The diagnostic efficiency of artificial intelligence based 2 hours Holter monitoring in premature ventricular and supraventricular contractions detection.

BACKGROUND: Electrocardiography (ECG) and 24 hours Holter monitoring (24 h-Holter) provided valuable information for premature ventricular and supraventricular contractions (PVC and PSVC). Currently, artificial intelligence (AI) based 2 hours single-lead Holter (2 h-Holter) monitoring may provide an improved strategy for PSVC/PVC diagnosis. HYPOTHESIS: AI combined with single-lead Holter monitoring improves PSVC/PVC detection. METHODS: In total, 170 patients were enrolled between August 2022 and 2023. All patients wore both devices simultaneously; then, we compared diagnostic efficiency, including the sensitivity/specificity/positive predictive-value (PPV) and negative predictive-value (NPV) in detecting PSVC/PVC by 24 h-Holter and 2 h-Holter. RESULTS: The PPV and NPV in patients underwent 2 h-Holter were 76.00%/87.50% and 96.35%/98.55, respectively, and the sensitivity and specificity were 79.17%/91.30%, and 95.65%/97.84% in PSVC/PVC detection compared with 24 h-Holter. The areas under the ROC curves (AUCs) for PSVC and PVC were 0.885 and 0.741, respectively (p < .0001). CONCLUSIONS: The potential advantages of the 2 h-Holter were shortened wearing period, improved convenience, and excellent consistency of diagnosis.

Effect of different revascularization times on intermediate-risk non-ST-elevation acute coronary syndrome.

Non-ST-elevation acute coronary syndrome (NSTE-ACS) is a specific type of acute coronary syndrome. We applied the Thrombolysis in Myocardial Infarction (TIMI) score for risk stratification of patient prognosis. There was uncertainty about the routine revascularization time in patients with intermediate-risk NSTE-ACS. A total of 2835 patients with intermediate-risk NSTE-ACS (TIMI score 3-4) included in the China Acute Myocardial Infarction Registry from November 2014 to January 2017 were analyzed according to the time window from symptom onset to revascularization: within 24 h, Group I (814/28.7%); within 24 to 48 h, Group II (526/18.6%); within 48 to 72 h, Group III (403/14.2%); and after 72 h, Group IV (1092/38.5%). Risk factors, management and in-hospital outcomes were analyzed in the four groups. The results of the chi-square test showed that there was a significant difference in the incidence of in-hospital major adverse cardiovascular events (MACEs) when revascularization was completed within 48 h than when it was completed after 48 h (P < 0.05). The results of revascularization within 48 h were similar, and the incidence of in-hospital MACEs was lower than when revascularization was completed after 48 h. The incidence of in-hospital MACEs among patients who underwent revascularization within 48 h is lower than that of patients who underwent revascularization after 48 h.

A novel numerical model of combination levels of C-peptide and insulin in coronary artery disease risk prediction.

OBJECTIVE: Insulin resistance is a major risk factor for coronary artery disease (CAD). The C-peptide-to-insulin ratio (C/I) is associated with hepatic insulin clearance and insulin resistance. The current study was designed to establish a novel C/I index (CPIRI) model and provide early risk assessment of CAD. METHODS: A total of 865 adults diagnosed with new-onset diabetes mellitus (DM) within one year and 54 healthy controls (HC) were recruited to develop a CPIRI model. The CPIRI model was established with fasting C/I as the independent variable and homeostasis model assessment of insulin resistance (HOMA-IR) as the dependent variable. Associations between the CPIRI model and the severity of CAD events were also assessed in 45 hyperglycemic patients with CAD documented via coronary arteriography (CAG) and whom underwent stress echocardiography (SE) and exercise electrocardiography test (EET). RESULTS: Fasting C-peptide/insulin and HOMA-IR were hyperbolically correlated in DM patients and HC, and log(C/I) and log(HOMA-IR) were linearly and negatively correlated. The respective correlational coefficients were -0.83 (p < 0.001) and -0.76 (p < 0.001). The equations CPIRI(DM) = 670/(C/I)2.24 + 0.25 and CPIRI(HC) = 670/(C/I)2.24 - 1 (F = 1904.39, p < 0.001) were obtained. Patients with insulin resistance exhibited severe coronary artery impairment and myocardial ischemia. In CAD patients there was no significant correlation between insulin resistance and the number of vessels involved. CONCLUSIONS: CPIRI can be used to effectively evaluate insulin resistance, and the combination of CPIRI and non-invasive cardiovascular examination is of great clinical value in the assessment of CAD.

