterations of gut microbiota in obese diabetic ob/ob mice. Methods: The ob/ob mice were subjected to a normal, low-capsaicin (0.01%), or high-capsaicin (0.02%) diet for 6 weeks, respectively. Obesity phenotypes, glucose homeostasis, the gut microbiota structure and composition, short-chain fatty acids, gastrointestinal hormones, and pro-inflammatory cytokines were measured. Results: Both the low- and high-capsaicin diets failed to prevent the increase in body weight, adiposity index, and Lee's obesity index. However, dietary capsaicin at both the low and high doses significantly inhibited the increase of fasting blood glucose and insulin levels. These inhibitory effects were comparable between the two groups. Similarly, dietary capsaicin resulted in remarkable improvement in glucose and insulin tolerance. In addition, neither the low- nor high-capsaicin diet could alter the α-diversity and ß-diversity of the gut microbiota. Taxonomy-based analysis showed that both the low- and high-capsaicin diets, acting in similar ways, significantly increased the Firmicutes/Bacteroidetes ratio at the phylum level as well as increased the Roseburia abundance and decreased the Bacteroides and Parabacteroides abundances at the genus level. Spearman's correlation analysis revealed that the Roseburia abundance was negatively while the Bacteroides and Parabacteroides abundances were positively correlated to the fasting blood glucose level and area under the curve by the oral glucose tolerance test. Finally, the low- and high-capsaicin diets significantly increased the fecal butyrate and plasma total GLP-1 levels, but decreased plasma total ghrelin, TNF-α, IL-1ß, and IL-6 levels as compared with the normal diet. Conclusions: The beneficial effects of dietary capsaicin on glucose homeostasis are likely associated with the alterations of specific bacteria at the genus level. These alterations in bacteria induced by dietary capsaicin contribute to improved glucose homeostasis through increasing short-chain fatty acids, regulating gastrointestinal hormones and inhibiting pro-inflammatory cytokines. However, our results should be interpreted cautiously due to the lower caloric intake at the initial stage after capsaicin diet administration.

The changes of gut microbiota after acute myocardial infarction in rats.

Recent studies suggested that gut microbiota was involved in the development of coronary artery disease. However, the changes of gut microbiota following acute myocardial infarction (AMI) remain unknown. In this study, a total of 66 male Wistar rats were randomly divided into control, AMI and SHAM groups. The controls (n = 6) were sacrificed after anesthesia. The AMI model was built by ligation of left anterior descending coronary artery. The rats of AMI and SHAM groups were sacrificed at 12 h, 1 d, 3 d, 7 d and 14 d post-operation respectively. Gut microbiota was analyzed by 16S rDNA high throughput sequencing. The gut barrier injuries were evaluated through histopathology, transmission electron microscope and immunohistochemical staining. The richness of gut microbiota was significantly higher in AMI group than SHAM group at 7 d after AMI (P<0.05). Principal coordinate analysis with unweighted UniFrac distances revealed microbial differences between AMI and SHAM groups at 7 d. The gut barrier impairment was also the most significant at 7 d post-AMI. We further identified the differences of microorganisms between AMI and SHAM group at 7 d. The abundance of Synergistetes phylum, Spirochaetes phylum, Lachnospiraceae family, Syntrophomonadaceae family and Tissierella Soehngenia genus was higher in AMI group compared with SHAM group at 7 d post-operation (q<0.05). Our study showed the changes of gut microbiota at day 7 post AMI which was paralleled with intestinal barrier impairment. We also identified the microbial organisms that contribute most.

Circulating microRNAs as potential biomarkers for unstable angina.

