Sacubitril Valsartan Enhances Cardiac Function and Alleviates Myocardial Infarction in Rats through a SUV39H1/SPP1 Axis.

Sacubitril valsartan (lcz696) has been demonstrated as a substitute for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the treatment of heart failure. This research is aimed at examining the effects of lcz696 and its target molecules on myocardial infarction (MI). A rat model of MI was induced by left anterior descending artery ligation and treated with lcz696. Lcz696 treatment significantly reduced cardiac injury and heart failure, restored the left ventricular fractional shortening and ejection fraction, and reduced oxidative stress and inflammatory responses in rat myocardium. By analyzing the heart failure-related GSE47495 dataset and performing gene ontology (GO) functional enrichment analysis, we obtained histone lysine methyltransferase SUV39H1 and secreted phosphoprotein 1 (SPP1) as two molecules implicated in the oxidative stress and inflammation processes. An elevation of SUV39H1 whereas a decline of SPP1 were detected in cardiac tissues after lcz696 treatment. Enrichments of SUV39H1 and H3K9me3 at the SPP1 promoter were identified by chromatin immunoprecipitation assay. SUV39H1 catalyzed H3K9me3 modification to suppress the expression of SPP1. Preconditioning of SUV39H1 silencing blocked the protective roles of lcz696, but SPP1 silencing alleviated the myocardial injury. In conclusion, this study demonstrates that lcz696 enhances cardiac function and alleviates MI in rats through a SUV39H1/SPP1 axis.

Prediction of marker genes associated with hypertension by bioinformatics analyses.

This study aimed to explore the underlying marker genes associated with hypertension by bioinformatics analyses. A gene expression profile (GSE54015) was downloaded. The differentially expressed genes (DEGs) between the normotensive female (NF) and hypertensive female (HF), and between the normotensive male (NM) and hypertensive male (HM) groups were analyzed. Gene Ontology (GO) and pathway enrichment analyses were performed, followed by protein-protein interaction (PPI) network construction. The transcription factors (TFs), and the common DEGs between the HF and HM groups were then analyzed. In total, 411 DEGs were identified between the HF and NF groups, and 418 DEGs were identified between the HM and NM groups. The upregulated DEGs in the HF and HM groups were enriched in 9 GO terms, including oxidation reduction, such as cytochrome P450, family 4, subfamily b, polypeptide 1 (Cyp4b1) and cytochrome P450, family 4, subfamily a, polypeptide 31 Cyp4a31). The downregulated DEGs were mainly enriched in GO terms related to hormone metabolic processes. In the PPI network, cytochrome P450, family 2, subfamily e, polypeptide 1 (Cyp2e1) had the highest degree in all 3 analysis methods in the HF group. Additionally, 4 TFs were indentified from the 2 groups of data, including sterol regulatory element binding transcription factor 1 (Srebf1), estrogen receptor 1 (Esr1), retinoid X receptor gamma (Rxrg) and peroxisome proliferator-activated receptor gamma (Pparg). The intersection genes were mainly enriched in GO terms related to the extracellular region. On the whole, our data indicate that the DEGs, Cyp4b1, Cyp4a31 and Loxl2, and the TFs, Esr1, Pparg and Rxrg, are associated with the progression of hypertension, and may thus serve as potential therapeutic targets in this disease.

Efficacy and safety of ticagrelor versus clopidogrel with different dosage in high-risk patients with acute coronary syndrome.

