Effect Of Tea Polyphenol On Lipid Metabolism Gene And Meta - Analysis Of Blood Pressure

Backgrounds:Coronary heart disease (CHD) remains a major disease as a threat to human health. Increased concentrations of serum total cholesterol and low density lipoprotein cholesterol (LDL-C) have been generally identified as the main risk factors for the occurrence of CHD. A healthy lifestyle such as good eating habits can prevent the occurrence of hyperlipidemia. Green tea is a kind of daily drink without fermentation processing and is consumed widely. Green tea mainly contains a variety of tea polyphenols, in which epigallocatechin gallate (EGCG) is the most important material. Recent epidemiological studies suggest that intake of tea polyphenols has cardiovascular protective effect and is associated with the decrease in the morbidity of cardiovascular disease. The large amount of basic research has proved that tea polyphenols can inhibit the intestinal absorption of cholesterol, upregulate the hepatic LDL receptor, and decrease the apolipoprotein B secretion. However, it is still unclear whether tea polyphenols can directly affect the expression level of cholesterol metabolism-related gene and the potential molecular mechanism. Increasing studies have revealed that long noncoding RNA (IncRNA), defined as a class of non-protein-coding transcripts over 200 nucleotides long, have a variety of important physiological processes, including dosage compensation, genomic imprinting, and embryonic stem cell differentiation. Recently, IncRNAs have been recognized to play an important role in cardiac development and be associated with susceptibility to CHD. Thus, our aim was to investigate the effects of EGCG on lipid metabolism-related gene and IncRNA expression profile by biochip technology and identify important IncRNAs that might play an important role in contributing to the benefits of EGCG on cholesterol metabolism.Methods:HepG2 cell was cultured with EGCG at 25 μM for 24 hours, and the total RNA was extracted and hybridized into the biochip of Human Transcriptome Array 2.0 for mRNA and IncRNA expression profile analysis. Differentially expressedmRNA and lncRNAs were considered significantly when fold change> 1.5 and P<0.05. Differentially expressed lncRNAs were selected for target prediction bybioinformatics technology. RNA interference was used to investigate the role oflncRNAs in cholesterol metabolism.Results: The microarray revealed that a total of 27 lipid metabolism genes weredifferentially expressed in HepG2 cells treated with EGCG, among which 11 involved in cholesterol metabolism. Importantly, EGCG can directly regulate the expressionlevel of 3 key genes involved in cholesterol metabolism: 3-hydroxy-3-methyl glutarylcoenzyme A reductase (HMGCR), LDL receptor and acetyl-CoA acetyltransferase 2 (ACAT2). In addition, a total of 285 lncRNAs were differentially expressed afterEGCG treatment. By bioinformatics technology, we found six matched lncRNA-mRNA pairs for six differentially expressed lncRNAs and five differentiallyexpressed mRNA. In particular, the lncRNA NONHSAT102202 and its potential targets mRNA-HMGCR were identified. RNA interference was used to determine the effect of lncRNA NONHSAT102202 knockdown on HMGCR expression in HepG2 cells treated with or without EGCG. Real-time polymerase chain reaction and Western blot showed that the mRNA and protein level of HMGCR was significantly increased relative to the scrambled RNA group after lncRNA NONHSAT102202 knockdown (P<0.05). Conclusion:Our results indicated that EGCG improved cholesterol metabolism bydirectly affecting cholesterol metabolism-related gene expression in hepatocytes. Inaddition, an amount of lncRNAs was differentially expressed after EGCG treatmentand lncRNAs play an important role in contributing to the benefits of EGCG oncholesterol metabolism.BACKGROUNDHypertension is an important risk factor for cardiovascular disease. Prehypertension, defined as blood pressure (BP) in the range of 120-139/80-89 mmHg, has hit 300 million in China. BP in the prehypertension range is linked with higher rates of incident hypertension and cardiovascular events than