Huafeng Yang

Oxidized Low-Density Lipoprotein Induces Apoptosis in Cultured Neonatal Rat Cardiomyocytes by Modulating the TLR4/NF-κB Pathway.

This study was designed to investigate the apoptosis induced by oxidized low-density lipoprotein (ox-LDL) in cultured neonatal rat cardiomyocytes and explore the possible mechanisms. We evaluated whether ox-LDL-induced apoptosis depended in part on the activation of toll-like receptor-4(TLR4)/Nuclear factor κB (NF-κB) signaling pathway. Cells were cultivated with and without ox-LDL. Cell apoptosis was evaluated by flow cytometry. Immunofluorescence, western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were conducted to assess protein or mRNA expressions. Resatorvid (TAK-242), an exogenous synthetic antagonist for TLR4, was used to inhibit TLR4 signal transduction. Dose- and time-dependent apoptotic index of cardiomyocytes occurred after ox-LDL treatment. Incubation of cardiomyocytes with ox-LDL (50 μg/mL) for 24 hours increased TLR4 and NF-κB expressions significantly. Decrease of Bcl-2/Bax protein ratio, activation of caspase-3 and 9 were also detected. Ox-LDL-induced cardiomyocyte apoptosis, TLR4 and NF-κB expressions were attenuated by pretreatment with TAK-242. In conclusion, our findings indicate that the apoptosis induced by ox-LDL in cultured neonatal rat cardiomyocytes at least in part by modulating the TLR4/NF-κB signaling pathway.

Ultrasound-Targeted Microbubble Destruction Enhances Gene Expression of microRNA-21 in Swine Heart via Intracoronary Delivery.

Ultrasound‐targeted microbubble destruction (UTMD) has proved to be a promising method for gene delivery. However, the feasibility and efficacy of UTMD‐mediated gene delivery to the heart of large animals remain unclear. The present study was to explore the probability of increasing the transfection of microRNA‐21 (miR‐21) in swine heart by UTMD, and to search for the most suitable transfection conditions.

The effect of alprostadil on preventing contrast-induced nephropathy for percutaneous coronary intervention in diabetic patients: A systematic review and meta-analysis.

Background:At present, there are a lot of research about the effect of Alprostadil on preventing contrast-induced nephropathy for percutaneous coronary intervention (PCI) in diabetic patients, but the clinical efficacy is not consistent, so we conduct this study and therefore determine the dominant strategy for the treatment of PCI in diabetic patients based on the best evidence currently. Methods:An electronic database search was conducted in MEDLINE, Embase, Cochrane library, CBM, CNKI, VIP, and WanFang to retrieve randomized controlled trial (RCT) comparing Alprostadil versus hydration on preventing CIN for PCI in diabetic patients. Reference lists of relevant articles were also screened manually to retrieve additional ones. Two investigators independently assessed the eligibility of retrieved articles using predefined inclusion and exclusion criteria. All characteristics as well as outcome variables including incidence of CIN, blood urea nitrogen (BUN), cystatin C (CysC), glomerular filtration rate (GFR), serum creatinine (Scr), serum beta 2-microspheres (&bgr;2-MG) presented in each included study were extracted. Heterogeneity was thought to be significant when I2 > 50%. All of the meta-analytic procedures were performed by using Review Manager software, version 5.3. Results:Finally, data from 8 articles including 969 patients were included into this meta-analysis, among them, 487 patients in the experience group, and 482 patients in the control group. Meta analysis showed that the incidence of CIN in the experimental group was significantly lower than that in the control group (OR = 0.28,95%CI[0.18,0.42]). The incidence of adverse reactions in the experimental group was significantly lower than that in the control group (OR = 0.46,95%CI[0.24,0.85]). The BUN of 24 hours, 48 hours, and 72 hours in the experimental group were significantly lower than that of control group (MD = –0.77, 95%CI [−1.22, –0.32]; MD = –1.38, 95%CI [−1.83,–0.92]; MD = –2.43, 95%CI [−2.68,–2.19], respectively). The CysC of 24 hours, 48 hours, and 72 hours in the experimental group were significantly lower than that of control group (MD = –0.30, 95%CI [−0.40, –0.21]; MD = –0.54, 95%CI [−0.68,–0.41]; MD = –0.49, 95%CI [−0.63, –0.35], respectively). The GFR of 24 hours, 48 hours, and 72 hours in the experimental group were significantly higher than that of control group (MD = 7.86, 95%CI [4.44, 11.29], MD = 18.23, 95%CI [13.76,22.69], MD = 12.81, 95%CI [8.51,17.11], respectively). The Scr of 24 hours, 48 hours, and 72 hours in the experimental group were significantly lower than that of control group (MD = –9.09, 95%CI [−12.67, –5.51], MD = –19.14, 95%CI [−23.61, –14.66], MD = –6.50, 95%CI [−8.29, –4.71], respectively). The &bgr;2-MG of 24 hours, 48 hours, and 72 hours in the experimental group were significantly lower than that of control group (MD = –0.12, 95%CI [−0.27, 0.03], MD = –0.55, 95%CI [−0.71, –0.39], MD = –0.50, 95%CI [−0.60, –0.39], respectively). Conclusion:Our result suggested that comparing with conventional Hydration, Alprostadil can significantly reduce the incidence of CIN, adverse reaction, and protect renal function in PCI in diabetic patients. Due to the limitations of the quality and quantity of the articles, this conclusion still needs further research to confirm.