BACKGROUND: Dual antiplatelet therapy is recommended as a standard antiplatelet strategy in acute coronary syndrome. For those with reduced pharmacologic response to clopidogrel, strengthening antiplatelet therapy (clopidogrel 150mg daily) may reduce adverse clinical events. Ticagrelor is a direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and offset than clopidogrel. METHODS: In this retrospective study, we compared ticagrelor (180mg loading dose 90mg twice daily thereafter), clopidogrel (300mg loading dose, 75mg or 150mg daily thereafter) for the prevention of cardiovascular events in 273 high-risk patients admitted to coronary care unit with acute coronary syndrome. RESULTS: The rate of IST in hospital was significantly reduced in patients of ticagrelor group comparing with those receiving clopidogrel 75mg (0.69% vs 8.2%, p=0.009). Moreover, the TVR rate was less in the ticagrelor group than clopidogrel 75mg group (2.7% vs 13.1%, p=0.007) 6months follow-up. The incidence of MACCE has no difference between the two clopidogrel groups. Kaplan-Meier analysis of MACCE-free indicated that there was no difference between the three groups. Ticagrelor significantly increased the rate of minor bleeding compared with clopidogrel 75mg daily during hospital (45.5% vs 26.2%,p=0.012) and 6-month follow-up (66.9% vs 45.9%,p=0.004).Bleeding-free prognosis was significantly better in the clopidogrel 75mg daily group. CONCLUSIONS: In patients with acute coronary syndrome undergoing PCI, the rate of in-stent thrombosis and TVR were significantly reduced treated with ticagrelor compared with clopidogrel 75mg daily, without an increase of overall major bleeding, but with an increase of minor bleeding.

The efficacy of N-acetylcysteine plus sodium bicarbonate in the prevention of contrast-induced nephropathy after cardiac catheterization and percutaneous coronary intervention: A meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of combining use of N-acetylcysteine (NAC) and sodium bicarbonate (SOB) in the prevention of contrast-induced nephropathy (CIN) after cardiac catheterization and percutaneous coronary intervention (PCI) is unclear. METHODS: All relevant studies that compared the effect of combining the use of NAC and SOB with individual use on CIN in patients undergoing cardiac catheterization and PCI were identified by searching the databases including Pubmed, Embase, Cochrane Library, and Web of Science without time and language limitation. Only randomized controlled trials (RCTs) with full-text published were considered. RESULTS: Sixteen RCTs involving 4432 cases were included into this meta-analysis. The results showed there were no additional benefit in reduction of CIN in COM group (COM versus NAC: RR 0.85, 95% CI 0.70-1.03, P=0.103; COM versus SOB: RR 0.91, 95% CI 0.71-1.16, P=0.449), even in patients with diabetes mellitus (COM versus NAC: RR 1.11, 95% CI 0.71-1.75, P=0.646; COM versus SOB: RR 1.06, 95% CI 0.45-2.47, P=0.893), undergoing PCI procedure (COM versus NAC: RR0.76, 95% CI 0.39-1.47, P=0.411; COM versus SOB: RR0.96, 95% CI 0.65-1.40, P=0.814), or with baseline renal dysfunction (COM versus NAC: RR 0.89, 95% CI 0.70-1.14, P=0.366; COM versus SOB: RR 0.95, 95% CI 0.67-1.36, P=0.788). CONCLUSIONS: The present study demonstrated combining use of NAC and SOB was not significantly superior to individual use method in the prevention of CIN after cardiac catheterization and PCI.

Bioinformatics Analyses of Differentially Expressed Genes Associated with Acute Myocardial Infarction.

BACKGROUND: We aimed to predict key genes associated with acute myocardial infarction (AMI) by bioinformatics analysis. METHODS: The microarray data of GSE48060, including peripheral blood samples from 31 first-time AMI patients within 48-h post-MI and 21 normal controls, were obtained from Gene Expression Omnibus database. The differentially expressed genes (DEGs) in AMI samples compared with normal controls were identified. Functional enrichment analysis was then performed, followed by analysis of protein-protein interaction (PPI) network and transcription regulatory network (TRN). RESULTS: A total of 385 up- and 504 down-regulated DEGs were identified. They were mainly enriched in five pathways, such as natural killer (NK) cell-mediated cytotoxicity and chemokine signaling pathway. Chemokine (C-C motif) ligand 5 (CCL5) was hub protein in PPI network. Besides, four transcription factors (TFs), including nuclear receptor subfamily 2, group C, member 2 (NR2C2), MYC-associated factor X (MAX), general transcription factor IIIC, polypeptide 2, beta 110 kDa (GTF3C2), and B-cell CLL/lymphoma 3 (BCL3), were identified. Notably, nuclear receptor coactivator 7 (NCOA7) interacted with GTF3C2 and MAX directly. CONCLUSIONS: CCL5, BCL3, NR2C2, MAX, GTF3C2, and NCOA7 might play important roles in AMI development.