BACKGROUND: Chest pain is a typical presentation in the emergency department (ED), often due to acute coronary syndrome. Accurate and fast identification is crucial. The diagnosis and proper treatment of unstable angina (UA) can reduce the chance of acute myocardial infarction, and reduce high mortality and morbidity rates. However there is a lack of reliable and valid biomarkers in the diagnosis of UA. This study investigated the usefulness of circulating microRNAs (miRNAs) for differentiating UA from non-ischemic chest pain (NICP) in the ED. Methods The expressions of circulating miRNAs in patients with UA were evaluated relative to individuals with NICP (control subjects). Circulating miR-21, miR-25, miR-92a, miR-106b, miR-126* and miR-451 levels were measured in 98 patients with UA and 95 control subjects in the ED. To investigate the underlying functions of miRNAs in UA, bioinformatic analysis of validated miRNAs was conducted. RESULTS: Circulating miRNAs were upregulated in UA compared with the control group. The combination of the modified HEART score (m-HS) and miR-25 (AUC 0.901, NRI 0.096) could better distinguish UA than m-HS alone. Bioinformatic analysis indicated that miRNAs may take part in platelet activation, cGMP-PKG signaling pathways etc. Conclusion: The circulating levels of miRNAs (miR-21, miR-25, miR-106b, miR-126*) are significantly higher in UA patients compared with patients with NICP, and the addition of the m-HS that combined ECG, age, risk factors and troponin is useful to detect or rule out UA. The associated signaling pathways are involved in the pathogenesis of vulnerable plaque.

Predictors and in-hospital prognosis of recurrent acute myocardial infarction.

OBJECTIVE: To investigate the contributing factors and in-hospital prognosis of patients with or without recurrent acute myocardial infarction (AMI). METHODS: A total of 1686 consecutive AMI patients admitted to Peking University People's Hospital from January 2010 to December 2015 were recruited. Their clinical characteristics were retrospectively compared between patients with or without a recurrent AMI. Then multivariable logistic regression was used to estimate the predictors of recurrent myocardial infarction. RESULTS: Recurrent AMI patients were older (69.3 ± 11.5 vs. 64.7 ± 12.8 years, P < 0.001) and had a higher prevalence of diabetes mellitus (DM) (52.2% vs. 35.0%, P < 0.001) compared with incident AMI patients, they also had worse heart function at admission, more severe coronary disease and lower reperfusion therapy. Age (OR = 1.03, 95% CI: 1.02-1.05; P < 0.001), DM (OR = 1.86, 95% CI: 1.37-2.52; P < 0.001) and reperfusion therapy (OR = 0.74; 95% CI: 0.52-0.89; P < 0.001) were independent risk factors for recurrent AMI. Recurrent AMI patients had a higher in-hospital death rate (12.1% vs. 7.8%, P = 0.039) than incident AMI patients. CONCLUSIONS: Recurrent AMI patients presented with more severe coronary artery conditions. Age, DM and reperfusion therapy were independent risk factors for recurrent AMI, and recurrent AMI was related with a high risk of in-hospital death.

Total ischemic time and outcomes for patients with ST-elevation myocardial infarction: does time of admission make a difference?

OBJECTIVE: To investigate whether admission time was associated with the delay of reperfusion therapy and in-hospital death in patients with ST-elevation myocardial infarction (STEMI). METHODS: All patients with STEMI who were admitted to the emergency department and underwent primary percutaneous coronary intervention at Peking University People's Hospital between April 2012 and March 2015 were included. We examined differences in clinical characteristics, total ischemic time, and in-hospital death between patients admitted during off-hours and those admitted during regular hours. Multivariate logistic regression was used to estimate the relationship between off-hours admission and clinical outcome. RESULTS: The sample comprised 184 and 105 patients with STEMI admitted to hospital during off-hours and regular hours, respectively. Total ischemic and onset-to-door times were significantly shorter in patients admitted during off-hours than among those admitted during regular hours (all P < 0.05). Door-to-balloon (DTB) time, the rate of DTB time ≤ 90 min, and in-hospital death were comparable between groups. Multivariate logistic regression showed that age and creatinine level, but not off-hours admission, were associated independently with increased in-hospital death. CONCLUSIONS: Off-hours admission did not result in delayed reperfusion therapy or increased in-hospital mortality in patients with STEMI. Further efforts should focus on identifying pivotal factors associated with the pre-hospital and in-hospital delay of reperfusion therapy, and implementing quality improvement initiatives for reperfusion programs.

