Astaxanthin Alleviates the Process of Cardiac Hypertrophy by Targeting the METTL3/Circ_0078450/MiR-338-3p/GATA4 Pathway.

Astaxanthin (ASX) is a natural antioxidant with preventive and therapeutic effects on various human diseases. However, the role of ASX in cardiac hypertrophy and its underlying molecular mechanisms remain unclear.Cardiomyocytes (AC16) were used with angiotensin-II (Ang-II) to mimic the cardiac hypertrophy cell model. The protein levels of hypertrophy genes, GATA4, and methyltransferase-like 3 (METTL3) were determined by western blot analysis. Cell size was assessed using immunofluorescence staining. The expression of circ_0078450, miR-338-3p, and GATA4 were analyzed by quantitative real-time PCR. Also, the interaction between miR-338-3p and circ_0078450 or GATA4 was confirmed by dual-luciferase reporter and RIP assays, and the regulation of METTL3 on circ_0078450 was verified by MeRIP and RIP assays.ASX reduced the hypertrophy gene protein expression and cell size in Ang-II-induced AC16 cells. Circ_0078450 was promoted under Ang-II treatment, and ASX reduced circ_0078450 expression in Ang-II-induced AC16 cells. Circ_0078450 could sponge miR-338-3p to positively regulate GATA4 expression, and GATA4 overexpression overturned the suppressive effect of circ_0078450 knockdown on Ang-II-induced cardiomyocyte hypertrophy. Also, the inhibitory effect of ASX on Ang-II-induced cardiomyocyte hypertrophy could be reversed by circ_0078450 or GATA4 overexpression. In addition, METTL3 mediated the m6A methylation of circ_0078450 to enhance circ_0078450 expression. Moreover, METTL3 knockdown suppressed Ang-II-induced cardiomyocyte hypertrophy by inhibiting circ_0078450 expression.Our data showed that ASX repressed cardiac hypertrophy by regulating the METTL3/circ_0078450/miR-338-3p/GATA4 axis.

Development of a prediction model for exercise tolerance decline in the exercise assessment of patients with acute myocardial infarction undergoing percutaneous coronary intervention revascularization in the acute phase.

Background: Early cardiopulmonary exercise test (CPET) may predict the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). However, data from CPET to assess the exercise capacity of patients with AMI PCI are still scarce. This study aimed to evaluate the safety of the CPET and assess the predictors and clinical influence of exercise capacity measured by CPET in patients with AMI within 1 week after PCI. Methods: A total of 275 patients with AMI who underwent PCI in the acute phase were selected. Reduced exercise capacity was defined as peak oxygen uptake (VO2peak) <16 mL/kg/min. According to VO2peak, patients were divided into a normal exercise tolerance group and a reduced exercise tolerance group. The general clinical conditions were compared between the 2 groups to investigate the safety of CPET and the influencing factors of exercise tolerance. A nomogram model for predicting patients' exercise capacity was further developed. Clinical outcomes were recorded. Results: The median time of CPET in all patients was 5 days after PCI. Among the 275 patients, exercise tolerance decreased in 90 cases (32.72%). Multivariate logic analysis showed that E/e', age, glycosylated hemoglobin, and estimated glomerular filtration rate (eGFR) were independent predictors of early exercise capacity reduction in these patients. Utilizing the correlation coefficients from pre-assessment clinical and CPET indicators within the logistic regression framework, we constructed a nomogram model to forecast the diminishing exercise tolerance in AMI patients. The predictive accuracy of this model, as indicated by a C-index of 0.771 and an area under the receiver operating characteristic (ROC) curve of 0.771 (95% CI: 0.710-0.832), demonstrates its potential as a robust tool in clinical settings. During a follow-up of 24 months, the incidence of clinical outcomes in patients with low exercise tolerance was significantly higher than that in patients with normal exercise tolerance, among which all-cause mortality and reinfarction were statistically different (P=0.009 and P=0.043). Conclusions: The reduced exercise capacity in patients with AMI after initial PCI is related to age, diastolic dysfunction, renal function, and blood glucose control, which may lead to poor clinical prognosis. The nomogram prediction model performed well in predicting the declining exercise tolerance of patients with AMI.