Relationship between low-density lipoprotein levels on admission and 1-year outcome in patients with acute ST-segment-elevation myocardial infarction.

This study assessed the relationship between low-density lipoprotein cholesterol (LDL-C) levels on admission and the incidence of major adverse cardiovascular events (MACE) in patients with acute ST-segment-elevation myocardial infarction (ASTEMI). Patients with ASTEMI who had a lipid profile tested within 24 hours of symptom onset were enrolled. They were stratified into high and low LDL-C groups according to whether their LDL-C was above (n = 501) or below (n = 575) the median level, respectively. The incidence of MACE, cardiovascular death, non-fatal MI, revascularization, and stroke was compared between the groups at 1 month, 6 months, and 1 year. Survival analysis and Cox proportional hazard analysis were performed. In-hospital use of beta blockers was better in the high than in the low LDL-C group (76.6% vs. 69.7%, p = 0.01). Statin use was significantly higher in the high than in the low LDL-C group during follow-up (86.8% vs. 80.0%, p = 0.003 at1 month; 71.6% vs. 62.4%, p = 0.002 at 6 months; 67.8% vs. 61.2%, p = 0.03 at 1 year). The incidence of MACE on follow-up at 1 month was higher in the low than in the high LDL-C group (12.0% vs. 8.1%, p = 0.04). At 1 year, survival was not significantly different between the groups. Cox proportional hazards analysis indicated that the incidence of MACE was significantly associated with hypertension, current smoking, high-density lipoprotein cholesterol (HDL-C), in-hospital use of beta blockers, and statin use on follow-up (p < 0.01). LDL-C levels on admission in patients with ASTEMI had no significant effect on the 6-month and 1-year incidence of MACE, but the incidence of MACE was significantly higher in the low LDL-C group at 1 month. It would be relevant to further investigate the HDL-C level on admission, in-hospital use of beta blockers, and statin use during follow-up in relation to MACE.

Effect of high-dose rosuvastatin loading before percutaneous coronary intervention in female patients with non-ST-segment elevation acute coronary syndrome.

BACKGROUND: Early loading statin therapy before percutaneous coronary intervention (PCI) is associated with reduced mortality and periprocedural myocardial injury. The aim of this study was to study the effect of rosuvastatin loading therapy before PCI in female patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). METHODS: Consecutive 117 female patients with NSTEACS were randomly assigned to either the group of rosuvastatin loading before PCI (20 mg 12 hours before angioplasty procedure, with a further 10 mg dose 2 hours before procedure, the loading dose group, n = 59) or the no rosuvastatin treatment group before PCI (control group, n = 58). Periprocedural myocardial injury, periprocedural changes of high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a in serum and the incidence of major adverse cardiac events (MACE) 3 months and 6 months later were assessed. RESULTS: The incidence of periprocedural myocardial injury was higher in control group than loading dose group (CKMB: 10.17% vs. 25.86%, P = 0.027; Troponin I: 11.86% vs. 29.31%, P = 0.019). MACE occurred in 1.69% of patients in loading dose group and 12.07% of those in control group 3 months after procedure (P = 0.026), 3.39% vs. 17.24% at 6 months (P = 0.014). The levels of hs-CRP, IL-1, IL-6, and TNF-a in serum were not significantly different between the two groups before PCI, but after PCI they were significantly higher in control group. CONCLUSIONS: High-dose rosuvastatin loading before PCI significantly reduced periprocedural myocardial injury and periprocedural inflammation cytokines release and improved 3-month and 6-month clinical outcomes in female patients with NSTEACS who underwent PCI.