Cited2 participates in cardiomyocyte apoptosis and maternal diabetes-induced congenital heart abnormality.

Gestational diabetes mellitus is a risk factor for abnormal heart development, but the molecular basis remains obscure. To further analyze this, the hyperglycemia rat and cell model were established in this study. The results showed that hyperglycemic rats gained significantly less weight during gestation than controls. The number of embryos per litter was significantly reduced in diabetic mothers compared to controls. Ventricular wall thickness was often decreased in the diabetic offspring and cardiomyocyte apoptosis participated in ventricular wall thinness. Our results also indicated that Cited2 expression decreased in the heart tissues of diabetic-exposed embryos comparing with the control. The vitro results showed that down-regulation of Cited2 was associated with high glucose-induced apoptosis in cardiomyocytes in vitro. Over-expression of Cited2 gene restrained the cardiomyocyte apoptosis induced by high glucose. Furthermore, Cited2 S192G mutation partly inhibited the capacity of Cited2 to suppress apoptosis induced by high glucose in cardiomyocytes. This showed the critical role of Cited2 in high glucose-induced cardiomyocytes apoptosis. Data from this study found the association of Cited2 down regulation with cardiomyocytes apoptosis and maternal diabetes-induced ventricular wall thinness genesis.

MiR-106b-5p Inhibits Tumor Necrosis Factor-α-induced Apoptosis by Targeting Phosphatase and Tensin Homolog Deleted on Chromosome 10 in Vascular Endothelial Cells.

BACKGROUND: Apoptosis of endothelial cells (ECs) plays a key role in the development of atherosclerosis and there are also evidence indicated that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a viable target in therapeutic approaches to prevent vascular ECs apoptosis. Aberrant miR-106b-5p expression has been reported in the plasma of patients with unstable atherosclerotic plaques. However, the role and underlying mechanism of miR-106-5p in the genesis of atherosclerosis have not been addressed. In this study, we explored the anti-apoptotic role of miR-106-5p by regulating PTEN expression in vascular ECs. METHODS: Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the expression levels of miR-106b-5p in human atherosclerotic plaques and normal vascular tissues. Human umbilical vein endothelial cells (HUVEC) were transfected with miR-106b-5p mimic or negative control mimic, and apoptosis was induced by serum starvation and tumor necrosis factor-α (TNF-α) treat. Western blotting and real-time RT-PCR experiments were used to detect PTEN expression levels and TNF-α-induced apoptosis was evaluated by the activation of caspase-3 and cell DNA fragmentation levels in HUVEC. RESULTS: The expression of miR-106b-5p was significantly downregulated in plaques than in normal vascular tissues. TNF-α significantly downregulated miR-106b-5p expression levels and upregulated activation of caspase-3 and cell DNA fragmentation levels in HUVEC. Overexpression of miR-106b-5p with miR-106b-5p mimic inhibited PTEN expression and TNF-α-induced apoptosis in HUVEC. Luciferase reporter assays confirmed that miR-106b-5p binds to PTEN mRNA 3' untranslated region site. CONCLUSION: MiR-106b-5p could inhibit the expression of PTEN in vascular ECs, which could block TNF-α-induced activation of caspase-3, thus prevent ECs apoptosis in atherosclerosis diseases.

Angiotensin-(1-7): new perspectives in atherosclerosis treatment.

Angiotensin (Ang)-(1-7) is recognized as a new bioactive peptide in renin-angiotensin system (RAS). Ang-(1-7) is a counter-regulatory mediator of Ang-II which appears to be protective against cardiovascular disease. Recent studies have found that Ang-(1-7) played an important role in reducing smooth muscle cell proliferation and migration, improving endothelial function and regulating lipid metabolism, leading to inhibition of atherosclerotic lesions and increase of plaque stability. Although clinical application of Ang-(1-7) is restricted due to its pharmacokinetic properties, identification of stabilized compounds, including more stable analogues and specific delivery compounds, has enabled clinical application of Ang-(1-7). In this review, we discussed recent findings concerning the biological role of Ang-(1-7) and related mechanism during atherosclerosis development. In addition, we highlighted the perspective to develop therapeutic strategies using Ang-(1-7) to treat atherosclerosis.