Exercise electrocardiography combined with stress echocardiography for predicting myocardial ischemia in adults.

Myocardial ischemia (MI) has the highest mortality rate in the world. Traditional noninvasive MI examinations include exercise electrocardiography tests (EETs) and stress echocardiography (SE). Treadmill and dobutamine tests are commonly used as stress protocols. In the present study, 278 patients with suspected MI were examined, 66 of whom were diagnosed with MI and 212 did not show evidence of MI by coronary angiography (CAG)/coronary CT angiography (CCTA). All patients underwent clinical EET and SE evaluations prior to CAG/CCTA. All groups were compared based on specific clinical parameters including age, sex, blood pressure, heart rate, blood oxygen saturation, underlying conditions and ejection fraction/fraction shortening. The data indicated superior diagnostic efficiency of the combined EET+SE method for the diagnosis of suspected MI compared with either EET or SE alone. The sensitivity/specificity/positive predictive value and negative predictive value for detecting MI were excellent compared with those of traditional examinations. The diagnostic efficiency of the combination analysis may reduce the prevalence of MI and medical costs. The present study provided novel insight for the development of methods that may be used for MI detection and prediction.

A long noncoding RNA CHAIR protects the heart from pathological stress.

Mammalian genomes have been found to be extensively transcribed. In addition to classic protein coding genes, a large numbers of long noncoding genes (lncRNAs) have been identified, while their functions, especially in heart diseases, remain to be established. We hypothesized that heart failure progression is controlled by tissue-specific lncRNAs. In the present study, we found that the cardiac-enriched lncRNA 4632428C04Rik, named as cardiomyocyte hypertrophic associated inhibitory RNA (CHAIR), is dynamically regulated during heart development, is expressed at low levels in embryonic hearts and accumulated at high levels in adult hearts. More interestingly, the lncRNA was down-regulated during cardiac hypertrophy and failure both in mice and humans. Importantly, loss of lncRNA CHAIR has no effects on normal hearts, whereas it results in accelerated heart function decline, increased hypertrophy, and exacerbated heart failure in response to stress. In contrast, restoring the expression of lncRNA CHAIR rescued the hearts from hypertrophy and failure. DNMT3A was recruited to CHAIR promoter during heart failure to suppress its expression. Reciprocally, CHAIR interacted with DNMT3A to inhibit its DNA-binding activity. Taken together, our data revealed a new cardioprotective lncRNA that represses heart failure through an epigenetic mechanism.

p27kip1 haploinsufficiency preserves myocardial function in the early stages of myocardial infarction via Atg5­mediated autophagy flux restoration.

Myocardial infarction (MI) is a leading cause of mortality in adults worldwide. Over the last two decades, gene therapy has been a hot topic in cardiology, and there has been a focus on cell cycle inhibitors and their protective effects on the myocardium post­MI. In our previous study, the haploinsufficiency of p27kip1 (p27) was demonstrated to improve cardiac function in mice post­MI by promoting angiogenesis and myocardium protection through the secretion of growth factors. Autophagy is an adaptive response of cells to environmental changes, such as nutrient deprivation, ischemia and hypoxia. The appropriate regulation of autophagy may improve myocardial function by preventing apoptosis of cardiomyocytes. In this study, we used immunoassays, transmission electron microscopy and cardiac ultrasound to confirm that p27 haploinsufficiency prevents myocardial apoptosis by restoring autophagy protein 5­mediated autophagy flux in the early stages of MI. The present study provides a novel method for studying MI or ischemic heart disease therapy.

Prognostic value of fractalkine/CX3CL1 concentration in patients with acute myocardial infarction treated with primary percutaneous coronary intervention.

