MiR-146a rs2910164 (G/C) polymorphism is associated with the development and prognosis of acute coronary syndromes: an observational study including case control and validation cohort.

BACKGROUND: Polymorphisms in microRNAs (miRNAs) play an important role in acute coronary syndromes (ACS). The purpose of this study was to assess the association of miR-146a rs2910164 and miR-34b rs4938723 polymorphisms with the development and prognosis of ACS and to explore the underlying mechanisms. METHODS: A case-control study of 1171 subjects was included to determine the association of miR-146a rs2910164 and miR-34b rs4938723 polymorphisms with ACS risk. An additional 612 patients with different miR-146a rs2910164 genotypes, who underwent percutaneous coronary intervention (PCI) were included in the validation cohort and followed for 14 to 60 months. The endpoint was major adverse cardiovascular events (MACE). A luciferase reporter gene assay was used to validate the interaction of oxi-miR-146a(G) with the IKBA 3'UTR. Potential mechanisms were validated using immunoblotting and immunostaining. RESULTS: The miR-146a rs2910164 polymorphism was significantly associated with the risk of ACS (Dominant model: CG + GG vs. CC, OR = 1.270, 95% CI (1.000-1.613), P = 0.049; Recessive model: GG vs. CC + CG, OR = 1.402, 95% CI (1.017-1.934), P = 0.039). Serum inflammatory factor levels were higher in patients with the miR-146a rs2910164 G allele than in those with the C allele. MiR-146a rs2910164 polymorphism in dominant model was associated with the incidence of MACE in post-PCI patients (CG + GG vs. CC, HR = 1.405, 95% CI (1.018-1.939), P = 0.038). However, the miR-34b rs4938723 polymorphism was not associated with the prevalence and prognosis of ACS. The G allele of miR-146a rs2910164 tends to be oxidized in ACS patients. The miRNA fractions purified from monocytes isolated from ACS patients were recognized by the 8OHG antibody. Mispairing of Oxi-miR-146a(G) with the 3'UTR of IKBA results in decreased IκBα protein expression and activation of the NF-κB inflammatory pathway. P65 expression was higher in atherosclerotic plaques from patients carrying the miR-146a rs2910164 G allele. CONCLUSION: The variant of miR-146a rs2910164 is closely associated with the risk of ACS in Chinese Han population. Patients carrying miR-146a rs2910164 G allele may have worse pathological change and poorer post-PCI prognosis, partly due to the oxidatively modified miR-146a mispairing with 3'UTR of IKBA and activating NF-κB inflammatory pathways.

The Usefulness of C-Reactive Protein to Albumin Ratio in the Prediction of Adverse Cardiovascular Events in Coronary Chronic Total Occlusion Undergoing Percutaneous Coronary Intervention.

Inflammation and nutrition as main factors can affect the prognosis of patients with chronic total coronary occlusion (CTO) undergoing percutaneous coronary intervention (PCI). The C-reactive protein to albumin ratio (CAR) can clarify the inflammation and nutrition status, which are highly related to clinical outcomes. This study aims to investigate the association between CAR and adverse cardiovascular events in patients with CTO undergoing PCI. For this study, 664 patients were divided into three groups based on the tertiles of CAR. The primary endpoint was all-cause mortality and the secondary endpoint was major adverse cardiovascular events (MACE). Over a median follow-up of 33.7 months, the primary endpoint occurred in 64 patients (9.6%) and the secondary endpoint occurred in 170 patients (25.6%). The patients with higher CAR represented a worse prognosis with all-cause death and cardiovascular death after the adjustment for the baseline risk factors. Adding the CAR values raised the predictive value for the incidence of the all-cause death and cardiovascular death but not MACE. The capacity of prognosis prediction was improved after the addition of the CAR value to the traditional prediction model.

Interplay Between Gut Microbiota and Amino Acid Metabolism in Heart Failure.

Heart failure (HF) is a complex clinical syndrome of which the incidence is on the rise worldwide. Cardiometabolic disorders are associated with the deterioration of cardiac function and progression of HF. Recently, there has been renewed interest in gut microbiota (GM) and its metabolites in the cardiovascular disease. HF-caused hypoperfusion could increase intestinal permeability, and a "leaky" bowel leads to bacterial translocation and make its metabolites more easily enter the circulation. Considerable evidence shows that the composition of microbiota and amino acids (AAs) has been altered in HF patients, and AAs could serve as a diagnostic and prognostic biomarker in HF. The findings indicate that the gut-amino acid-HF axis may play a key role in the progression of HF. In this paper, we focus on the interrelationship between the AA metabolism and GM alterations during the development of heart failure. We also discuss the potential prognostic and therapeutic value of the gut-amino acid-HF axis in the cortex of HF.

Glycoursodeoxycholic acid ameliorates diet-induced metabolic disorders with inhibiting endoplasmic reticulum stress.

Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed, and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, was decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared with vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.

HDL-C/apoA-I Ratio Is Associated with the Severity of Coronary Artery Stenosis in Diabetic Patients with Acute Coronary Syndrome.