High density lipoprotein suppresses lipoprotein associated phospholipase A2 in human monocytes-derived macrophages through peroxisome proliferator-activated receptor-γ pathway.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is mainly secreted by macrophages, serving as a specific marker of atherosclerotic plaque and exerting pro-atherogenic effects. It is known that high-density lipoprotein (HDL) plays an important role against atherosclerosis by inhibiting pro-inflammatory factors, however, the relationship between HDL and Lp-PLA2 remains elusive. METHODS: In this study, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and a platelet-activating factor (PAF) acetylhydrolase assay were performed to determine the Lp-PLA2 mRNA level, protein expression and activity in human monocyte-derived macrophages upon HDL treatment of different concentrations and durations. To investigate the underlying mechanism of HDL-induced Lp-PLA2 action, pioglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) ligand, was introduced to human monocyte-derived macrophages and mRNA and protein levels of Lp-PLA2, as well as its activity, were determined. RESULTS: Lp-PLA2 mRNA levels, protein expression and activity were significantly inhibited in response to HDL treatment in a dose and time dependent manner in human monocyte-derived macrophages. Pioglitazone treatment (1 - 10 ng/ml) upregulated the Lp-PLA2 mRNA level, protein expression and activity in human monocyte-derived macrophages, while the effects were markedly reversed by HDL. In addition, pioglitazone resulted in a significant increase in PPARγ phosphorylation in human monocyte-derived macrophages, which could be inhibited by HDL. CONCLUSION: These findings indicate that HDL suppresses the expression and activity of Lp-PLA2 in human monocyte-derived macrophages, and the underlying mechanisms may be mediated through the PPARγ pathway.

Elevated plasma lipoprotein-associated phospholipase A2 activity is associated with plaque rupture in patients with coronary artery disease.

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has recently been shown to be positively related to coronary events in patients with coronary artery disease (CAD). However, direct evidence about the relationship between circulation Lp-PLA(2) activity and vulnerable plaque in patients with CAD remains lacking. METHODS: Plasma Lp-PLA(2) activity was determined in 146 consecutive patients with CAD who underwent clinically-indicated coronary angiography and preinterventional intravascular ultrasound (IVUS). RESULTS: Eighty-three patients were included in the final analysis after the initial screening. Sixty (72.3%) were acute coronary syndrome (ACS) patients and 23 (27.7%) were stable angina pectoris (SAP) patients. Plaque rupture occurred in 39 (47.0%) patients, and 34 (87.2%) were from ACS patients and 5 (12.8%) from SAP patients. There were no significant differences in clinical and angiographic characteristics between patients with plaque rupture and those without plaque rupture, except for smoking, high-sensitive C-reactive protein (hs-CRP) level and Lp-PLA(2) activity (all P < 0.05). IVUS measurement uncovered that patients with plaque rupture had more frequent positive remodeling (74.4% vs. 43.2%, P = 0.004), soft plaques (64.1% vs. 36.4%, P = 0.012) and higher remodeling index (1.13 ± 0.16 vs. 0.99 ± 0.11, P = 0.041) as compared with those without plaque rupture. Multivariate Logistic regression analysis showed that plasma Lp-PLA(2) activity was independently associated with plaque rupture after adjusting for smoking, positive remodeling and soft plaque (Model 1: odds ratio (OR) 1.13, 95% confidence interval (CI): 1.06 - 1.20) or adjusting for smoking, hs-CRP level, positive remodeling and soft plaque (Model 2: OR 1.11, 95%CI: 1.04 - 1.19). CONCLUSIONS: Plasma Lp-PLA(2) activity is associated with plaque rupture in patients with CAD, independently of traditional CAD risk factors, hs-CRP level and IVUS parameters. Lp-PLA(2) may be a risk marker for vulnerable plaques.