BACKGROUND: Recent studies demonstrated that fractalkine (FKN) is critically involved in the regulation of inflammation and cardiac function. OBJECTIVE: This study aimed to investigate the prognostic value of circulating FKN in patients with ST-elevated acute myocardial infarction (STEMI) after primary PCI. METHODS: We enrolled ninety consecutive STEMI patients and investigated the association of circulating FKN with myocardial salvage and the occurrence of major adverse cardiac events (MACE) after PCI. RESULTS: During a median follow-up of 387 days, total 15 MACE (16.67%) were registered in the study population. Patients with MACE were more likely to be occurred in elderly patients with 3-vessel disease. Correlation analysis demonstrated the level of FKN at day 1 after PCI (FKN@day-1) not only significantly correlated with the levels of hs-TnT at day 7 after PCI (R2 = 0.06; p = 0.02) but inversely correlated with the measurements of LVEF at 1-month observation (R2 = 0.10; p = 0.00). Kaplan-Meier survival analyses further revealed that patients with the level of FKN@day-1 above the median had a higher incidence of MACE compared with those whose FKN@day-1 levels below the median (log-rank test x2 = 13.29, p < 0.001). In addition, multivariate Cox regression analysis demonstrated that FKN@day-1 was an independent predictor of MACE (hazard ratio: 4.63; 95% confidence interval: 1.53-14.01; p = 0.00), together with WBC count and 3-vessel disease for STEMI patients. CONCLUSIONS: Our study demonstrates that FKN@day-1 is negative correlated with myocardial salvage after acute myocardial infarction and might be a valuable prognostic marker of MACE in patients with STEMI undergone PCI.

Necroptosis Induced by Ad-HGF Activates Endogenous C-Kit+ Cardiac Stem Cells and Promotes Cardiomyocyte Proliferation and Angiogenesis in the Infarcted Aged Heart.

BACKGROUND/AIMS: The discovery of c-kit+ cardiac stem cells (CSCs) provided us with new therapeutic targets to repair the damaged heart. However, the precise mechanisms regulating CSC proliferation and differentiation in the aged heart remained elusive. Necroptosis, a type of regulated cell death, has recently been shown to occur following myocardial infarction (MI); however, its effect on c-kit+ CSCs remains unknown. We investigated the effects of hepatocyte growth factor (HGF) and necroptosis on the proliferation and differentiation of endogenous c-kit+ CSCs in aged rat hearts following MI. METHODS: The c-kit+ CSCs and HGF/p-Met expression levels in neonatal, adult and aged rats were compared using immunofluorescence and Western blotting. Immediately after MI, adenovirus carrying the HGF gene (Ad-HGF) was injected into the left ventricular wall surrounding the infarct areas of the aged rat heart. The proliferation and differentiation of the endogenous c-kit+ CSCs were studied using immunofluorescence. The signalling pathways were analysed via Western blotting and ELISA. RESULTS: HGF/p-Met expression levels and c-kit+ CSC abundance gradually decreased with age. Ad-HGF promoted c-kit+ CSC differentiation into precursor cells of cardiomyocyte, endothelial and smooth muscle cell lineages and enhanced cardiomyocyte proliferation and angiogenesis in aged rats; these effects were reversed by the inhibition of necroptosis. Ad-HGF administration induced necroptosis by increasing the expression of receptor interacting protein kinase (RIP) 1 and receptor interacting protein kinase (RIP) 3 proteins in the infarcted heart. Moreover, Ad-HGF-induced necroptosis increased high-mobility group box 1 protein (HMGB1) levels and enhanced the abundance of c-kit+ cells in the bone marrow, which may partly account for the beneficial effect of necroptosis on the c-kit+ CSCs. CONCLUSION: Ad-HGF-induced necroptosis facilitated aged heart repair after MI by promoting c-kit+ CSC proliferation and differentiation. These findings may lead to the development of new methods for the treatment of ischaemic heart disease in aged populations.

Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis.

