The effectiveness and safety of nicorandil in the treatment of patients with microvascular angina: A protocol for systematic review and meta-analysis.

BACKGROUND: Microvascular angina has become a clinical and frequent cardiovascular disease in recent years, which is complicated and there is no clear treatment. Today, Western medicine still deals with microvascular angina with standardized treatment based on the stable angina. Firstly, it is to control the risk factors of atherosclerosis, and the second is to reduce the oxygen consumption of the patient's heart muscle. In the previous randomized controlled clinical trials, it has shown that nicorandil can improve the symptoms of angina for the treatment of microvascular angina, but there is a lack of high-quality randomized controlled trials on the clinical effectiveness and safety of nicorandil in the treatment of microvascular angina, and the lack of evaluation of its effectiveness and safety. Therefore, this paper aims to understand whether nicorandil can further improve the prognosis of patients with microvascular angina and the safety of the drug through the method of systematic evaluation. METHODS: Retrieval of relevant network electronic databases by computer: SinoMed, CNKI, WanFang Data, VIP, PubMed, EMbase and The Cochrane Library, the retrieval time is from the establishment of each database to December 2017, to collect randomized controlled studies of nicorandil in the treatment of microvascular angina. At the same time, it is supplemented by manual search of the included literature references, as far as possible to increase the included literature imformation. Two researchers independently browse the topics and abstracts, and select, find, read the full text of the relevant literature, and screen the literature according to the criteria for inclusion and exclusion established in advance, then extract the data, and cross-check, and resolve the differences through multi-person discussion. Data analysis of collected information is performed by using RevMan 5.3 software. RESULTS: The data of the included literature are statistically analyzed by meta-analysis, and the key outcome indicators are used to determine whether nicorandil can further improve the prognosis of patients with microvascular angina and the safety of the drug. CONCLUSION: Through the method of evidence-based medicine, this study finds the existing problems and defects in the current research, which will provide high-quality evidence-based medical evidence for nicorandil's treatment of microvascular angina, and it help the clinical treatment and further research. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/DSQG9.

Interaction between nonsynonymous polymorphisms in PLA2G7 gene and smoking on the risk of coronary heart disease in a Chinese population.

To investigate the impact of PLA2G7 polymorphism, and additional their interactions with smoking and drinking on coronary heart disease (CHD) risk based on Chinese population. GMDR model was used to screen the best gene-smoking and gene-drinking interaction combinations. Logistic regression was performed to investigate association between 4 SNPs and CHD, and the interaction effect between rs1805017 and smoking. For CHD patient-control haplotype analyses, the SHEsis online haplotype analysis software ( http://analysis.bio-x.cn/myAnalysis.php ) was employed. CHD risks were higher in carriers of homozygous mutant of rs1805017 and rs1805018 than those with wild-type homozygotes, OR (95% CI) were 1.45 (1.16-1.92) and 1.51 (1.23-1.97), respectively, but the other two SNPs, rs16874954 and rs1051931 were not significant associated with CHD risks. GMDR analysis indicated that there was a significant two-locus model (p = 0.0107) involving rs1805017 and smoking, indicating a potential gene-environment interaction between rs1805017 and smoking. But we did not found any gene-drinking and gene-gene interaction combinations in GMDR models. The haplotype R-I was observed most frequently in two groups, with 47.43 and 54.38% in the case and control group of the population, respectively. The results also indicated that the haplotype containing the rs1805017-H and rs1805018-T alleles were associated with a statistically increased CHD risk, OR (95% CI) 1.43 (1.10-1.86), p = 0.0021. Polymorphisms in rs1805017 and rs1805018, additional interaction between rs1805017 and smoking, and haplotype containing the rs1805017-H and rs1805018-T alleles were associated with increased CHD risk.

Gene-gene interaction between PPARG and CYP1A1 gene on coronary artery disease in the Chinese Han Population.