Intravenous insulin preparation administration for myocardial viability 18F-FDG imaging has the potential to reduce radiation exposure dose.

OBJECTIVE: Fluorine-18-fluorodeoxyglucose (18F-FDG) injection activity is positively associated with radiation dose and positron emission tomography (PET) image count. Measurement error is greater with smaller counts; therefore, precise analysis is needed to avoid high doses of radiation exposure caused by high 18F-FDG injection. We aimed to identify and validate the optimal 18F-FDG injection activity and acquisition time for cardiac viability imaging with intravenous insulin preparation administration based on fixed 18F-FDG activity. MATERIALS AND METHODS: Cardiac PET images from 30 patients with coronary artery disease (CAD) were retrospectively reconstructed into different durations. An optimal product of the maximum standardized uptake value (SUV) of the myocardium, and segmental uptake (SU), and acquisition time (MSAT) was determined through a receiver operating characteristic curve. RESULTS: The optimal acquisition time (OAT) was equal to MSAT divided by mean SUV of the myocardium (MyoSUV) and was validated in another 26 patients with CAD. The optimal MSAT was 848.2s. In the validation group, the OAT was 129±76s (95% confidence interval, 99-160s), approximately one-third of the usual acquisition time. The MyoSUV and SU were equivalent between PET image duration of OAT and 600s (7.71±3.01 vs. 7.56±2.94; 67.1±15.4% vs. 67.7±15.6%). CONCLUSION: Intravenous insulin preparation administration has the potential to decrease the radiation exposure or acquisition time in cardiac viability 18F-FDG imaging to one-third, without losing the accurate measurement of MyoSUV or SU when reaching an OAT.

Uric acid promotes myocardial infarction injury via activating pyrin domain-containing 3 inflammasome and reactive oxygen species/transient receptor potential melastatin 2/Ca2+pathway.

Cardiomyocytes injury has been considered as a key contributor for myocardial infarction (MI). Uric acid (UA) can induce cardiomyocytes injury, which is closely related to NLRP3 activation and inflammatory factor generation. However, the mechanism how UA modulates cardiomyocytes remains elusive. Western blotting and qRT-PCR were applied for measuring protein and mRNA expression, respectively. ROS production and Ca2+ influx were measured by flow cytometry. Patch clamp technique was used for measuring transient receptor potential melastatin 2 (TRPM2) channel. Ligation of left anterior descending for 2 h was performed to induce MI animal model. The rats were treated by different concentration of uric acid. The artery tissues were stained by HE and collected for measurement of NLRP3 and inflammatory factors. Supplementation of UA significantly promoted apoptosis, and augmented the expression of intercellular adhesion molecule-1, chemoattractant protein-1, vascular cell adhesion molecule-1, and NLRP3 inflammasome. Knockdown of NLRP3 reversed the influence of UA on MI by decreasing collagen deposition, fibrotic area, apoptosis. The expression of NLRP3 inflammasome increased markedly after treatment of UA. UA activated ROS/TRPM2/Ca2+ pathway through targeting NLRP3. UA activated NLRP3 inflammasome and augments inflammatory factor production, which in turn exacerbates cardiomyocytes injury. Knockdown of NLRP3 reversed the influence of UA on apoptosis and cell cycle. UA may promote cardiomyocytes injury through activating NLRP3 inflammasome and ROS/TRPM2 channel/Ca2+ pathway.

Silencing of Long Noncoding RNA TUG1 Ameliorates Atherosclerosis-Induced Myocardial Injury by Upregulating microRNA-30b-3p and Downregulating Brd4.

