Ivabradine protects rats against myocardial infarction through reinforcing autophagy via inhibiting PI3K/AKT/mTOR/p70S6K pathway.

Ivabradine (Iva), a heart rate reducing agent that specifically inhibits the pacemaker I(f) ionic current, has been demonstrated to be cardioprotective in many cardiovascular diseases. Autophagy is an evolutionarily conserved metabolic process that regulates cardiac homeostasis. This study is aimed to explore whether autophagy is functionally involved in the cardioprotective effect of Iva in a rat model of myocardial infarction (MI). We observed that Iva treatment (po, 10 mg/kg/day) showed significant recovery on the hemodynamics parameters in MI rats, including left ventricular systolic pressure, left ventricular end diastolic pressure, and maximal ascending/descending rate of left ventricular pressure. Also, Iva treatment dramatically decreased infarct size, inhibited myocardial apoptosis, and reduced the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 in MI rats. Moreover, Iva treatment enhanced autophagy and inhibited PI3K/AKT/mTOR/p70S6K pathway in MI rats. Simultaneously, we observed that autophagy enhancer rapamycin (ip, 10 mg/kg/day) showed similar cardioprotective effects with Iva. Furthermore, we observed that addition of autophagy inhibitor 3-methyladenine (ip, 10 mg/kg/day) counteracted the therapeutic effect of Iva, addressing that Iva attenuated post-MI cardiac injury by enhancing autophagy. In summary, these findings demonstrated that Iva attenuated MI in rats by enhancing autophagy, and PI3K/AKT/mTOR/p70S6K pathway might be involved in the process. Autophagy activation by Iva may be a potential therapeutic strategy for the treatment of MI.

The protective effects of azilsartan against oscillatory shear stress-induced endothelial dysfunction and inflammation are mediated by KLF6.

BACKGROUND AND PURPOSE: Atherosclerosis is a common cardiovascular disease with high morbidity and mortality. It is reported to be related to oscillatory shear stress (OSS)-induced endothelial dysfunction and excessive production of inflammatory factors. Azilsartan, a specific antagonist of the angiotensin II receptor, has been approved for the management of hypertensive subjects with diabetes mellitus type II (DMII). The present study will investigate the effects of azilsartan against OSS-induced endothelial dysfunction and inflammation, as well as the underlying mechanism. MATERIALS AND METHODS: Cell viability was detected using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay were used to determine the expression levels of IL-6, TNF-α, IL-1ß, VCAM-1, and ICAM-1 in human aortic endothelial cells (HAECs). Generation of reactive oxygen species (ROS) was measured using 2'-7'dichlorofluorescin diacetate (DCFH-DA) staining, and the level of reduced glutathione (GSH) was evaluated using a commercial kit. The adhesion of THP-1 monocytes to HAECs was evaluated using calcein-AM staining. The expression level of KLF6 was determined using qRT-PCR and Western blot analysis. RESULTS: According to the result of the MTT assay, 5 and 10 µM azilsartan were considered as the optimized concentrations applied in the present study. The elevated production of IL-6, TNF-α, and IL-1ß, increased levels of ROS, decreased levels of reduced GSH, upregulated VCAM-1, ICAM-1, and E-selectin, and the aggravated adhesion of THP-1 cells to HAECs induced by OSS were all reversed by the introduction of azilsartan. The downregulation of KLF6 induced by OSS was significantly reversed by azilsartan. By knocking down the expression of KLF6, the suppressed adhesion of THP-1 cells to the HAECs, and the downregulation of VCAM-1 and ICAM-1 induced by azilsartan in OSS-stimulated HAECs were greatly reversed. CONCLUSION: The protective effects of azilsartan against OSS-induced endothelial dysfunction and inflammation might be mediated by KLF6.

Improved Dynamic Mode Decomposition and Its Application to Fault Diagnosis of Rolling Bearing.