Cell death in MI is the most critical determinant of subsequent left ventricular remodeling and heart failure. Besides apoptosis, autophagy and necroptosis have been recently found to be another two regulated cell death styles. HGF has been reported to have a protective role in MI, but its impact on the three death styles remains unclear. Thus, our study was performed to investigate the distribution of autophagy, apoptosis and necroptosis in cardiac tissues after MI and explore the role and mechanism of Ad-HGF on cardiac remodeling by regulating the three death styles. We firstly showed the distribution of autophagy, apoptosis and necroptosis differs in temporal and spatial context after MI using immunofluorescence. Notably, Ad-HGF treatment improves the cardiac remodeling of SD rats following MI by preserving the heart function, reducing the scar size and aggresomes. Further mechanism study reveals Ad-HGF promotes autophagy and necroptosis and inhibits apoptosis in vivo and in vitro. Co-immunoprecipitation assays showed Ad-HGF treatment significantly decreased the binding of Bcl-2 to Beclin1 but enhanced Bcl-2 binding to Bax in H9c2 cells under hypoxia. Moreover, HGF-induced sequestration of Bax by Bcl-2 allows Bax to become inactive, thereby inhibiting apoptosis. In addition, Ad-HGF markedly increased the formation of Beclin1-Vps34-Atg14L complex, which accounted for promoting autophagy. Both the western blot and activity assay showed Ad-HGF significantly decreased the caspase 8 protein and activity levels, which obligated the cell to undergo necroptosis under hypoxia and block apoptosis. Thus, our findings offer new evidence and strategies for the treatment of MI and post-MI cardiac remodeling.

Puerarin inhibits cardiac fibrosis via monocyte chemoattractant protein (MCP)-1 and the transforming growth factor-ß1 (TGF-ß1) pathway in myocardial infarction mice.

Transforming growth factor-ß1 (TGF-ß1) and inflammation play important roles in the cardiac fibrosis development associated with myocardial infarction (MI). Puerarin is wildly used for treatment of diabetes, cardiovascular disease and cerebrovascular disease in China, and recently some studies have shown its anti-cardiac fibrotic effect on myocardial hypertrophy. The purpose of our study was to determine whether puerarin has an anti-cardiac fibrotic effect after MI and find the potential mechanism. A mouse model of MI was established by standard LAD coronary artery ligation, and cardiac fibrosis was confirmed by Masson's staining and the expression of collagen I, III and α-SMA. The expression level of F4/80 (macrophage/monocyte marker in mouse), monocyte chemoattractant protein (MCP)-1 and TGF-ß1 in cardiac tissue treated with or without puerarin was evaluated by immunohistochemistry analysis, enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (qPCR). The downstream protein phospho-Smad (small mother against decapentaplegic) 2/3 was evaluated by westernblot. The results displayed that puerarin could inhibit the recruitment and activation of monocytes/macrophages, decrease the expression of TGF-ß1 in the cardiac tissues, and consequently significantly attenuated cardiac fibrosis after MI. Our results also displayed a strong positive correlation between MCP-1 and TGF-ß1 expression in MI. Thus, this study revealed the mechanism by which prevented cardiac fibrosis after MI through a decrease in MCP-1 expression and an inhibition TGF-ß1 pathway, and indicated puerarin could be a potential agent in attenuating MI-induced cardiac fibrosis.

Exogenous HGF Prevents Cardiomyocytes from Apoptosis after Hypoxia via Up-Regulating Cell Autophagy.

BACKGROUND: Hepatocyte growth factor (HGF) is widely known as a protective factor in ischemic myocardium, however HGF sensitive cellular mechanism remained ill-defined. Autophagy at early stage of hypoxia has been demonstrated to play a role in protecting myocardium both in vivo and vitro. We performed this study to investigate the association between the protective effect of HGF and autophagy. METHODS: Ventricular myocytes were isolated from neonatal rat heart (NRVMs). We evaluated cardiomyocytes apoptosis by Hoechst staining and flow cytometry. Autophagy was assessed by transmission electron microscope and mRFP-GFP-LC3 adenovirus infection. Mitochondrial membrane potential was estimated by JC-1 staining. Western blotting and ELISA assay were used to quantify protein concentrations. RESULTS: We found that autophagy in NRVMs increased at early stage after hypoxia and HGF release was consistent with the change of autophagy. Exogenous HGF enhanced autophagy and decreased apoptosis, while neutralizing HGF yielded opposite effects. Besides, inhibition of autophagy increased apoptosis of myocytes. Furthermore, exogenous HGF induced Parkin, the marker of mitochondrial autophagy, indicating increased clearance of injured mitochondria. CONCLUSIONS: Our results revealed a potential mechanism in which exogenous HGF prevented NRVMs from apoptosis after hypoxia. Upregulation of Parkin through administration of exogenous HGF may be a potential therapeutic strategy ptotecting myocytes during ischemia.