MiRNA Expression Profile of the Myocardial Tissue of Pigs with Coronary Microembolization

Background/Aims: Coronary microembolization (CME) is a serious complication of coronary heart disease and is considered as a strong predictor of poor long-term prognosis and major cardiac adverse events. Here, we identified differentially expressed microRNAs (miRNAs) in the myocardial tissue of CME pigs, and predicted and analyzed the possible functions of their target genes. Methods: Twelve Bama mini-pigs were randomly assigned to the sham and CME group (n = 6 in each group). The two groups were compared with regard to heart function, area of infarction, cardiomyocyte apoptosis, and myocardial expression of TNF-α, IL-1β and IL-6. Further, miRNA chip analysis was used to screen for differentially expressed miRNAs, and the results were validated by real-time PCR. Bioinformatics methods were used to predict and analyze the functions of the target genes of the identified miRNAs. Results: The model CME pigs showed significantly increased expression of TNF-α, IL-1β and IL-6, as well as micro-infarction lesions and cell apoptosis in the myocardial tissue. Thus, the model was established successfully. In the myocardial tissue of the CME pigs, the expression of ssc-miR-92b-5p, ssc-miR-491, ssc-miR-874, ssc-miR-425-3p, ssc-miR-376a-5p, ssc-miR-370, ssc-miR-30c-3p, ssc-miR-493-5p and ssc-miR-323 was significantly increased, whereas the expression of ssc-miR-136 and ssc-miR-142-3p was significantly decreased. GO and KEGG pathway analysis indicated that the target genes of these miRNAs are mainly associated with cell proliferation, apoptosis, necrosis, inflammation, and fibrosis. Conclusion: The differentially expressed miRNAs identified in the myocardial tissue of CME pigs could be new biomarkers or potential treatment targets for CME.