To solve the intractable problems of optimal rank truncation threshold and dominant modes selection strategy of the standard dynamic mode decomposition (DMD), an improved DMD algorithm is introduced in this paper. Distinct from the conventional methods, a convex optimization framework is introduced by applying a parameterized non-convex penalty function to obtain the optimal rank truncation number. This method is inspirited by the performance that it is more perfectible than other rank truncation methods in inhibiting noise disturbance. A hierarchical and multiresolution application similar to the process of wavelet packet decomposition in modes selection is presented so as to improve the algorithm's performance. With the modes selection strategy, the frequency spectrum of the reconstruction signal is more readable and interference-free. The improved DMD algorithm successfully extracts the fault characteristics of rolling bearing fault signals when it is utilized for mechanical signal feature extraction. Results demonstrated that the proposed method has good application prospects in denoising and fault feature extraction for mechanical signals.

MicroRNA-9 inhibits high glucose-induced proliferation, differentiation and collagen accumulation of cardiac fibroblasts by down-regulation of TGFBR2.

To investigate the effects of miR-9 on high glucose (HG)-induced cardiac fibrosis in human cardiac fibroblasts (HCFs), and to establish the mechanism underlying these effects. HCFs were transfected with miR-9 inhibitor or mimic, and then treated with normal or HG. Cell viability and proliferation were detected by using the Cell Counting Kit-8 (CCK-8) assay and Brdu-ELISA assay. Cell differentiation and collagen accumulation of HCFs were detected by qRT-PCR and Western blot assays respectively. The mRNA and protein expressions of transforming growth factor-ß receptor type II (TGFBR2) were determined by qRT-PCR and Western blotting. Up-regulation of miR-9 dramatically improved HG-induced increases in cell proliferation, differentiation and collagen accumulation of HCFs. Moreover, bioinformatics analysis predicted that the TGFBR2 was a potential target gene of miR-9 Luciferase reporter assay demonstrated that miR-9 could directly target TGFBR2. Inhibition of TGFBR2 had the similar effect as miR-9 overexpression. Down-regulation of TGFBR2 in HCFs transfected with miR-9 inhibitor partially reversed the protective effect of miR-9 overexpression on HG-induced cardiac fibrosis in HCFs. Up-regulation of miR-9 ameliorates HG-induced proliferation, differentiation and collagen accumulation of HCFs by down-regulation of TGFBR2. These results provide further evidence for protective effect of miR-9 overexpression on HG-induced cardiac fibrosis.

Effects of rhBNP on myocardial fibrosis after myocardial infarction in rats.

PURPOSE: We aimed to observe the effects and mechanism of rhBNP treatment on myocardial fibrosis (MF) after myocardial infarction (MI). METHODS: SPF rats were separated into 3 groups: normal, MI (ligation of left coronary artery), and MI + rhBNP (recombinant human brain natriuretic peptide). Rats in MI + rhBNP group were given 30 µg/kg for 2 days before modeling and for 4 weeks after modeling. mRNA levels and the expression levels of TGF-ß1 (transforming growth factor) and CTGF (connective tissue growth factor) in 3 groups were analyzed using the RT-qPCR and western blotting analysis, respectively. Furthermore, myocardial volume fraction (CVF) was analyzed using the Sirius Red F3B (SR) while the percentage of type I and III collagen in 3 groups were analyzed using the immunohistochemical staining. RESULTS: Compared with the normal group, the levels of TGF-ß1, CTGF, CVF, type I and III collagen were higher in MI group. However, mRNA levels of TGF-ß1 and CTGF were significantly decreased in MI + rhBNP compared to MI groups. Expression of TGF-ß1 was lower while that of CTGF was higher in MI + rhBNP group than that in MI group. Besides, CVF, and type I and III collagen were lower in MI + rhBNP group compared with MI group. CONCLUSION: rhBNP could significantly decrease the TGF-ß1 and CTGF levels in post-MI so as to inhibit the type I and III collagen deposition in MF of post-MI. rhBNP will be benefit for the improvement of MF.

Glatiramer acetate (GA) prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway.

Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of endothelial dysfunction. Exposure to TNF-α induces the expression of a number of proinflammatory chemokines, such as monocyte chemotactic protein-1 (MCP-1), and adhesion molecules, including vascular adhesion molecule-1 (VCAM-1) and E-selectin, which mediate the interaction of invading monocytes with vascular endothelial cells. Glatiramer acetate (GA) is a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). The effects of GA in vascular disease have not shown before. In this study, we found that GA significantly inhibited TNF-α-induced binding of monocytes to endothelial cells. Mechanistically, we found that GA ameliorated the upregulation of MCP-1, VCAM-1, and E-selectin induced by TNF-α. Notably, this process is mediated by inhibiting the nuclear translocation and activation of NF-κB. Our results also indicate that GA pretreatment attenuates the up-regulation of COX-2 and iNOS. These data suggest that GA might have a potential benefit in therapeutic endothelial dysfunction related diseases.

Prediction of long-term outcome after acute myocardial infarction using circulating miR-145.

BACKGROUND: Recent reports have shown that miR-145 concentration correlates with infarct size. In this paper, we attempt to predict heart failure and cardiovascular death after acute myocardial infarction using circulating miR-145 concentration. METHODS: We assessed 246 patients with first ST-segment-elevation myocardial infarction who underwent successful percutaneous coronary intervention. We measured circulating miR-145, N-terminal fragment of the precursor B-type natriuretic peptide, myocardial-band creatine kinase, and cardiac troponin-I concentrations on day 5 after primary percutaneous coronary intervention and assessed their correlations with long-term clinical outcome. RESULTS: During the one-year follow-up period, 72 patients experienced primary composite cardiac events (cardiac death or hospitalization for worsening heart failure). Multivariable Cox proportional hazards analysis indicated that circulating miR-145 (hazard ratio 7.174, 95% confidence interval 4.208-12.229); p < 0.0001) was a significant independent predictor of cardiac events after adjustment for multiple confounders. CONCLUSION: Circulating miR-145 may be a novel biomarker for predicting long-term outcome after acute myocardial infarction.

Coronary flow reserve in the remote myocardium predicts left ventricular remodeling following acute myocardial infarction.

PURPOSE: Coronary flow reserve (CFR) in the non-infarcted myocardium is often impaired following acute myocardial infarction (AMI). However, the clinical significance of CFR in the non-infarcted myocardium is not fully understood. The objective of the present study was to assess whether a relationship exists between CFR and left ventricular remodeling following AMI. MATERIALS AND METHODS: We enrolled 18 consecutive patients undergoing coronary intervention. Heart function was analyzed using real-time myocardial contrast echocardiography at one week and six months after coronary angioplasty. Ten subjects were enrolled as the control group and were examined using the same method at the same time to assess CFR. Cardiac troponin I (cTnI) levels were routinely analyzed to estimate peak concentration. RESULTS: CFR was 1.55±0.11 in the infarcted zone and 2.05±0.31 in the remote zone (p<0.01) at one week following AMI. According to CFR values in the remote zone, all patients were divided into two groups: Group I (CFR <2.05) and Group II (CFR >2.05). The levels of cTnI were higher in Group I compared to Group II on admission (36.40 vs. 21.38, p<0.05). Furthermore, left ventricular end diastolic volume was higher in Group I compared to Group II at six months following coronary angioplasty. CONCLUSION: Microvascular dysfunction is commonly observed in the remote myocardium. The CFR value accurately predicts adverse ventricular remodeling following AMI.

Bioinformatics analysis of time series gene expression in left ventricle (LV) with acute myocardial infarction (AMI).