ABSTRACT: Long noncoding RNAs and microRNAs (miRNAs) are emerging biomarkers involved in human diseases, and we focused on the roles of long noncoding RNA taurine upregulated gene 1 (TUG1) and miR-30b-3p in the related mechanisms of atherosclerosis-induced myocardial injury. ApoE-deficient mice were fed with high-fat diet to establish atherosclerotic models and then were subjected to either TUG1 downregulation or miR-30b-3p upregulation treatment. The serum myocardial enzymes, inflammatory biomarkers, pathological changes, intramyocardial macrophage infiltration, and apoptosis of cardiomyocytes in atherosclerotic mice were determined. The expression of TUG1, miR-30b-3p, and bromodomain protein 4 (Brd4) in atherosclerotic models was evaluated. Moreover, the correlations of TUG1, miR-30b-3p, and Brd4 were verified. TUG1 and Brd4 were increased while miR-30b-3p was decreased in atherosclerotic mice. The silenced TUG1 or elevated miR-30b-3p attenuated atherosclerosis-induced myocardial injury mainly by reducing serum myocardial enzyme content and inflammatory response, improving pathological changes, and preventing macrophage infiltration and cardiomyocyte apoptosis in atherosclerotic mice. Mechanistically, TUG1 could competitively bind with miR-30b-3p to prevent the degradation of its target gene Brd4. This study reveals that the silencing of TUG1 ameliorates atherosclerosis-induced myocardial injury by upregulating miR-30b-3p and downregulating Brd4, which may provide novel targets for atherosclerosis treatment.

Elevated standardised uptake value of the free wall of the right ventricular myocardium is correlated with enlarged left ventricular end-diastolic volume among patients with heart failure with reduced ejection fraction: A retrospective study.

This study aimed to investigate the relationship between the standardised uptake value of the free wall of the right ventricular myocardium (SUVrv) and left ventricular end-diastolic volume (LVEDV) among patients with heart failure with reduced ejection fraction (HFrEF) with coronary artery disease (CAD). This retrospective study included 50 patients with CAD and HFrEF scheduled for cardiac viability imaging with electrocardiography-gated fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). The maximal SUVrv was measured. The LVEDV and left ventricular ejection fraction (LVEF) were automatically measured using quantitative gated single-photon emission computed tomography. Plasma brain natriuretic peptide (BNP) levels were obtained from medical records.The LVEF (0.24±0.06) was markedly reduced while the LVEDV (201.5±59.9mL) and BNP level (1348.1±1382.9pg/mL) were remarkably elevated. The SUVrv was 3.7±1.7 and was similar between patients with and without diabetes. The SUVrv was significantly positively correlated with the LVEDV and BNP level (r=0.35, 0.45; P=0.01, ≤0.01, respectively) but was unrelated to the LVEF (r=0.11, P=0.44). Herein, SUVrv was elevated and significantly positively correlated with LVEDV and BNP levels among patients with CAD and HFrEF but was unrelated to LVEF and diabetic status.

CYP2C19 metabolizer phenotypes may affect the efficacy of statins on lowering small dense low-density lipoprotein cholesterol of patients with coronary artery disease.