Effects of Trimetazidine on PDCD4/NF-κB/TNF-α Pathway in Coronary Microembolization

Background/Aims: The local inflammatory response caused by coronary microembolization (CME) is the primary cause of progressive cardiac dysfunction. The PDCD4/NF-κB/TNF-α signaling pathway plays a significant role in CME-induced myocardial Inflammation. Trimetazidine (TMZ) reduces myocardial injury, caused by percutaneous coronary intervention, through relieving the CME-induced myocardial systolic dysfunction. Therefore, the present study investigated the role of TMZ pre-treatment in the protection of myocardium after CME and PDCD4/NF-κB/TNF-α in mini pigs. Methods: 20 Bama mini pigs were randomized into sham operation (sham), microembolization (CME), TMZ, and siRNA-PDCD4 groups (n = 5). The CME model was established by injecting polyethylene microspheres via microcatheter into the left anterior descending coronary artery. The TMZ group was injected 2.5 mg/kg drug via ear vein 30 min before CME; whereas, the siRNA-PDCD4 group was transfected with PDCD4 siRNA at the left anterior descending coronary artery via microcatheter 72h before CME. Cardiac function indexes were measured using cardiac echocardiography. The mRNA expression of PDCD4 and TNF-α in the myocardium was detected by quantitative fluorescence PCR, and the protein expression of PDCD4, NF-κB (p65), and TNF-α by Western blot. Results: Echocardiographic parameters showed lower cardiac function and higher serum cTnI level in the CME group than sham, which was manifested as reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS), cardiac output (CO), and increased left ventricular diastolic diameter (LVEDd). Compared to the CME group, the CME-induced cardiac function injury was reduced, and the serum cTnI level was decreased in the TMZ and siRNA-PDCD4 groups. The expressions of PDCD4, NF-κB (p65), and TNF-α were significantly increased in the CME than the sham groups (P < 0.05), and significantly decreased in the TMZ and siRNA-PDCD4 groups than the CME group (P < 0.05). Conclusion: TMZ pretreatment effectively reduced the myocardial damage caused by CME via inhibiting the PDCD4/NF-κB/ TNF-α pathway in cardiomyocytes.

Effects of the TLR4/Myd88/NF-κB Signaling Pathway on NLRP3 Inflammasome in Coronary Microembolization-Induced Myocardial Injury

Background/Aims: Coronary microembolization (CME) is a common complication of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI); Myocardial inflammation, caused by CME, is the main cause of cardiac injury. TLR4/MyD88/NF-κB signaling plays an important role in the development of myocardial inflammation, but its effects on CME remain unclear. To assess the cardiac protective effects of TAK-242 (TLR4 specific inhibitor) on CME-induced myocardial injury, and explore the underlying mechanism. Methods: Cardiac function, serum c-troponin I level, microinfarct were examined by cardiac ultrasound, myocardial enzyme assessment, HBFP staining. The levels of TLR4/MyD88/NF-κB signaling and NLRP3 inflammasome pathway were detected by ELISA, qRT-PCR and western blot. Results: The results showed inflammatory responses in the myocardium after CME, with increased expression levels of pro-inflammatory factors TNF-α, IL-1β and IL-18. Meanwhile, TLR4/MyD88/NF-κB signaling and the NLRP3 inflammasome were involved in the inflammatory process. TAK-242 administration before CME effectively inhibited the inflammatory response in the rat myocardium after CME and reduced myocardial injury, mainly by inhibiting TLR4/ MyD88/NF-κB signaling and reducing NLRP3 inflammasome activation. In addition, in vitro assays with neonatal rat cardiomyocytes further confirmed that TLR4/MyD88/NF-κB signaling was significantly activated in the inflammatory response of LPS-induced cardiomyocytes, via activation of the NLRP3 inflammasome. Inhibition of TLR4/MyD88/NF-κB signaling resulted in increased survival of cardiomyocytes mainly by reducing the release of inflammatory cytokines and decreasing NLRP3 inflammasome activation. Conclusions: TLR4/MyD88/NF-κB signaling participates in the inflammatory response of the myocardium after CME, activating the NLRP3 inflammasome, promoting the inflammatory cascade, and aggravating myocardial injury. Blocking TLR4/MyD88/NF-κB signaling may help reduce myocardial injury and improve cardiac function after CME.