This study is to investigate the key genes and their possible function in acute myocardial infarction (AMI). The data of GSE4648 downloaded from the Gene Expression Omnibus (GEO) database include 6 time points (15 min, 60 min, 4h, 12h, 24h and 48 h) of 12 left ventricle (LV) samples, 12 surviving LV free wall (FW) samples, 12 inter-ventricular septum (IVS) samples after AMI operation and corresponding sham-operated samples. The data of each sample were analyzed with Affy and Bioconductor packages, and differentially expressed genes (DEGs) were screened out using BETR package with false discovery rate (FDR)<0.01. Then, functional enrichment analysis for DEGs was conducted with Database for Annotation, Visualization and Integrated Discovery (DAVID). Totally 194 DEGs were identified in LV, and only the gene tubulin beta 2a (Tubb2a) and natriuretic peptide B (Nppb) were respectively up-regulated in surviving FW tissue and IVS tissue. The biological process response to wounding and inflammatory response were significantly enriched, as well as leukocyte transendothelial migration pathway. Besides, the expression pattern analysis showed the DEGs mostly up-regulated at 4h after AMI, and these genes were mainly associated with immunity. Additionally, in transcriptional regulatory network, early growth response 1 (Egr1), activating transcription factor 3 (Atf3), Atf4, Myc and Fos were considered as the key transcription factors related to immune response. The key transcription factors and potential target genes might provide new information for the development of AMI, and leukocyte transendothelial migration pathway might play a vital role in AMI.

Effect of continuous positive airway pressure on blood pressure in hypertensive patients with coronary artery bypass grafting and obstructive sleep apnea.

BACKGROUND: Previous studies have documented that obstructive sleep apnea (OSA) increases the incidence of hypertension, respiratory failure and unexpected post-operative deaths during night in coronary artery bypass grafting (CABG) patients. We hypothesized that continuous positive airway pressure (CPAP) reduces blood pressure in these patients. METHODS: We conducted a prospective, controlled study in 51 patients. The subjects received CPAP treatment were defined as CPAP group, whereas those refused to use CPAP were served as controls. Blood pressure was measured by 24 h ambulatory blood pressure at baseline and at six months. RESULTS: Fifty-one patients completed the study. CPAP group and controls had similar characteristics. Compared with the control group, the 24-h SBP and 24-h DBP in the CPAP group had a tendency towards lower levels, but the differences were not statistically significant. But the change of SBP in CPAP treatment was significantly higher than controls (CPAP: 10.0 ± 13.5 mm Hg vs. CONTROL: 2.9 ± 10.5 mm Hg, P = 0.040). The rate of hypertension control was improved in the CPAP treatment, but had no statistical difference compared to the controls (CPAP, 76.0% vs. CONTROL, 61.5%; P = 0.260). Compared with controls, the proportion of non-dipping hypertension had a markedly improvement in the CPAP group (CONTROL, 46.2% vs. CPAP, 16.0%; P = 0.034). CONCLUSIONS: CPAP therapy decreased SBP and improved the status of non-dipping hypertension and alleviated daytime somnolence in hypertensive patients with CABG and OSA on standardized antihypertensive treatment. But DBP and hypertension control did not significantly change compared with the control group.

The level of serum bilirubin associated with coronary lesion types in patients with coronary artery disease.

BACKGROUND: Serum bilirubin has been proven to be associated with coronary artery disease (CAD). However, how serum bilirubin is related to the complexity of coronary artery lesions is still unknown. METHODS AND RESULTS: One thousand two hundred and sixty patients (men 775, 61.5%, mean age, 59.3  ±â€Š 8.2 years) diagnosed with unstable angina were enrolled in the study. Patients were categorized into three major groups and group III was further divided into four subgroups according to the guidelines of AHA/ACC 1993 described in the Methods section. The total serum bilirubin levels showed significant differences among the three major groups (group I vs. group II, 14.8 ± 5.8 vs. 13.7 ± 4.7 µmol/l, P=0.017; group I vs. group III, 14.8 ± 5.8 vs. 12.6 ±  4.4 µmol/l, P<0.001; group II vs. group III, 13.7 ± 4.7 vs. 12.6 ± 4.4 µmol/l, P=0.009). The difference was further seen among the subgroups. Logistic regression analysis demonstrated that age, male sex, histories of hypertension and diabetes, and total serum bilirubin were independent risk factors for CAD. However, in the subgroups, only age, male sex, history of hypertension and total serum bilirubin were associated with CAD. Total serum bilirubin showed the strongest relationship (odds ratio=0.95, 95% confidence interval 0.91-0.98, P=0.001). CONCLUSION: Total serum bilirubin level is an independent risk factor for CAD. It has a strong relationship with coronary artery lesion types.