Background: Dyslipidemia is a major cause of arteriosclerotic cardiovascular disease (ASCVD), and low-density lipoprotein cholesterol (LDL-C) is the profile to be reduced to prevent disease progression. Small dense low-density lipoprotein cholesterol (sdLDL-C) has been proven to be a more effective biomarker than LDL-C for ASCVD primary and secondary prevention. CYP2C19 is an important drug metabolism gene. This study aimed to investigate the relationship between sdLDL-C and coronary artery disease (CAD) risk factors and explore the influence of CYP2C19 metabolizer phenotypes on the sdLDL-C lowering efficacy of statins. Methods: This study recruited 182 patients with CAD and 200 non-CAD controls. Baseline laboratory indices of fasting blood were detected, including blood lipids, glucose, and creatinine. In addition, LDL-C subfractions were separated and quantified. Gene polymorphisms of SLCO1B1 and CYP2C19 were detected in patients with CAD. The LDL-C subfractions levels of patients with CAD were followed up after statin drug treatment. Results: Total cholesterol, LDL-C, LDLC-2, LDLC-3, LDLC-4, LDLC-5, LDLC-6, LDLC-7, and sdLDL-C levels of patients with CAD were significantly higher than those in non-CAD controls. Meanwhile, sdLDL-C (AUC = 0.838) and LDLC-4 (AUC = 0.835) performed outstandingly in distinguishing patients with CAD from controls. Based on CYP2C19 metabolizer phenotypes, 113 patients with CAD were divided into the extensive metabolizer (EM, n = 49), intermediate metabolizer (IM, n = 52), and poor metabolizer (PM, n = 12) groups. The patients with IM and PM metabolizer phenotypes had better sdLDL-C lowering efficacy after taking statin drugs than patients with EM phenotype (P = 0.0268, FDR = 0.0536). The SLCO1B1 genotype had no significant impact on the efficacy of statins (P = 0.1611, FDR = 0.1611). Conclusion: sdLDL-C and LDLC-4 outperformed other blood lipids such as LDL-C for CAD risk screening. CYP2C19 metabolizer phenotypes had the potential to predict the efficacy of statins in lowering sdLDL-C.

Can Clinical and Functional Outcomes Be Improved with an Intelligent "Internet Plus"-Based Full Disease Cycle Remote Ischemic Conditioning Program in Acute ST-elevation Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention? Rationale and Design of the i-RIC Trial.

BACKGROUND: Acute ST-elevation myocardial infarction (STEMI) is associated with a high incidence of complications as well as a considerable hospitalization rate and economic burden. Preliminary evidence suggests that remote ischemic conditioning (RIC) is a promising non-invasive intervention that may effectively and safely reduce myocardial infarct size, subsequent cardiac events and complications, and mortality. However, RIC's cardio-protective effect remains under debate, especially for single timepoint RIC programs. Adequately powered large-scale randomized controlled trials investigating clinical outcomes are thus needed to clarify the role of full disease cycle RIC programs. METHODS: The intelligent "Internet Plus"-based full disease cycle remote ischemic conditioning (i-RIC) trial is a pragmatic, multicenter, randomized controlled, parallel group, clinical trial. The term, intelligent "Internet Plus"-based full disease cycle, refers to smart devices aided automatic and real-time monitoring of remote ischemic pre-, per- or post-conditioning intervention for patients with STEMI undergoing percutaneous coronary intervention (PCI). Based on this perspective, 4700 STEMI patients from five hospitals in China will be randomized to a control and an intervention group. The control group will receive PCI and usual care, including pharmacotherapy, before and after PCI. The intervention group will receive pre-, per-, and post-operative RIC combined with long-term i-RIC over a one-month period in addition. A smartphone application, an automated cuff inflation/deflation device and "Internet Plus"-based administration will be used in the long-term phase. The primary outcome is the combined cardiac death or hospitalization for heart failure rate. Secondary outcomes include clinical and functional outcomes: major adverse cardiac and cerebrovascular events rate, all-cause mortality, myocardial reinfarction rate, readmission rate for heart failure and ischemic stroke rate, unplanned revascularization rate, plasma concentration of myocardial infarction-related key biomarkers, infarct size, cardiac function, cardiopulmonary endurance, health-related quality of life, total hospital length of stay, total medical cost, and compliance with treatment regime. DISCUSSION: The i-RIC trial is designed to test the hypothesis that clinical and functional outcomes can be improved with the i-RIC program in STEMI patients undergoing PCI. The concept of RIC is expected to be enhanced with this intelligent "Internet Plus"-based program focusing on the full disease cycle. If the i-RIC program results in superior improvement in primary and secondary outcomes, it will offer an innovative treatment option for STEMI patients and form the basis of future recommendations. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ): ChiCTR2000031550, 04 April 2020.