Increased poly(ADP-ribosyl)ation in peripheral leukocytes and the reperfused myocardium tissue of rats with ischemia/reperfusion injury: prevention by 3-aminobenzamide treatment.

The overactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is considered a final common effector in ischemia/reperfusion (I/R) injury. The aim of the current study was to examine the precise time course of the activation of PARP in peripheral leukocytes and the reperfused myocardium tissue on myocardial I/R injury from the same rat and to identify the relationship between myocardial infarct size and the degree of PARP activation in circulating leukocytes. Another aim of the study was to test the effect of 3-aminobenzamide (a well-known and widely used PARP inhibitor) on the activation of PARP in the reperfused myocardium and peripheral leukocytes. Poly(ADP-ribose) polymerase activation was measured by Western blotting for its product, poly(ADP-ribose) (PAR). The localization of PARP activation was determined by PAR immunohistochemistry. The results showed that poly(ADP-ribosyl)ation was detected 15 min, peaked 2 to 6 h, and remained markedly detectable 24 h in the reperfused heart after I/R model. Similarly, PAR content of the leukocytes increased in cells isolated just after reperfusion from the same rat. Immunohistochemical studies localized the staining of PAR primarily to the cardiac myocytes and vascular endothelial cells. At 6 h, there was a significant linear correlation between infarct size and PARP activity, whereas at 2 and 24 h, no relationship was found. The PARP inhibitor 3-aminobenzamide (3-AB, 20 mg kg⁻¹ i.v. injection 15 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced infarct size through depressing the activation of the enzyme in myocytes and peripheral leukocytes even when the treatment is initiated at 2 h after reperfusion.

The effect of hypoxia-inducible factor 1-alpha on hypoxia-induced apoptosis in primary neonatal rat ventricular myocytes.

AIM: To study the role of hypoxia-inducible factor 1-alpha (HIF-1alpha) on hypoxia-induced apoptosis in primary neonatal rat ventricular myocytes. METHODS: Primary neonatal rat ventricular myocytes were exposed to hypoxia for 24 hours. HIF-1alpha activity was suppressed by treating the cells with 3-(5'-hydroxymethyl-2'- furyl)-1-benzyl indazole (YC-1). The degree of cell apoptosis was assessed by Hoechst 33258 DNA staining. The levels of HIF-1alpha and the pro-apoptotic proteins Bnip3, Bax and Bad were measured with western blotting. RESULTS: On exposure to hypoxia, there was an increase in the expression levels of HIF-1alpha, and the pro-apoptotic protein Bnip3 was upregulated. Suppression of HIF-1alpha activity by YC-1 treatment was followed by blockade of hypoxia-induced apoptosis and Bnip3 expression; however, the changes in the levels of Bax and Bad expression were unclear. CONCLUSION: Acute hypoxia enhanced primary neonatal rat ventricular myocyte apoptosis through the activation of HIF-1alpha and a mechanism that perhaps involved Bnip3. Targeting HIF-1alpha may be a new strategy for reducing the degree of hypoxia-induced apoptosis in ventricular myocytes.

[Pitavastatin enhances angiogenesis and perfusion in a murine mode of limb ischemia].