Puerarin improves cardiac function through regulation of energy metabolism in Streptozotocin-Nicotinamide induced diabetic mice after myocardial infarction.

It is well recognized that the incidence of heart failure and the risk of death is high in diabetic patients after myocardial infarction (MI). Accumulating evidence showed that puerarin (PUE) has protecting function on both cardiovascular disease and diabetes. The aim of this study is to explore whether puerarin could improve cardiac function in diabetic mice after MI and the underlying mechanism. The left anterior of Streptozotocin (STZ)-Nicotinamide (NA) induced diabetic mice were ligated permanently except for the Shame group. Then the operated mice were randomly treated with PUE or saline. Cardiac function was evaluated by echocardiograph before and at 1, 2, 4 weeks after MI. GLUT4/CD36/p-Akt/PPAR α of the heart was examined after treatment for 4 weeks. The results indicated that PUE significantly increased survival rate, improved cardiac function compared with MI group. Moreover, PUE increased expression and translocation of GLUT4 while attenuated expression and translocation of CD36. Western blot analysis showed that PUE enhanced phosphorylation of Akt and decreased PPAR α. This study demonstrated that PUE improved cardiac function after MI in diabetic mice through regulation of energy metabolism, the possible mechanism responsible for the effect of PUE was increasing the expression and translocation of GLUT4 while attenuating the expression and translocation of CD36.

p27 kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation.

p27(kip1) (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.

Association of admission serum calcium levels and in-hospital mortality in patients with acute ST-elevated myocardial infarction: an eight-year, single-center study in China.

OBJECTIVE: The relationship between admission serum calcium levels and in-hospital mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) has not been well definitively explored. The objective was to assess the predictive value of serum calcium levels on in-hospital mortality in STEMI patients. METHODS: From 2003 to 2010, 1431 consecutive STEMI patients admitted to the First Affiliated Hospital of Nanjing Medical University were enrolled in the present study. Patients were stratified according to quartiles of serum calcium from the blood samples collected in the emergency room after admission. Between the aforementioned groups,the baseline characteristics, in-hospital management, and in-hospital mortality were analyzed. The association of serum calcium level with in-hospital mortality was calculated by a multivariable Cox regression analysis. RESULTS: Among 1431 included patients, 79% were male and the median age was 65 years (range, 55-74). Patients in the lower quartiles of serum calcium, as compared to the upper quartiles of serum calcium, were older, had more cardiovascular risk factors, lower rate of emergency revascularization,and higher in-hospital mortality. According to univariate Cox proportional analysis, patients with lower serum calcium level (hazard ratio 0.267, 95% confidence interval 0.164-0.433, p<0.001) was associated with higher in-hospital mortality. The result of multivariable Cox proportional hazard regression analyses showed that the Killip's class≥3 (HR = 2.192, p = 0.026), aspartate aminotransferase (HR = 1.001, p<0.001), neutrophil count (HR = 1.123, p<0.001), serum calcium level (HR = 0.255, p = 0.001), and emergency revascularization (HR = 0.122, p<0.001) were significantly and independently associated with in-hospital mortality in STEMI patients. CONCLUSIONS: Serum calcium was an independent predictor for in-hospital mortality in patients with STEMI. This widely available serum biochemical index may be incorporated into the current established risk stratification model of STEMI patients. Further studies are required to determine the actual mechanism and whether patients with hypocalcaemia could benefit from calcium supplement.

Beneficial effects of muscone on cardiac remodeling in a mouse model of myocardial infarction.