Role of high mobility group A1/nuclear factor-kappa B signaling in coronary microembolization-induced myocardial injury

OBJECTIVE Coronary microembolization (CME) is a common complication in percutaneous coronary intervention (PCI). Local myocardial inflammation caused by CME is the major cause of progressive cardiac dysfunction. High mobility group A1 (HMGA1)/nuclear factor-kappa B (NF-κB) signaling plays an important role in the development and progression of inflammation, but its role in CME remains unclear. This study evaluated the effect of HMGA1/NF-κB signaling on CME-induced myocardial inflammation and cardiac dysfunction. METHODS Forty Sprague-Dawley rats were randomly divided into four groups: sham, CME, CME + HMGA1 small interfering RNA (HMGA1 siRNA), and CME + scrambled siRNA (control siRNA) groups, with 10 animals each. The CME model group was established by clamping the ascending aorta and injecting microspheres through the left ventricular apex for embolization, and the sham group was established by injecting the same amount of normal saline. The HMGA1 siRNA group was injected with HMGA1 siRNA transfection complexes into the tail vein 72 h before CME modeling, and the control siRNA group was caudally injected with the same amount of scrambled siRNA 72 h before CME modeling. Twelve hours after the operation, cardiac function, serum c-troponin I level, and microinfarct size were examined. The levels of HMGA1, NF-κB p65, TNF-α, and IL-1β were detected. RESULTS Myocardial dysfunction, enhanced serum c-troponin I, and microinfarct were induced following CME. Moreover, CME induced an increased expression of HMGA1, NF-κB p65, TNF-α, and IL-1β. The HMGA1 siRNA reversed these effects by CME, while the scrambled siRNA had no effect. CONCLUSIONS HMGA1/NF-κB signaling is involved in CME-induced myocardial inflammation. Inhibition of HMGA1/NF-κB signaling attenuated the CME-induced myocardial injury and improved cardiac function, suggesting a new potential target for the prevention and treatment of CME-induced myocardial injury.

Clinical effect of trimetazidine on prevention of contrast-induced nephropathy in patients with renal insufficiency: An updated systematic review and meta-analysis

Background: With the continuous development of cardiac interventional medicine, the incidence of contrast-induced nephropathy (CIN) is increasing every year, which is a serious threat to peoples physical and mental health. Trimetazidine (TMZ) is a type of anti-ischemic drug developed in recent years, which can significantly reduce the incidence of CIN. At present, a systematic review and meta-analysis was conducted to evaluate the clinical effect of TMZ on prevention of CIN in patients with renal insufficiency. However, the study did not include patients from other countries and speaking different languages. So we conducted this study to update the previous meta-analysis that investigated the effects of TMZ on prevention of CIN in patients with renal insufficiency, and provided some theoretical reference for clinical. Methods: By searching PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, VIP database, and Wang Fang database for randomized controlled trial, which is comparing TMZ versus conventional hydration for prevention of CIN. Two researchers independently screened literature, and then evaluated the quality of literature and extracted the relevant data. Stata 11.0 software was used for statistical analysis. Results: Finally, this updated review showed that 3 studies that were not included in the previous meta-analysis were included in our study (3 articles were published in the Chinese Journal, 1 study for CIN, 1 study for CIN, serum creatinine (Scr), and superoxide dismutase, 1 study for CIN and Scr), and 1 outcome (Scr) reflecting the change of renal function was additionally included in our study. Of the 932 studies, 6 randomized controlled trials met the criteria, including 377 patients in TMZ group and 387 patients in control group. This meta-analysis for all studies showed that TMZ can significantly reduce the incidence of CIN (relative risk 0.27, 95% confidence interval [CI] 0.16, 0.46, P = 0.000), and can decrease the level of Scr after operation, including Scr of postoperative 24 hours (standardized mean difference [SMD] −0.30, 95% CI −0.51, −0.09, P = 0.005), Scr of postoperative 48 hours (SMD −0.66, 95% CI −1.23, −0.10, P = 0.022), and Scr of postoperative 7 days (SMD −0.74, 95% CI −1.36, −0.11, P = 0.021). However, the Scr of postoperative 72 hours between TMZ group and control group has no statistical significance (P = 0.362). Conclusion: Our study showed that when comparing with conventional hydration, TMZ can significantly reduce the incidence of CIN and the level of postoperative Scr. Therefore, we could suggest that TMZ was superior to conventional hydration for the treatment of CIN in patients with renal insufficiency. However, due to the restriction of quality and number of included articles, it still needs to carry out multicenter, randomized, double-blind clinical trials to confirm this conclusion in the future.