BACKGROUND: Emerging evidence demonstrates that the lipid metabolism in acute coronary syndrome (ACS) patients with type 2 diabetes mellitus (T2DM) differs from nondiabetic patients. However, the distinct lipid profiles and their relationships with the severity of coronary artery stenosis and prognosis in patients with T2DM remain elusive. METHOD AND RESULT: This single-center, prospective cohort study enrolled 468 patients diagnosed with ACS undergoing coronary angiography, consisting of 314 non-DM and 154 DM patients. The HDL-C/apoA-I ratio was significantly higher in DM patients with a multivessel (≥3 affected vessels) lesion than a single-vessel (1-2 affected vessels) lesion. Regression analyses showed that the HDL-C/apoA-I ratio was positively correlated to the number of stenotic coronary arteries in DM patients but not non-DM patients. However, Kaplan-Meier survival analysis revealed no significant difference in the major adverse cardiovascular event rate regarding different HDL-C/apoA-I levels in DM or non-DM ACS patients at the end of the 2-year follow-up. CONCLUSION: A higher HDL-C/apoA-I ratio is associated with increased severity of coronary artery stenosis in DM patients with ACS but not with the rate of major adverse cardiovascular events at the end of the 2-year follow-up.

Circulating lipid and lipoprotein profiles and their correlation to cardiac function and cardiovascular outcomes in patients with acute myocardial infarction.

Recent studies showed that lipoproteins represent major risk factors, both positive and negative, for atherosclerotic cardiovascular disease. The aim of the present study was to describe the relationship between plasma lipid profile and cardiac function and cardiovascular outcomes in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Two independent groups of subjects including a total of 797 patients diagnosed of AMI undergoing PCI admitted to the First Affiliated Hospital of Xi'an Jiaotong University were included in the present study. We performed a cross-sectional study for the correlation between plasma lipid profile and cardiac function based on the first group, including 503 patients with AMI. We further validated the correlation and did the follow-up of 2.4 years of major cardiovascular outcomes on the second group, including 294 patients with AMI. Our results showed that apolipoprotein A-I (ApoA-I) level was significantly reduced, and the high-density lipoprotein cholesterol (HDL-C):ApoA-I ratio was increased in the patients with lower LVEF or higher N-terminal pro-B-type natriuretic peptide levels compared with the control; there was a positive correlation between cardiac function and ApoA-I, and a negative correlation between cardiac function and the HDL-C:ApoA-I ratio. Meanwhile, multivariate Cox analysis showed that ApoA-I was independent predictors of major adverse cardiovascular events (MACEs). Kaplan-Meier survival analysis showed the ApoA-I levels exhibited a significant effect on predicting the incidence of MACEs. In sum, plasma ApoA-I level is positively associated with the cardiac function of patients with AMI after PCI, and ApoA-I is an independent indicator to predict the incidence of MACEs.

LGR4 silence aggravates ischemic injury by modulating mitochondrial function and oxidative stress via ERK signaling pathway in H9c2 cells.

It is reported that LGR4 (leucine-rich repeat domain containing G protein-coupled receptor 4) plays a crucial role in the physiological function of many organs. However, few data are available on the function and mechanism of LGR4 in myocardial ischemia-reperfusion (I/R) injury. The aim of this study was to explore the function and mechanism of LGR4 in I/R injury. We incubated H9c2 cells in simulating ischemia buffer and then re-incubated them in normal culture medium to establish a model of I/R injury in vitro. The expression of LGR4 was evaluated by RT-PCR and western blot. Besides, the cell apoptosis was evaluated by flow cytometric analysis and the content of ROS, SOD, MDA, LDH, CK, ATP, cyt c were detected by special commercial kits. The expression of mitochondrial function-related proteins were detected by western blot. Then, the roles of ERK signaling pathway was determined with TBHQ (ERK activator) treatment. Our data have demonstrated that I/R boosted the expression of LGR4 in H9c2 cells. Knockdown of LGR4 increased the apoptosis rate of H9c2 cells and led to excessed oxidant stress and impaired mitochondrial function by increasing the levels of ROS, MDA, LDH, CK and cyt c and inhibiting SOD activity, ATP production. In addition, LGR4 silence inhibited the activation of ERK pathway. And TBHQ partially reversed the effects of LGR4 knockdown on H9c2 cells. To conclude, our study indicated that LGR4 regulated mitochondrial dysfunction and oxidative stress by ERK signaling pathways, which provides a potential cardiac protective target against I/R.

GRB2-associated binding protein 2 regulates multiple pathways associated with the development of prostate cancer.

