Pivotal role of microRNAs in cardiac development and heart diseases

MicroRNAs (miRNAs) are non-coding small RNAs, which bind to the 3'-UTR of target mRNAs and negatively regulate the gene expression. Accumulating evidence demonstrates that miRNAs are involved in many biological processes such as embryo development, cell proliferation, differentiation, apoptosis and tumorigenesis. Heart development and heart diseases are complex processes controlled by various signaling pathways. Recent researches indicate the importance of miRNAs in the process of cardiac development and heart diseases. In this review, the role of miRNAs in cardiac development and the pathogenesis of heart diseases are overviewed. The insight into the regulating miRNAs will significantly expand the cardiovascular therapeutic strategies beyond classical pharmacology.     

Progress in role of lncRNA in cardiovascular diseases

Cardiovascular diseases are closely related to proliferation, injury and apoptosis of the cells in the cardiovascular system. For instance, endothelial cells play an important role in the pathogenic process of hypertension and atherosclerosis, and smooth muscle cells and monocytes/macrophages involve in the formation of atherosclerotic plaque. Recently, it has been confirmed that long noncoding RNA (lncRNA) regulates proliferation, apoptosis, injury, autophagy and differentiation of the cells by a series of regulatory mechanisms, thus participating in the development and progression of cardiovascular diseases. This article is to review the recent research progress on the function of lncRNAs and their regulatory roles in the cardiovascular diseases at cellular and molecular levels.     

Mechanisms of heart failure induced by adriamycin

AIM: To investigate the changes of cardiac function, oxidative stress and apoptosis in myocardium of rat model of heart failure induced by adriamycin (ADR). METHODS: At the end of the study, we observed content of malondialdehyde (MDA), activity of superoxide dismutase (SOD) and apoptosis. Expression of P53 protein and p53 mRNA were measured with immunohistochemical method and RT-PCR, respectively. RESULTS: Our data showed that content of MDA increased, activity of SOD decreased and apoptosis in myocardium happened while cardiac function decreased after ADR treatment. p53 gene expression and P53 protein obviously increased in heart failure group. CONCLUSION: There were oxidative stress and apoptosis occurred significantly in a model of heart failureinduced by ADR. p53 gene might play an important role in the apoptosis. Correlation analyses suggested that apoptosis in myocardium was related to oxidative stress in ADR-induced heart failure model.     

Microparticles and acute coronary syndrome

Coronary heart disease (CHD) is an important cause of death in the world. Among them, acute coronary syndrome (ACS) is a type of CHD that has a high mortality rate. Microparticles (MPs) are tiny particles formed in the process of cell activation and apoptosis, carrying specific markers of their mother cells. There is more and more evidence that MPs derived from endothelial cells, platelets, white blood cells and other cells are closely related to the formation of ACS. Through a variety of pathways, they take part in endothelial cell damage, vascular dysfunction, plaque erosion and rupture, and thrombosis. The findings of MPs enrich our knowledge about ACS, and may provide a new approach to the treatment of ACS.     

Roles of reactive oxygen species in pluripotent stem cell functions

Pluripotent stem cells are characterized by the properties of self-renewal and the ability to differentiate into multiple cell types. Reactive oxygen species (ROS) are highly reactive metabolites. High levels of ROS are toxic and involved in stem cell senescence and apoptosis. However, regulation of ROS has an important role in maintaining “stemness” and differentiation of the stem cells. The role of ROS in the stem cells varies among different stem cell types. NADPH oxidase is one of the major sources of ROS in stem cells. Excessive amounts of ROS are produced in various pathophysiological states such as atherosclerosis, heart failure, hypertension, diabetes, and aging. Induced pluripotent stem cells have the potential to be used in modeling of ROS-associated diseases.Understanding the molecular mechanisms how ROS regulate the functions of stem cells will greatly enhance their translational applications. In this review, we summarize the recent progress regarding the roles of ROS in regulating the functions of embryonic and induced pluripotent stem cells.     

