MicroRNA-323a-3p Promotes Pressure Overload-Induced Cardiac Fibrosis by Targeting TIMP3.

BACKGROUND/AIMS: Cardiac fibrosis is a major cause of diverse cardiovascular diseases. MicroRNAs have recently been proven a novel class of regulators of cardiac fibrosis. In this study, we sought to investigate the role of miR-323a-3p and its mechanisms in regulating cardiac fibrosis. METHODS: The transverse aortic constriction (TAC) mice model was induced and neonatal cardiac fibroblasts (CFs) were cultured. MTT (3- [4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay was used to detect the cell viability. Echocardiography was used to evaluate cardiac function. Masson's Trichrome stain was used to evaluate the development of fibrosis. Luciferase activity assay was performed to confirm the miRNA's binding site. Real-time PCR and Western blot were used to evaluate the level of mRNA and protein. RESULTS: MiR-323a-3p was found up-regulated in myocardial tissues subjected to TAC and in CFs cultured with Angiotensin Ⅱ (Ang Ⅱ). Overexpression of miR-323a-3p significantly increased the mRNA levels of collagen Ⅰ, collagen Ⅲ, MMP2 and MMP9, while inhibition of miR-323a-3p prevented the proliferation, collagen production and the protein level of transforming growth factor (TGF-ß) in rat neonatal CFs. Strikingly, injection of antagomiR-323a-3p elevated cardiac function and inhibited the expression of TGF-ß in the TAC mice. TIMP3 was a direct target of miR-323a-3p, as the overexpression of miR-323a-3p decreased the protein and mRNA levels of TIMP3. In the CFs with pre-treatment of Ang Ⅱ, siRNA-TIMP abolished the effects of AMO-323a-3p on the inhibition of the proliferation of CFs, the down-regulation of collagen Ⅰ and collagen Ⅲ, and the expression of TGF-ß. CONCLUSION: Our findings provide evidence that miR-323a-3p promotes cardiac fibrosis via miR-323a-3p-TIMP3-TGF-ß pathway. miR-323a-3p may be a new marker for cardiac fibrosis progression and that inhibition of miR-323a-3p may be a promising therapeutic target for the treatment of cardiac fibrosis.

Niacin Suppresses Progression of Atherosclerosis by Inhibiting Vascular Inflammation and Apoptosis of Vascular Smooth Muscle Cells.

BACKGROUND Niacin is a broad-spectrum lipid-regulating drug used for the clinical therapy of atherosclerosis; however, the mechanisms by which niacin ameliorates atherosclerosis are not clear. MATERIAL AND METHODS The effect of niacin on atherosclerosis was assessed by detection of atherosclerotic lesion area. Adhesion molecules in arterial endothelial cells were determined by using qRT-PCR and Western blot analysis. The levels of serum inflammatory cytokines in ApoE-/- mice were detected by using ELISA. We detected the expression levels of phosphorylated nuclear factors-kB (NF-κB) p65 in aortic endothelial cells of mice using Western blot analysis. Furthermore, we investigated the anti-inflammation effect and endothelium-protecting function of niacin and their regulatory mechanisms in vitro. RESULTS Niacin inhibited the progress of atherosclerosis and decreased the levels of serum inflammatory cytokines and adhesion molecules in ApoE-/- mice. Niacin suppressed the activity of NF-κB and apoptosis of vascular smooth muscle cells (VSMCs). Furthermore, niacin induced phosphorylated focal adhesion kinase (FAK) and FAK inhibitor PF-573228 reduced the level of Bcl-2 and elevated the level of cleaved caspase-3 in VSMCs. CONCLUSIONS Niacin inhibits vascular inflammation and apoptosis of VSMCs via inhibiting the NF-κB signaling and the FAK signaling pathway, respectively, thus protecting ApoE-/- mice against atherosclerosis.

Preventive use of intra-aortic balloon pump in patients undergoing high-risk coronary artery bypass grafting: a retrospective study.

BACKGROUND: Coronary artery bypass grafting (CABG) is an important therapeutic measure for CHD patients. The patients who score more than 12 EuroSCORE points cannot achieve good results because of their low cardiac output and delicate left ventricular function. Therefore, use of an intra-aortic balloon pump (IABP) is essential for coronary surgical patients in the peri-operative period. At present, there is no unified standard about when to insert an IABP. This study aimed to compare the short-term clinical outcomes of the IABP inserted in the preoperative condition with its use in the emergency condition for extremely high-risk patients. MATERIAL AND METHODS: IABP support time, respirator support time, and ICU stay time were significantly shorter (all p<0.05) in the preoperative IABP group compared to the emergency IABP group, and the rates of low cardiac output syndrome (LCOS), acute myocardial infarction, and acute kidney injury in the preoperative group were also significantly lower in the preoperative IABP group (all p<0.05). There were no significant differences in IABP-related complications and the mortality (p=0.106) between two groups. RESULTS: Compared to the emergency IABP group, the IABP support time, respirator support time and ICU stay time were significantly lower in the preoperative IABP group (all p<0.05), and the rates of LCOS, acute myocardial infarction, and acute kidney injury in the preoperative group were also significantly lower (all p<0.05). There were no significant differences in IABP-related complications and the mortality (p=0.106) between the 2 groups. CONCLUSIONS: For high-risk patients with CABG, preoperative IABP insertion is a safe and effective measure.