Long Non-Coding RNA MEG8 Suppresses Hypoxia-Induced Excessive Proliferation, Migration and Inflammation of Vascular Smooth Muscle Cells by Regulation of the miR-195-5p/RECK Axis.

It has been recognized that rebalancing the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) helps relieve vascular injury. Presently, we aim to investigate whether long non-coding RNA (lncRNA) maternally expressed 8 (MEG8) plays a role in affecting the excessive proliferation and migration of VSMCs following hypoxia stimulation. A percutaneous transluminal angioplasty balloon dilatation catheter was adopted to establish vascular intimal injury, the levels of MEG8 and miR-195-5p in the carotid artery were tested by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Hypoxia was used to stimulate VSMCs, then the cell counting kit-8 (CCK-8) assay, Transnwell assay, and wound healing assay were conducted to evaluate the proliferation, and migration of VSMCs. The protein levels of RECK (reversion inducing cysteine rich protein with kazal motifs), MMP (matrix metalloproteinase) 3/9/13, COX2 (cytochrome c oxidase subunit II), macrophage inflammatory protein (MIP)-1beta, VCAM-1 (vascular cell adhesion molecule 1), ICAM-1 (intercellular adhesion molecule 1), and HIF-1α (hypoxia inducible factor 1 subunit alpha) were determined by western blot or cellular immunofluorescence. As the data showed, MEG8 was down-regulated in the carotid artery after balloon injury in rats and hypoxia-treated VSMCs, and miR-195-5p was overexpressed. Forced MEG8 overexpression or inhibiting miR-195-5p attenuated hypoxia-promoted cell proliferation and migration of VSMCs. In addition, miR-195-5p up-regulation reversed MEG8-mediated effects. Hypoxia hindered the RECK expression while boosted MMP3/9/13 levels, and the effect was markedly reversed with MEG8 up-regulation or miR-195-5p down-regulation. Mechanistically, MEG8 functioned as a competitive endogenous (ceRNA) by sponging miR-195-5p which targeted RECK. Moreover, the HIF-1α inhibitor PX478 prevented hypoxia-induced proliferation, and migration of VSMCs, upregulated MEG8, and restrained miR-195-5p expression. Overall, lncRNA MEG8 participated in hypoxia-induced excessive proliferation, inflammation and migration of VSMCs through the miR-195-5p/RECK axis.

Mechanism of Isosorbide Dinitrate Combined with Exercise Training Rehabilitation to Mobilize Endothelial Progenitor Cells in Patients with Coronary Heart Disease.

it was to explore effect of isosorbide dinitrate combined with exercise training and rehabilitation on endothelial progenitor cells (EPCs) in coronary heart disease. EPCs were isolated and cultured from peripheral blood of coronary heart disease patients, and morphology and surface markers were detected. Then, 116 patients were rolled into treatment group (isosorbide dinitrate + exercise rehabilitation training) and control group (isosorbide dinitrate). Characteristics of EPCs cells after treatment were compared. The mononuclear cells were round and small in size and were not evenly distributed in the culture plate. EPCs cells grew as colonies after 8d-culture, and the surrounding cells grew outward in a germinating manner with colonies as the center, forming multiple cell populations. Positive rates of EPCs surface markers CD133, CD34, and vascular endothelial growth factor receptor (KDR) were 11.25±3.07%, 48.18±9.13%, and 76.36±8.27%, respectively. Proliferation activity of EPCs in the treatment group was dramatically higher versus controls at day three, five, and seven (P<0.05). Adhesion ability of EPCs in treatment group was dramatically higher than controls at day three, five, and seven (P<0.05). Migration ability of EPCs in treatment group was dramatically higher versus control group at day three, five, and seven (P<0.05). In short, isosorbide dinitrate plus exercise rehabilitation greatly enhanced the proliferation activity, adhesion ability, and migration ability of EPCs cells, which also played a beneficial role in the repair of endothelial injury, with notable effects.