Mechanism of endothelial microparticle generation in hypertension and its pathophysiological roles

Hypertension is closely related to many target organ damage. Endothelial microparticles (EMPs), derived from endothelial cells in response to endothelial cell activation or apoptosis, are complex vesicular structures with a membrane skeleton and express various antigens specific to parental endothelial cells. EMPs circulate in human plasma and show elevated levels in many vascular damage diseases, such as hypertension, atherosclerotic vascular diseases, sepsis and diabetes. Recent studies have shown that EMPs could be a comprehensive index for endothelial homeostasis monitoring, such as vasomotor activity, anti-inflammatory status and so on. Especially, more and more evidence suggests that EMPs play an important role in hypertension. Patients with hypertension show higher circulating levels of EMPs compared with healthy controls. Furthermore, increasing evidence demonstrates that EMPs can induce endothelial dysfunction in vitro and in vivo, and then further promote the development of hypertension and its complications. This review will summarize the progress in the definition and formation mechanisms of EMPs, levels of EMPs and their phenotypes in patients with hypertension, and the pathophysiological roles of EMPs in hypertension.     

Influence of energetic metabolism alteration on cardiac myocyte apoptosis

Many studies indicate that apoptosis is involved in the progression of congestive heart failure. At present, mechanisms that mitochondria regulates cell apoptosis is widely accepted.Cardiac myocytes have abundant mitochondria, which plays an important role in maintenance of cell physiological function. Recent studies find that cardiac energy metabolic shifts occur as a normal response to diverse physiologic and dietary conditions and as a component of the pathophysiologic processes which accompany cardiac hypertrophy, heart failure, and myocardial ischemia.Both clinical and experimental studies show that cardiac function can be improved and apoptosis is inhibited by intervention in energetic metabolism of myocytes.     

Formation and activity of lymphocyte-derived microparticles

Lymphocyte-derived microparticles (LMPs) are small membrane vesicles that are released upon activation or during apoptosis from lymphocytes.The LMPs were detected at elevated levels in the patients with inflammatory diseases, cardiovascular diseases or diabetes. In addition, LMPs are important mediators of transferring biological information and switching on the biological effects through their interaction with the target cells. Moreover, LMPs play completely distinct roles in different physiological and pathological conditions. This article describes the possible mechanism involved in the formation, composition, key biological activities and the relationship with diseases.     

Function and relationship between c-Jun N-terminal kinase and caspase in apoptosis

Apoptosis is important to the development of diseases.Research recently indicates that c-Jun N-terminal kinase (JNK) and cysteinyl aspartate-specific protease (caspase) play key roles in apoptosis and affect the development of diseases.This article is to introduce the function and relationship between JNK and caspase in apoptosis during the process of diseases.     

The effect of Shenmai injection on cardiac myocyte apoptosis after hypoxia

AIM: To observe the effect of Shenmai injection, a chinese medicine, on apoptosis of cardiac myocytes after hypoxia. METHODS: Cardiac myocytes were separated from neonate rat heart and cultivated in vitro. Hypoxia condition was induced by mixture of 95%N2 and 5%CO2. Cells were exposed to hypoxia for 6 h or 12 h and treated with Shenmai injection (5 mL/L) from 24 h before hypoxia until the end of hypoxia. First, apoptosis was detected with Annexin V-FITC and PI staining by flowcytometry. Then, the activity of cardiac myocyte mitochondria was observed by MTT method. Mitochondria membrane potential and the activity of caspase 3,7 were also measured by laser scan microscopy and multi-detection microplate reader, respectively. RESULTS: The apoptotic cells became more and more with prolonged hypoxia. Shenmai injection enhanced mitochondria activity, kept membrane potential, inhibited the activation of caspase3,7 and then decreased apoptotic cells (P<0.01). CONCLUSION: Hypoxia induces apoptosis in cardiac myocytes by mitochondria pathway. Shenmai injection can decrease cardiomyocyte apoptosis after hypoxia, the mechanism is related to mitochondria membrane potential stabilization and caspase inhibition.     

Emerging roles of p53 in ferroptosis and its potential application

p53 is a widely recognized tumor suppressor. Recent studies show that its classical functions such as inducing apoptosis and arresting cell cycle cannot be the essential role in explaining its effects on tumors properly. Instead, its role as a cell metabolism regulator is more important to suppress tumor development. Ferroptosis is a unique cell death form and is associated with many diseases, such as tumors, neurodegenerative diseases and ischemic diseases. The sensitivity of cells to ferroptosis is closely related to the intracellular metabolic state, suggesting that induction or inhibition of ferroptosis may be significant ways in which p53 plays a role in tumor pathology. Meanwhile, the potential mechanism of p53 involved in neurodegenerative diseases and ischemic diseases should also be noticed. Therefore, our study aims to review the latest development in theoretical and practical knowledge of p53's role in ferroptosis, thus widening the understanding of the tumor suppression mechanism, finding new therapeutic targets for tumors that are resistant to chemotherapy and providing new insights into the treatment of neurodegenerative diseases and ischemic diseases.     