normal, previously considered ’optimal’, BP of<120/80 mmHg. The increased risk for incident hypertension and cardiovascular events may be attributed to the induced subclinical target organ damage, including vascular sclerosis, left ventricular hypertrophy and microalbuminuria. There is a current debate over the ideal means of intervening in prehypertension. Tea, including black and green tea, is a popular beverage worldwide and is usually the major source of population polyphenols intake. Tea polyphenols are recognised to have various pleiotropic effects, such as antiinflammatory effects, antioxidant effects, protective effects on endothelial function. Therefore, the aim of this meta-analysis was to investigate the BP-lowering effect of tea intake in patients with prehypertension or hypertension.METHODSA systematic search was conducted in MEDLINE, EMBASE and the Cochrane Controlled Trials Register up to May 2014. Randomised controlled trials that evaluated the acute (<1 week) or chronic (≥1 week) effects of tea on BP were included in the meta-analysis. Search, data extraction and quality assessment were completed independently by two reviewers. Any discrepancies were resolved by consensus. Heterogeneity was measured using the Cochran Q and I2 statistic:for the Q statistic, a p value of<0.1 was considered statistically significant for heterogeneity, and for I2, a value of>50% was considered significant for heterogeneity. The weighted mean difference and 95% confidential interval (CI) were calculated for net changes in systolic and diastolic BP using fixed-effects or random-effects models. Previously defined subgroup analyses were performed to examine the effects of factors (ethnicity, type of tea, polyphenol dose, healthy status, study duration and caffeine intake) on the primary outcomes after chronic intake of tea.RESULTSA total of twenty-five eligible studies with 1,476 subjects were selected. Pooled analysis showed that the acute intake of tea had no effects on systolic and diastolic BP. However, after long-term tea intake, the pooled mean systolic and diastolic BP were significantly lowered by-1.8 (95%CI-2.4,-1.1) and-1.4 (95%CI-2.2,-0.6) mmHg, respectively. When stratified by type of tea, green tea significantly reduced systolic BP by 2.1 (95%CI-2.9,-1.2) mmHg and decreased diastolic BP by 1.7 (95%CI-2.9,-0.5) mmHg, and black tea showed a reduction in systolic BP of 1.4 (95%CI-2.4,-0.4) mmHg and a decrease in diastolic BP of 1.1 (95%CI-1.9,-0.2) mmHg. The subgroup analyses showed that the BP-lowering effect was apparent in subjects who consumed tea more than 12 weeks (systolic BP-2.6 (95%CI-3.5,-1.7) mmHg and diastolic BP-2.2 (95%CI-3.0,-1.3) mmHg, both P<0.001).CONCLUSIONSThe present findings suggest that long-term (≥12 weeks) ingestion of tea could result in a significant reduction in systolic and diastolic BP in patients with prehypertension.BACKGROUNDCoronary heart disease (CHD) is a major health problem worldwide. China currently has nearly 40 million patients with CHD and more than 1 million patients die each year from the complication of this disease. At present, percutaneous coronary intervention (PCI) has become the preferred treatment option for patients with CHD. And dual antiplatelet therapy with aspirin and clopidogrel has become the cornerstone of the medical regimen for prevention of ischemic events in patients with PCI with stent placement. However, about 4%-33% of post-PCI patients show no or low response to clopidogrel, which now called high on-treatment platelet reactivity (HTPR). Epidemiological data have confirmed that HTPR is associated with an increased risk of adverse events after PCI. Therefore, optimization of post-PCI platelet inhibition in patients with HTPR is a controversial issue, with little information available about the use of strategies of more benefit for such patients.Ticagrelor, an oral, direct-acting, reversible, P2Y12 receptor antagonist, was associated with less ischemic event occurrence than clopidogrel in patients with acute coronary syndromes in the Platelet Inhibition and Patient Outcomes (PLATO) trial. This beneficial effect may be related to more uniform and greater