AIMS: To observe the influence of the peroxisome proliferator-activator receptor-G (PPAR-G) gene and cytochrome P4501A1 (CYP1A1) single-nucleotide polymorphisms (SNPs), and interactions among several SNPs on coronary artery disease (CAD) risk. METHODS: A total of 1106 participants (including 583 males and 523 females) including 550 CAD patients and 556 control subjects were recruited in this study, and the mean age for these participants was 55.5 ± 11.8 years old. Logistic regression was used to observe association of SNP within PPARG and CYP1A1 with CAD risk and GMDR model was used to screen the best interaction combinations. RESULTS: CAD susceptibility was higher in those with homozygous mutant of rs10865710, rs1805192 and rs4646903 than those with wild-type homozygotes, OR (95%CI) were 1.47 (1.15-1.92), 1.69 (1.27-2.09) and 1.72 (1.35-2.32), respectively. We also found a significant two-locus model involving rs1805192 and rs4646903 (p = 0.0107), and the cross-validation consistency of this locus model was 10 of 10, the testing accuracy of this model is 62.17%. Logistic regression shown that CAD risk was the highest in those with rs1805192- Pro/Ala or Ala/Ala and rs4646903- AG+GG genotype, and was lowest in those with rs1805192- Pro/ Pro and rs4646903- AA genotype, OR(95%CI) = 3.56 (1.91-5.42). CONCLUSIONS: Polymorphism in rs10865710, rs1805192 and rs4646903 and interaction between rs1805192 and rs4646903 were related with increased CAD susceptibility.

Forkhead box O (FOXO) 3 modulates hypoxia-induced autophagy through AMPK signalling pathway in cardiomyocytes.

Autophagy is promoted as a response to such environmental stress conditions as ATP depletion and excessive accumulation of reactive oxygen species (ROS). Multiple signalling pathways, including AMP-activated protein kinase (AMPK), are indicated to promote autophagy in ischaemic/hypoxic (I/R) heart. However, it's far more to clarify the orchestrated cross-talk between AMPK and other signalling pathways in the autophagy. In the present study, we investigated the autophagy induction by hypoxia in Rat H9C2 cardiomyocytes with LC3-EGFP reporter, EM and Western blot analysis. Then, we examined the promotion of forkhead box O (FOXO) 3, one member of FOXO transcriptional protein family, by hypoxia in Rat H9C2 cells and determined the mediation of FOXO 3 in the hypoxia-induced autophagy in H9C2 cells. In addition, we investigated the role of AMPK signalling in the FOXO3-mediated, hypoxia-induced autophagy in H9C2 cells. It was demonstrated that hypoxia induced significant autophagy in H9C2 cells, via promoting autophagic vesicles, inducing the conversion of LC3-I to LC3-II and up-regulating autophagy-related (ATG) markers. Moreover, FOXO3 was up-regulated by the hypoxia in H9C2 cells; and the knockdown of FOXO3 significantly reduced the hypoxia-induced autophagy. In addition, AMPK signalling was significantly promoted by hypoxia in H9C2 cells, and the chemical manipulation of AMPK exerted significant influence on the hypoxia-induced autophagy and on the FOXO3 level. In conclusion, FOXO3 regulated the hypoxia-induced autophagy in cardiomyocytes, and AMPK mediated the FOXO3 promotion during the autophagy induction by hypoxia, implying the key regulatory role of FOXO3 and AMPK signalling in the hypoxia-induced autophagy in cardiomyocytes.

Ambra1 modulates starvation-induced autophagy through AMPK signaling pathway in cardiomyocytes.

Recent research has revealed a role for Ambra1, an autophagy-related gene-related (ATG) protein, in the autophagic pro-survival response, and Ambra1 has been shown to regulate Beclin1 and Beclin1-dependent autophagy in embryonic stem cells and cancer cells. However, whether Ambra1 plays an important role in the autophagy pathway in cardiomyocytes is unknown. In this study, we hypothesized that Ambra1 is an important regulator of autophagy and apoptosis in cardiomyocytes. To test this hypothesis, we confirmed autophagic activity in serum-starved cardiomyocytes by assessing endogenous microtubule-associated protein 1 light chain 3 (LC3) localization, the presence of autophagosomes and LC3 protein levels. Cell apoptosis and viability were measured by annexin-V and PI staining and MTT assays. We determined that serum deprivation-induced autophagy was associated with Ambra1 upregulation in cardiomyocytes. When Ambra1 expression was reduced by siRNA, the cardiomyocytes were more sensitive to staurosporine-induced apoptosis. In addition, co-immunoprecipitation of Ambra1 and Beclin1 demonstrated that Ambra1 and Beclin1 interact in serum-starved or rapamycin-treated cardiomyocytes, suggesting that Ambra1 regulates autophagy in cardiomyocytes by interacting with Beclin1. Finally, we determined that starvation stress-induced activation of Ambra1 contributes to the attenuation of adaptive AMP-activated protein kinase (AMPK) signaling. In conclusion, Ambra1 is a crucial regulator of autophagy and apoptosis through AMPK signaling pathway in cardiomyocytes that maintains the balance between autophagy and apoptosis.

WITHDRAWN: Ambra1 modulates starvation-induced autophagy through AMPK signaling pathway in cardiomyocytes.

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