OBJECTIVE: We investigated the effects of pitavastatin on angiogenesis and perfusion in C3H/He mice with unilateral hind limb ischemia. METHODS: C3H/He mice treated with saline (n = 15) or pitavastatin (1 mg.kg(-1).d(-1), n = 15) per gavage for 1 week underwent unilateral hind limb ischemia surgery and were treated for another 5 weeks. Hind-limb blood flow was measured by Laser Doppler perfusion imager (LDPI, ischemic/nonischemic limb, %) at baseline, immediately after ischemia and weekly thereafter for 5 weeks. Endpoints included local vessel counts by immunofluorescence, phospho-Akt positive cell counts by immunoenzyme histochemical technique, vascular endothelial growth factors (VEGFs) expression in ischemic limbs by Western blot and serum nitric oxide metabolite (NOx) by chrome dioxide Griess method. RESULTS: Lower extremity perfusion was significantly improved in pitavastatin treated mice vs. controls as measured by LDPI% at 1 week post ischemia and thereafter (P < 0.05). Pitavastatin treatment was associated with significantly increased capillary count [(47 +/- 11) vs. (26 +/- 14)/per high-power field (x 200), P < 0.05] and greater percentage of phospho-Akt positive cells [(6 +/- 1) vs. (2 +/- 0)/per high-power field (x 200), P < 0.05] in ischemic limbs. Serum NOx [(77.3 +/- 21.8) vs. (52.1 +/- 11.2) mol/L, P < 0.05) and VEGF protein expression in ischemic limbs were also significantly increased in pitavastatin group than those in control group. CONCLUSIONS: Pitavastatin enhances angiogenesis and perfusion in CsH/He mice with limb ischemia.

[The pro-angiogenesis effect of Pitavastatin in the Klotho gene-knockout mice].

AIM: To discuss the effect of Pitavastatin on angiogenesis in vivo and its mechanism in Klotho heterozygous deficient mice. METHODS: The heterozygous deficient Klotho mice (kl +/-) and wild mice (kl +/+) from the same litter were used to establish the animal model of hind-limb ischemia and grouped into control and Pitavastatin group, respectively. Hind-limb blood flow was evaluated using Laser Doppler perfusion imager (LDPI) before treatment and after operation of hind-limbs. The capillaries in muscle of limbs were counted by means of CD-31 labeled immuno-fluorescence. The phosphorylation of Akt (Protein kinase B) in cells was measured by direct immunohistochemical technique. The expression of vascular endothelial growth factors (VEGFs) in muscle of limbs was assessed using Western blotting. RESULTS: After treatment of Pitavastatin, the blood flow in ischemic limbs of the Kl +/- and wild mice improved obviously, the ratio of blood flow area in ischemic limb to that in non-ischemic limb increased and the density of capillaries increased in ischemic limbs of the Kl +/- and wild mice. Pitavastatin enhanced the phosphorylation of Akt and the expression of VEGF in ischemic limbs of the Kl +/- and wild mice. CONCLUSION: Pitavastatin has the pro-angiogenesis effect in vivo and the VEGF-p-Akt-NO pathway may be involved in the mechanism of the effect of Pitavastatin.

[The epidemiological survey of prevalence rate of hypertension in the countryside of Zhangwu county, Liaoning province].

OBJECTIVE: To investigate the prevalence state of essential hypertension in the countryside of Zhangwu county, Liaoning province to confirm whether this county is the high prevalence region of essential hypertension. METHODS: Five thousand, two hundred and eight 15-year olds or older were sampled by means of whole population random sampling. Blood pressure was measured and the related risk factors were investigated with the uniform questionnaire. SPSS 10.0 of statistical software was used for data analysis. RESULTS: The standardized prevalence rate of hypertension was 35.0% at this region, 40.0% in male, 32.0% in female. The prevalence rates of hypertension were increased with the increasing of the age in both males and females. There were significant statistically differences in the prevalence rates of hypertension between the different age groups, different countrysides and different villages. The standardized prevalence rate of hypertension were 43.0% the highest and 29.0% lowest respectively in the countryside, with prevalence rates, were 59.4% highest and 26.9% lowest respectively in the village. In all the patients with hypertension, 72.0% having hypertension II, III. CONCLUSION: The countryside of Zhangwu county was a high prevalence region of essential hypertension which was unusual in our country. The reason of this status was still unknown which called for further study.