Engineered bioactive nanoparticles incorporated biofunctionalized ECM/silk proteins based cardiac patches combined with MSCs for the repair of myocardial infarction: In vitro and in vivo evaluations.

The development of cardiac patches by the combination of bioactive nano- and bio-materials with mesenchymal stem cells signifies an auspicious approach for the treatment of cardiac repair in myocardial infarction. In the present investigation, we study about the cardiac function of morphology improved gold nanoparticles combined with extracellular matrix/silk proteins for the cell proliferation and expansion of cardiomyocytes. The physico-chemical and morphological characteristics demonstrated that spherical and homogeneous Au particles are distributed on the matrix porous surface for providing favorable conductivity and biological influences in cardiac repair. The in vitro cell studies of prepared patches have established enhanced cell compatibility and retention of cardiomyocytes survival. The in vivo determinations imply that Au-ESF group decreases infarct size to 65% from 89% in control group. These developed cardiac patches can be highly suitable in the cardiac regeneration and offer new platform in cardiac tissue engineering.

Epicardial ganglionated plexi ablation increases the inducibility of ventricular tachyarrhythmias in a canine postmyocardial infarction model.

INTRODUCTION: Previous studies have shown that epicardial ganglionated plexi ablation (EGPA) could increase the risk of ventricular arrhythmias induced by acute myocardial ischemia. However, the long-term effect of EGPA in a canine postmyocardial infarction (MI) model is not well established. MATERIALS AND METHODS: Twenty mongrel dogs were randomly divided into two groups: an MI group (n = 10) and an EGPA group (EGPA plus MI, n = 10). EGPA was achieved by ablation of four major ganglion plexi and the ligament of Marshall. The electrocardiograph (ECG) parameters, ventricular effective refractory period (ERP), inducibility of tachyarrhythmias, and ventricular fibrillation threshold (VFT) were measured at baseline and after 8 weeks. Tyrosine hydroxylase (TH) and nerve growth factor (NGF) expression levels in the peri-infarcted zone were also determined by immunohistochemistry in both groups at the end of the study. RESULTS: No significant differences were found in electrophysiological parameters at the baseline between the two groups. At the end of the 8-week follow-up, however, the EGPA group was associated with a longer QT interval, corrected QT (QTc) interval and ventricular ERP, larger dispersion of QT, QTc, and ERP, and higher inducibility of tachyarrhythmia and VFT when compared to the MI group. In addition, the density of TH and NGF in the peri-infarcted zone was also significantly increased in the EGPA group in comparison to the MI group. CONCLUSIONS: After the 8-week follow-up, EGPA increased the ventricular arrhythmia inducibility in the canine post-MI model, likely by increasing ventricular electrophysiological instability and promoting ventricular sympathetic remodeling.

Astragaloside IV inhibits Angiotensin II-stimulated proliferation of rat vascular smooth muscle cells via the regulation of CDK2 activity.

AIMS: Astragaloside IV (AS-IV) is the central active component extracted from Radix astragali, an herbal remedy widely used in traditional Chinese medicine for the treatment of cardiovascular diseases. Aberrant proliferation of vascular smooth muscle cells (VSMCs) is closely involved in the initiation and progression of cardiovascular complications, such as atherosclerosis. Here we investigated whether AS-IV inhibited agonist-induced vascular smooth muscle cells (VSMCs) proliferation and the underlying mechanism. MAIN METHODS: Quiescent cultured A10 cells (adult rat VSMCs) were treated with Angiotensin II (AngII) or AngII plus AS-IV for 48 h. The growth rate of A10 cells was analyzed by CCK8 assay. RT-PCR analysis was carried out to examine the expression of α-smooth muscle actin (α-SMA), an important phenotypic modulation marker. In addition, whether the interference of AS-IV on AngII-mediated growth of VSMCs via regulation of cell cycle was evaluated by flow cytometry. In order to explore the role of cell cycle machinery, we measured kinase activity of CDK2 by Kinase assay and the protein level of Cdc25 by western blot, respectively. KEY FINDINGS: These data suggested that AS-IV exerted beneficial effects on AngII -induced abnormal growth in rat VSMCs through disturbing cell cycle, especially block G1/S transition by attenuating CDK2 activity, which may hinder the process of pathological vascular remodeling during atherosclerosis.