Musk has been traditionally used in East Asia to alleviate the symptoms of angina pectoris. However, it remains unclear as to whether muscone, the main active ingredient of musk, has any beneficial effects on persistent myocardial ischemia in vivo. The aim of the present study was to investigate whether muscone can improve cardiac function and attenuate myocardial remodeling following myocardial infarction (MI) in mice. Mice were subjected to permanent ligation of the left anterior descending coronary artery to induce MI, and then randomly treated with muscone (2 mg/kg/day) or the vehicle (normal saline) for 3 weeks. Sham-operated mice were used as controls and were also administered the vehicle (normal saline). Treatment with muscone significantly improved cardiac function and exercise tolerance, as evidenced by the decrease in the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, as well as an increase in the left ventricular ejection fraction, left ventricular fractional shortening and time to exhaustion during swimming. Pathological and morphological assessments indicated that treatment with muscone alleviated myocardial fibrosis, collagen deposition and improved the heart weight/body weight ratio. Muscone inhibited the inflammatory response by reducing the expression of transforming growth factor (TGF)­ß1, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and nuclear factor (NF)-κB. Treatment with muscone also reduced myocardial apoptosis by enhancing Bcl-2 and suppressing Bax expression. Muscone also induced the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS). Our results demonstrate that muscone ameliorates cardiac remodeling and dysfunction induced by MI by exerting anti-fibrotic, anti-inflammatory and anti-apoptotic effects in the ischemic myocardium.

Diagnostic and prognostic value of minor elevated cardiac troponin levels for percutaneous coronary intervention-related myocardial injury: a prospective, single-center and double-blind study.

Cardiac troponin-I (cTnI) and -T (cTnT) are sensitive and specific markers of myocardial injury. However, the role of increased cTnI and cTnT in percutaneous coronary intervention (PCI)-related myocardial injury remains controversial. In this prospective, single-center and double-blind study, we aimed to determine the diagnostic and prognostic value of cTnI as well as cTnT (cTns) in PCI-related myocardial injury in a Chinese population. A total of 1,008 patients with stable angina pectoris and non-ST-segment elevation acute coronary syndrome were recruited. The levels of cTnI and cTnT were examined before and after PCI. All patients were followed up for 26±9 months to observe the incidence of major adverse cardiac events (MACEs). Our results showed that post-PCI cTnI and/or cTnT levels were increased to more than the 99(th) percentile upper reference limit (URL) in 133 (13.2%) patients, among which 22 (2.2%) were more than 5 × 99(th) percentile URL. By univariate analysis, an elevation in cTns after PCI was not an independent predictor of increased MACEs, HR 1.35 (P  =  0.33, 95%CI: 0.74-2.46). In conclusion, our data demonstrate that the incidence of PCI-related myocardial injury is not common in a Chinese population and minor elevated cTns levels may not be a sensitive prognostic marker for MACEs.

Cardiac-specific expression of the hepatocyte growth factor (HGF) under the control of a TnIc promoter confers a heart protective effect after myocardial infarction (MI).

OBJECTIVE: Uncontrolled therapeutic gene expression and neovascularization in non-specific tissues has lowered the safety of gene therapy. The aim of the study was to identify a cardiac-specific promoter to control target gene expression in heart tissue in vitro and in vivo. METHODS: Adenovirus vectors containing the firefly luciferase or hepatocyte growth factor (HGF) genes under control of the Troponin I (TnIc) or Cytomegalievirus (CMV) promoters were transfected into cell lines or injected into the left ventricular wall of Sprague Dawley (SD) rats via thoracotomy. Myocardial infarction (MI) was induced immediately before direct injection. In vivo luciferase expression was assessed using a bioluminescence imaging system. Heart function was monitored via echocardiograph intermittently for eight weeks after injection. RESULTS: The constitutively active CMV promoter yielded luciferase expression throughout the body while luciferase expression driven by the TnIc promoter was largely restricted to the hypoxic heart. The CMV promoter was more efficient, yielding 100-1000 fold more light output than the TnIc promoter. Four weeks after injection, we observed a significant decline in the ejection fraction (EF) in saline and Ad-Null groups but a 17% increase in the Ad-CMV-HGF group. No change in EF was observed in the Ad-TnIc-HGF group. CONCLUSIONS: The adenovirus vector combined with the TnIc promoter largely restricts gene-targeted therapy in the hypoxic heart and prevents heart failure after myocardial infarction.