Pinocembrin protects endothelial cells from oxidized LDL-induced injury

HighlightsPinocembrin inhibits the induction of VCAM‐1, ICAM‐1, and E‐selectin by ox‐LDL.Pinocembrin ameliorates ox‐LDL‐induced attachment of monocytes to endothelial cells.Pinocembrin suppresses ox‐LDL induced production of pro‐inflammatory cytokines.Pinocembrin attenuates ox‐LDL induced production of ROS in HAECs.Pinocembrin inhibits ox‐LDL‐induced activation of p38 and IKK&agr;/I&kgr;B&agr;/NF‐&kgr;B signaling. Abstract Oxidized low‐density lipoprotein (ox‐LDL) is a major risk factor for atherosclerosis and often causes injury to vascular endothelial cells. We found that pinocembrin, a natural antioxidant found in honey and certain herbs, protects human aortic endothelial cells (HAECs) from ox‐LDL‐induced injury. Pinocembrin suppresses the expression of pro‐inflammatory vascular adhesion molecules (VCAM‐1, ICAM‐1 and E‐selectin) and cytokines (TNF‐&agr;, IL‐1&bgr;, and IL‐8), as well as ROS production induced by ox‐LDL. Pinocembrin potently inhibits the attachment of monocytes to HAEC cells. Mechanistically, pinocembrin suppresses activation of the MAPK kinase p38 and NF‐&kgr;B pathways in the context of ox‐LDL. Our data indicate that pinocembrin is a promising versatile natural compound that can protect endothelial cells from injury.

Effects of nicorandil on PI3K/Akt signaling pathway and its anti-apoptotic mechanisms in coronary microembolization in rats

Coronary microembolization (CME) is a common complication of percutaneous coronary intervention (PCI) for acute coronary syndrome. It leads to myocardial apoptosis and cardiac dysfunction. Nicorandil pretreatment can prevent PCI-related myocardial injury and reduce the incidence of no- or slow-reflow phenomena. This cardioprotective effect is probably attributable to the suppression of CME-induced cardiomyocyte apoptosis, but the specific mechanisms have not been clarified. We aimed to investigate the protective effects of nicorandil pretreatment on CME-induced myocardial injury and clarify the underlying mechanisms. In vivo studies, we used echocardiography, cardiac-enzymes measurement, hematoxylin–basic fuchsin–picric acid staining, TUNEL assay, and western blot, and found that CME significantly increased apoptotic cardiomyocytes in the infarct and peri-infarct areas in rats. The PI3K/Akt signaling pathway was involved in cardiomyocyte apoptosis. Nicorandil pretreatment given 7 days before CME effectively reduced cardiomyocyte apoptosis and myocardial injuries in rats, mainly through the activation of PI3K/Akt signaling. In vitro studies further showed that nicorandil reduced hypoxia-induced cardiomyocyte apoptosis and improved cardiomyocyte-survival rate. The PI3K-specific inhibitor LY294002 reduced these cardioprotective effects, indicating that they were attributable to the activation of the PI3K/Akt signaling pathway. In conclusion, nicorandil has significant cardioprotective effects in CME mainly through the activation of the PI3K/Akt signaling pathway and reduction of CME-induced cardiomyocyte apoptosis. Our findings may provide important support for the pre-PCI use of nicorandil to reduce post-PCI myocardial injuries.