Expression of TGF-β1 and apoptosis in myocardium of diabetic rats

AIM: To study the pathophysiological mechanism of cardiomyopathy, the expression of TGF-β₁ and apoptosis in myocardium of diabetic rats were investigated. METHODS:The diabetes models were established by single intravenous injection of streptozotocin (50 mg/kg) in rats. By the method of immunochemistry, the expression of TGF-β₁ in the cardiomyocytes was detected as the index to evaluate the degree of fibrosis. The method of TUNEL was used to measure the cardiomyocyte apoptosis as the index to explore its importance in process of diabetic cardiomyopathy. RESULTS:① The weight of diabetic rats was apparently lower than that in the rats before the diabetic model was built (P<0.01), and the increase in weight in diabetic rats within three month was less than that in normal group. ② Compared with control group, the concentration of blood glucose was continually elevated during the experiment. ③ The expression of TGF-β₁ in the diabetic cardiac muscle was much more than that in normal group (P<0.01). ④ The apoptosis of myocardium measured by the method of TUNEL was apparent in the diabetic groups than that in normal one (P<0.01). However, no significance was detected in the different courses of diabetic groups. CONCLUSIONS:The apoptosis might play an important role in leading the diabetic cardiomyopathy to heart failure. The expression of TGF-β₁ in the myocardium of diabetic rats was more than that in normal and had an increasing trend in the procession of diabetic cardiomyopathy. TGF-β₁ might be a significant factor in diabetic myocardium fibrosis. Apoptosis might play an important role in the initial stage of diabetes, which promotes the diabetic cardiomyopathy to heart failure.     

Effect of endoplasmic reticulum stress on cardiac myocyte apoptosis in mouse congestive heart failure induced by myocardial infraction

AIM: To explore the effect of endoplasmic reticulum stress on cardiac myocyte apoptosis in mouse congestive heart failure induced by myocardial infraction.METHODS: The mouse model of heart failure was established by ligating the left anterior descending coronary to produce acute myocardial infarction. Thirty-two mice were divided into 4 groups: sham group and groups of post-operation at time points of 2, 4 or 6 weeks, respectively. The ventricular dilatation and left ventricular functions were assessed by echocardiography. The expression of GRP78, CHOP, caspase-12, cleaved caspase-12, JNK and phosphorylated-JNK was detected by Western blotting. The cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL).RESULTS: The cardiac expression of endoplasmic reticulum chaperones GRP78 was significantly increased in the hearts with functional failure. The upregulated expression of CHOP, phosphorylated-JNK and cleaved caspase-12 illuminated that the CHOP-JNK- caspase-12 dependent pathways for endoplasmic reticulum-initiated apoptosis were activated in the heart with functional failure by myocardial infraction. CONCLUSION: These findings suggest that the congestive heart failure induced by myocardial infraction is associated with endoplasmic reticulum stress and activation of CHOP, JNK, caspase-12 dependent pathways for endoplasmic reticulum-initiated apoptosis.     

MicroRNA-24 regulates apoptosis of cardiomyocytes after myocardial infarction

AIM：To evaluate the expression of miR-24 in infarcted myocardial tissues and to investigate the function of miR-24 during cardiomyocyte apoptosis in vitro and in vivo. METHODS：The mouse model of myocardial infarcton (MI) was established. The expression of miR-24 in the sections of infarcted myocardial tissues was measured by qRT-PCR. The expression of miR-24 was modified by transfecting oligonucleotide mimic and inhibitor of miR-24 into cardiomyocytes, or injecting lentiviral vectors intramyocardially. The apoptosis of cardiomyocytes was detected by Caspase-Glo 3/7 Assay System. The heart functions were determined by echocardiography and the scar size in MI model was observed with Masson trichrome staining. The apoptosis of infarcted myocardial tissues was detected by TUNEL method. Microarray and bioinformatic analysis were also used to predict the targets of miR-24. RESULTS：The expression of miR-24 in the infarct and border areas was down-regulated after MI. Overexpression of miR-24 in cardiomyocytes reduced the apoptosis induced by hypoxia. miR-24 transfection resulted in reduction of the scar size, and improved left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) of the mice in treatment group after 2 weeks. Furthermore, miR-24 reduced cell apoptosis in the infarct region. BCL2L11, ANK3 and SGPL1 may be the targets of miR-24 during the process of anti-apoptosis. CONCLUSION：miR-24 is down-regulated in the infarcted myocardial tissues. In vitro, miR-24 reduces apoptosis of cardiomyocytes induced by hypoxia. In vivo, miR-24 attenuates cell apoptosis in the infarct and border areas of the heart 2 weeks after MI, and ultimately improves heart functions.     