The development of prostate cancer is complicated and involves a number of tumor-associated gene expression level abnormalities. Gene chip technology is a high-throughput method that can detect gene expression levels in different tissues and cells on a large scale. In the present study, gene chip technology was used to screen differentially expressed genes in PC-3 human prostate cancer cells following GRB-associated binding protein 2 (GAB2) gene knockdown, and the corresponding biological information was analyzed to investigate the role of GAB2 in prostate cancer. The PC-3 human prostate cancer cell GAB2 gene was knocked out and gene chip hybridization and bioinformatics methods were used to analyze the classical pathway and predict upstream regulatory molecules, disease and function associations and genetic interaction networks. According to the screening conditions |fold change|>1 and P<0.05, 1,242 differential genes were screened; 665 genes were upregulated, and 577 genes were downregulated. Ingenuity Pathway Analysis software demonstrated that GAB2 regulates pathways, such as the superpathway of cholesterol biosynthesis and p53 signaling in cells, and serves a role in diseases and functions such as 'non-melanoma solid tumors', 'viral infections' and 'morbidity or mortality'. In the occurrence and development of prostate cancer, factors such as the activation of genes involved in the proliferative cycle, abnormalities in metabolism-associated enzyme gene activities and viral infection play key roles. The present study provides novel research directions and therapeutic targets for prostate cancer.

MiR-210-3p attenuates lipid accumulation and inflammation in atherosclerosis by repressing IGF2.

Previous studies have shown that miR-210-3p is involved in the development and progression of atherosclerosis, but its specific mechanisms are still unclear. This study aims to reveal the mechanism of miR-210-3p and its target genes in macrophage lipid deposition and inflammatory response, and provide new ideas for the treatment of atherosclerosis. We found miR-210-3p increased sharply in the first 12 h induced by higher doses of ox-LDL in THP-1 macrophages and then gradually decreased. MiR-210-3p mimic transfection inhibited lipid uptake and inflammatory cytokine production in ox-LDL-induced macrophages. By inhibiting IGF2/IGF2R, miR-210-3p suppressed the expression of fatty acid transcriptase CD36 and transcription factor NF-κB in ox-LDL-induced macrophages. In conclusion, miR-210-3p inhibits the expression of CD36 and NF-κB by inhibiting IGF2 / IGF2R, thereby reducing lipid accumulation and inflammatory response in ox-LDL-induced macrophages. Enhancing miR-210-3p expression may be a new strategy for the treatment of atherosclerosis.

LncRNA AK094457 promotes AngII-mediated hypertension and endothelial dysfunction through suppressing of activation of PPARγ.

Hypertension is one of the major risk factors for cardiovascular disease worldwide and is striking more young people, which is characterized by impaired vascular endothelial function. To find the functional lncRNAs associated with hypertension, high throughput lncRNA microarray were used to analyze expression profile of the lncRNAs in the aortic vascular endothelial cells (VECs) of spontaneously hypertensive rats (SHRs). The tail vein injection of siRNA was used to study the influence of lncRNA AK094457 inhibition on endothelial function in vivo. In vitro, endothelial function was studied in endothelial cells transfected with lncRNA AK094457-overexpressed vectors and siRNAs. pPPARγ and iNOS protein levels were detected with Western blot. Elisa assay was used to analyze the secretion of AngII, ET-1, ROS and LDH level. The nitrite/nitrate (NO2-/NO3-) concentration was measured using a colorimetric assay. LncRNA AK094457 was a most upregulated lncRNA in SHRs. It is showed that downregulation of AK094457 significantly reduced rat arterial pressure, increased activation of endothelial PPARγ, and suppressed serum contents of AngII and NO in vivo. Furthermore, results from gain-and-loss of function in primary aortic endothelial cells indicated that AK094457 negatively regulated activation of PPARγ and promoted AngII-mediated endothelial dysfunction, manifested by decreased capacities of cell proliferation and migration, and increased levels of ROS production and LDH release. In conclusion, lncRNA AK094457 is identified as a key regulator in blood pressure and endothelial function, which can increase AngII-induced hypertension and endothelial dysfunction via suppression of PPARγ.

Knockdown of LSD1 meliorates Ox-LDL-stimulated NLRP3 activation and inflammation by promoting autophagy via SESN2-mesiated PI3K/Akt/mTOR signaling pathway.

AIMS: To explore the mechanism of how LSD1 regulates autophagy and the correlation between LSD1 and Ox-LDL-induced inflammation. MAIN METHODS: RAW264.7 cells were used during the whole study. Firstly, the effect of Ox-LDL-stimulation on LSD1 expression was detected. Through loss-of-function assay, the associations between LSD1 interference and SESN2 expression, autophagy, NLRP3 inflammasome and inflammatory cytokines were explored. Finally, the function of LSD1 exerted on activation of PI3K/Akt/mTOR signal pathway was detected using western blotting assay. KEY FINDINGS: The expression of LSD1 was significantly elevated in Ox-LDL-treated RAW264.7 cells. Inhibition of LSD1 promoted autophagy, inhibited inflammation and activated NLRP3 inflammasome. SESN2 was elevated by LSD1 inhibition, and thus activate the PI3K/Akt/mTOR signal pathway. What' more, Knockdown of SESN2 or deactivate the PI3K/Akt/mTOR signal pathway partly reversed the effect of LSD1 inhibition on autophagy. SIGNIFICANCE: Our present study drew the finding that the knockdown of LSD1 meliorated Ox-LDL-stimulated NLRP3 activation and inflammation through promoting autophagy via SESN2-mediated PI3K/Akt/mTOR pathway.