MicroRNA-200b stimulates tumour growth in TGFBR2-null colorectal cancers by negatively regulating p27/kip1.

Colorectal cancer (CRC) remains the most common malignancy worldwide. TGF-ß1 is often overexpressed in late stages of colorectal carcinogenesis and promotes tumour growth and metastasis. Several reports have verified that the loss of functional TGFBRII expression contributed to escape the tumour suppressor activity of TGF-ß1 and that the epithelial-to-mesenchymal transition (EMT) responded to TGF-ß1 involved in tumour invasion and metastasis. However, the mechanisms by which TGF-ß1 confers a growth advantage to TGFBRII-null colorectal cancer cells have not been elucidated. MicroRNAs (miRNAs) are post-transcriptional inhibitory regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for miR-200b in colorectal cancer. MiR-200b was highly expressed in TGFBRII-null tumour tissues and colorectal cancer cell lines and positively correlated with cell proliferation in tumour tissues and cell lines. In contrast, decreasing the miR-200b level in TGFBRII-null cells suppressed cell proliferation and cell cycle progression. Furthermore, in vivo studies also suggested a stimulating effect of miR-200b on TGFBRII-null cell-derived xenografts. CDKN1B (p27/kip1) and RND3 (RhoE) have miR-200b binding sequences within their 3' untranslated regions and were confirmed to be direct targets of miR-200b using fluorescent reporter assays. Meanwhile, CDKN1B (p27/kip1) played a role in miR-200b-stimulated TGFBR-null CRC. This study suggests that miR-200b plays a tumour-promoting role by targeting CDKN1B (p27/kip1) in CRCs.

Beneficial effects of schisandrin B on the cardiac function in mice model of myocardial infarction.

The fruit of Schisandra chinensis has been used in the traditional Chinese medicine for thousands of years. Accumulating evidence suggests that Schisandrin B (Sch B) has cardioprotection effect on myocardial ischemia in vitro. However, it is unclear whether Sch B has beneficial effects on continuous myocardial ischemia in vivo. The aim of the present study was to investigate whether Sch B could improve cardiac function and attenuate myocardial remodeling after myocardial infarction (MI) in mice. Mice model of MI was established by permanent ligation of the left anterior descending (LAD) coronary artery. Then the MI mice were randomly treated with Sch B or vehicle alone. After treatment for 3 weeks, Sch B could increase survival rate, improve heart function and decrease infarct size compared with vehicle. Moreover, Sch B could down-regulate some inflammatory cytokines, activate eNOS pathway, inhibit cell apoptosis, and enhance cell proliferation. Further in vitro study on H9c2 cells showed similar effects of Sch B on prevention of hypoxia-induced inflammation and cell apoptosis. Taken together, our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after ischemic injury. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.

Beneficial effects of ginsenoside-Rg1 on ischemia-induced angiogenesis in diabetic mice.

Neovascularization and the formation of collateral vessels are often impaired in diabetes mellitus (DM) population compared with non-diabetics. Alterations in vascular endothelial growth factor (VEGF) signaling and endothelial nitric oxide synthase (eNOS) dysfunction have been confirmed to play a crucial role in impaired neovascularization in diabetic mice. Accumulating data have suggested that Rg1, a main component of Panax ginseng, has the ability to promote tubulogenesis of human umbilical vein endothelial cells (HUVECs) in vitro, and that the mechanism involves increased expression level of VEGF as well as increased eNOS activation. Thus, we speculated that Rg1 might also have therapeutic effects on the impairment of neovascularization in diabetic individuals. The aim of the present study was to investigate whether Rg1 could improve angiogenesis in ischemic hindlimb of diabetic mice in vivo. Our data demonstrated that Rg1 treatment resulted in improved angiogenesis in the diabetic ischemic hindlimb, and the potential mechanism might involve increased eNOS activation, upregulated VEGF expression, and inhibited apoptosis. Our results suggest that Rg1 may be used as a novel and useful adjunctive drug for the therapy of peripheral arterial disease in DM.