Apoptosis induced by berbamine in K562 cells correlates with the expression levels of bcr/abl gene and P210

AIM: To explore the effect of berbamine(BER) on apoptosis in K562 cells and its possible molecular mechanisms. METHODS: The apoptosis rate was measured by flow cytometry while electron microscopy and DNA electrophoresis were used to evaluate the characteristic changes of apoptosis, RT-PCR and Western blot were used to examine the expression levels of apoptosis related gene bcr/abl and BCR/ABL protein. RESULTS: By FCM, the apoptosis rate of K562 cells treated with 8.0 mg/L BER for 24 h and 72 h increased from (29.20±3.82)% to (61.77±4.35)% (P＜0.01); The typical apoptosis morphologic changes and the DNA ladder were more clearly observed. After treated with BER 0 to 16.0 mg/L for 24 h, the expression levels of bcr/abl mRNA and P210 (semiquantity value) decreased quickly from 1.19±0.02 to 0.73±0.02 (P＜0.01) and from 1.04±0.02 to 0.63±0.01 (P＜0.01), respectively. CONCLUSION: BER induces apoptosis of K562 cells in a time-and-concentration-dependent manner, the decline of bcr/abl mRNA and P210 may play an important role in the apoptotic effect of BER in K562 cells. BER could be used as a new clinical trials for bcr-abl⁺ diseases such as CML.     

Histone deacetylase SIRT1 and cell autophagy

.Sirtuin 1 (SIRT1), one of the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, plays an important role in regulating cell cycle, cell aging, apoptosis and metabolism. Autophagy, a vital basic phenomenon that wildly exists in eukaryotic cells, plays an important part in waste scavenging, structure reestablishment, growth and development. In recent years, more and more attention has been paid to the connection between SIRT1 and autophagy. Clarifying the relationship between SIRT1 and autophagy will be of great importance in preventing and controlling aging-related diseases. This article overviews its research advancement.     

大连市草坪主要病害发生特点与可持续治理措施

大连是具有明显海洋性特点的暖温带大陆性季风气候,土壤比较贫瘠,草坪病虫害种类发生较多。该文对大连市中山区草坪上发生的草坪褐斑病、草坪腐霉枯萎病、草坪币斑病、草坪蘑菇圈、草坪锈病、草坪白粉病等主要病害的发生特点及其可持续治理措施进行论述。     

Role of nitric oxide in ischemia/reperfusion injury and ischemic preconditioning

AIM: To clarify the role of nitric oxide(NO) in ischemic preconditioning(IP) and its effects on apoptosis. METHODS: Seventy-two male Wistar rats were divided into the following six groups:ischemia/reperfusion (IR) group,IP group,IR+L-arg group,IP+L-arg group,IR+L-NAME group and IP+L-NAME group,The following changes were measured:cardiac hemodynamic parameters,infarct size,PMNs counting myocardial MPO activity and TUNEL staining.RESULTS: ①L-arg significantly attenuated ischemia/reperfusion-induced heart injury,reduced PMNs infiltration and cardiomyocyte apoptosis.②L-NAME also significantly reduced infarct size,PMNs infiltration and cardiomyocyte apoptosis compared with IR group,however,L-NAME aggravated ischemia/reperfusions-induced cardiac functional injury.③L-arg or L-NAME did not significantly alter the protective effect of ischemic preconditioning. CONCLUSION: Increased production of endogenous NO before prolonged ischemic period can protect hearts and inhibit apoptosis.L-NAME can inhibit iNOS activity and ONOO^- production in reperfusion period to protect heart.