platelet inhibition. However, the efficacy of ticagrelor in patients with HTPR is unclear. Therefore, the primary aim of this study was to compare the pharmacodynamic action of ticagrelor load dose (180 mg) with high dose clopidogrel (150 mg) in patients exhibiting HTPR while on clopidogrel. A secondary hypothesis generating endpoint was to explore any possible association of this antiplatelet response to CYP2C19*2 genotypingMETHODSFrom April 2014 to April 2015, all consecutive patients with angiographically documented CHD undergoing PCI with stent implantation at the Division of Special Medical Treatment Center, Fuwai Hospital (Beijing, China) were considered for enrollment in the present study. At the time of PCI, all patients are prescribed with aspirin (100 mg/day) and clopidogrel (75 mg/day) for at least 7 days or 300 mg clopidogrel loading dose in those on clopidogrel 75 mg for<7 days. Thrombelasography (TEG) and VerifyNow P2Y12 platelet function test were used to screen for HTPR. HTPR was defined as P2Y12 reaction units (PRU)≥235 according to the VerifyNow at 24 h following PCI. At last,40 eligible patients with HTPR were enrolled and randomized in a 1:1 ratio, using computerized random-number generation by an independent investigator, to receive 180 mg ticagrelor loading dose (maintenance 90 mg bid/day) or clopidogrel 150 mg/day. Residual platelet reactivity (PRU) was assessed at baseline (time of loading dose), and after 2,8, and 24 h by VerifyNow. Genotyping of the CYP2C19*2 loss-of-function polymorphism was based on previous method. In addition, the major adverse cardiac event (MACE), bleeding events and adverse reactions were recorded at 1-month follow-up.RESULTS1. A total of 465 patients with CHD (stable angina or acute coronary syndrome) undergoing PCI were screen for HTPR. Based on TEG and VerifyNow P2Y12 platelet function test,40 patients were identified for HTPR (PRU≥235) that met the inclusion and exclusion criteria and were randomized to ticagrelor group (n=20) or high dose clopidogrel group (n=20). The mean age for the entire study cohort was 61.5±10.6 years, and 44.4% of patients were diagnosed as ACS. After randomization, clinical, biochemical, and procedural variables were comparable in the two treatment arms.2. In both treatment group, The PRU values decreased significantly from baseline to each time point (2,8 and 24 h); by 2 h, the PRU value decreased markedly from 264.8±27.9 to 102.9±44.1 after ticagrelor loading dose as compared to clopidogrel group (from 274.2±36.1 to 224.1±41.1). In addition, patients in the ticagrelor group achieved significantly lower PRU than patients in the control group at 8 and 24h (P O.001).3. A higher number of patients randomized to ticagrelor changed their response status, becoming optimal responders at each time compared with patients in the control arm (HTPR rate 2 h:0% vs 45%; 8 h:5% vs 40%; 24 h:15% vs 50%, all P<0.05).4. Genotyping revealed carriage of 1 CYP2C19*2 loss-of-function allele in 45% of patients without any homozygote identified in ticagrelor. The PRU was significantly lower for ticagrelor in both noncarriers and carriers, and the HTPR rate was significantly decreased both in noncarriers and carriers.5. During 1 month follow-up, no MACE occurred in either treatment group.6 patients had TIMI minimal bleeding and 1 had TIMI minor bleeding in ticagrelor group; in the control arm,5 patients had TIMI minimal bleeding. Overall, the risk of bleeding showed no difference between the 2 groups. However, Dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 25% of patients vs.0%, P<0.05).CONCLUSION1. In patients with HTPR undergoing PCI,180 mg ticagrelor loading dose achieved more rapid and greater platelet inhibition than high-dose clopidogrel.2. In patients with HTPR after PCI, ticagrelor is effective in reducing the platelet reactivity, irrespective of CYP2C19 genotype eliminating the need for presently recommended genetic testing before dual antiplatelet treatment.3. Ticagrelor compared with clopidogrel was associated with similar total bleeding events after 1-month follow-up. Dyspnea was a common adverse drug reaction following ticagrelor treatment.