A meta-analytic evaluation of cholesteryl ester transfer protein (CETP) C-629A polymorphism in association with coronary heart disease risk and lipid changes.

Lipid metabolism plays an essential role in the pathogenesis of atherosclerosis, a major cause for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) is an important glycoprotein involved in lipid metabolism by transferring cholesteryl esters to apolipoprotein B-containing lipoproteins in exchange for triglycerides. The objective of this meta-analysis was to evaluate the association of CETP C-629A polymorphism with CHD risk and lipid changes. Four public databases were searched, and data from 17 qualified articles were extracted in duplicate and analyzed by STATA software. Overall association of C-629A with CHD risk was nonsignificant in 5441 patients and 7967 controls. Subgroup analyses by ethnicity revealed significance only in Caucasians, with the odds of CHD being 1.18, 1.43 and 1.41 under allelic, genotypic and dominant models, respectively (P < 0.001). Similarly, the -629C allele increased the corresponding risk of myocardial infarction by 1.23-, 1.28- and 1.29-fold (P < 0.02). The association of C-629A with CHD was significantly strengthened in prospective and large studies. Moreover, carriers of the -629C allele had significant higher levels of circulating CETP (weighted mean difference [WMD]: 0.45 µg/mL; 95% confidence interval [CI]: 0.25 to 0.65; P < 0.001), but lower levels of high-density lipoprotein cholesterol (HDL-C) (WMD: -3.65 mg/dL; 95% CI: -5.59 to -1.70; P < 0.001) relative to the -629AA homozygotes. The probability of publication bias was low. Our meta-analytic findings collectively demonstrate that the -629C allele was significantly associated with an increased risk of CHD in Caucasians, and this association may be mediated by its phenotypic regulation on circulating CETP and HDL-C.

Valsartan attenuates oxidative stress and NF-κB activation and reduces myocardial apoptosis after ischemia and reperfusion.

Myocardial apoptosis is primarily triggered during reperfusion. Various mechanisms are involved, including oxidative stress which activates the translocation of nuclear factor-kappa B (NF-κB) and stimulates the release of tumor necrosis factor-alpha (TNF-α). However, the relative contribution of the renin angiotensin system (RAS) to the development of myocardial apoptosis during reperfusion remains unknown. In the present study, we examined whether inhibition of RAS with Valsartan, an Angiotensin II 1 receptor (AT1) antagonist, could reduce apoptosis during reperfusion. We constructed a rat model of myocardial ischemia reperfusion injury. Rats were pretreated with Valsartan for 2 weeks, and then subjected to 30 min ischemia and 4h reperfusion. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Levels of malondialdehyde (MDA), superoxide dismutase (SOD), TNF-α, and caspase-3 were detected by ELISA. NF-κB, Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase expression was assessed by Western blot analysis. Valsartan inhibited apoptosis (TUNEL staining) in ischemic myocardium (P<0.05), consistent with reduced caspase-3 activity. Valsartan also inhibited of NF-κB translocation to nucleus (P<0.05), and decreased plasma TNF-α levels (P<0.05). Valsartan pretreatment suppressed MDA content and preserved SOD activity, consistent with reduced NADPH oxidase expression (P<0.01). These data provided substantial evidence that RAS was involved in NF-κB activation, mediated by AT1 dependent oxidative stress; thus, RAS might ultimately promote myocardial apoptosis during reperfusion pathogenesis.