[Evaluation of MC3 valve ring for management of functional tricuspid regurgitation].

OBJECTIVE: To evaluate the clinical efficacy of tricuspid valve (TV) annuloplasty with MC3 valve ring for management of functional tricuspid regurgitation (FTR). METHODS: A total of 85 patients who accepted TV annuloplasty with MC3 valve ring for management of FTR were retrospectively analyzed, of which included moderate tricuspid regurgitation (TR) (45 cases) and severe TR (40 cases). The ratio of regurgitant area to RA area, right atrium and ventricular transverse diameter, annulus diameter were measured by echocardiography at three different stages: before, early stage and 1 year after operation. RESULTS: At early stage after operation, there were 81 cases of mild TR, 4 cases of moderate TR. At 1 year after operation, there were 82 cases of mild TR , 3 cases of moderate TR. Compared with the results of pre-operation, the ratio of regurgitant area to RA area, right atrium transverse diameter, annulus diamete and right ventricular transverse diameter at early stage and 1 year after operation were significantly reduced ((14.9±4.6)% and (13.1±4.3)% vs (37.7±8.2)%, (37.2±4.9) and (29.6±5.6) vs (42.5±6.1) mm , (27.3±1.0) and (27.2±1.0) vs (32.2±2.4) mm, (35.5±3.7) and (28.1±4.0) vs (36.9±3.4) mm, all P<0.05).The ratio of regurgitant area to RA area, right atrium and ventricular transverse diameter at early stage after operation were significantly reduced than at 1 year after operation (all P<0.05), but there was no significant difference in the annulus diameter between early stage and 1 year after operation (P>0.05). No complications occurred during follow-up. CONCLUSION: TV annuloplasty with MC3 valve ring is effective for the management of FTR.

CFD-DEM method is used to study the multi-phase coupling slag discharge flow field of gas-lift reverse circulation in drilling shaft sinking.

To elucidate the distribution law of the multiphase coupling slag discharge flow field in gas-lift reverse circulation during drilling shaft sinking, a numerical analysis model of gas-liquid-solid multiphase coupling slag discharge was established by CFD-DEM (Coupling of computational fluid dynamics and discrete element method) method, taking the drilling of North Wind well in Taohutu Coal Mine as an example. This model presented the distribution of the multiphase flow field in the slag discharge pipe and at the bottom hole, and was validated through experimentation and theoretical analysis. Finally, the impact of factors, including bit rotation speed, gas injection rate, air duct submergence ratio, and mud viscosity on the slag discharge flow field was clarified. The results indicated that the migration of rock slag at the bottom of the well was characterized by "slip, convergence, suspension, adsorption, and lifting". The slag flow in the discharge pipe exhibited the states of "high density, low flow rate" and "low density, high flow rate", respectively. The multiphase fluid flow patterns in the well bottom and slag discharge pipe were horizontal and axial flows, respectively. The model test of the gas lift reversed circulation slag discharge and the theoretical model of the bottom hole fluid velocity distribution confirmed the accuracy of the multiphase coupling slag discharge flow field distribution model. The rotation speed of the drill bit had the most significant impact on the bottom hole flow field. Increasing the rotation speed of the drill bit can significantly enhance the tangential velocity of the bottom hole fluid, increase the pressure difference between the bottom hole and annular mud column, and improve the adsorption capacity of the slag suction port. These findings can provide valuable insights for gas lift reverse circulation well washing in western drilling shaft sinking.

Complement factor D derived from epicardial adipose tissue participates in cardiomyocyte apoptosis after myocardial infarction by mediating PARP-1 activity.

BACKGROUND: Acute myocardial infarction (MI) is considered to be the main cause of congestive heart failure. The aim of this study was to provide an in-depth analysis of athophysiological processes and provide key targets for intervention in the occurrence of acute MI. METHODS: A rat model of MI was established by ligation of left anterior descending branch. Heart tissue, epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) were collected. H9c2 cells were used to explore the mechanism of complement factor D (CFD) regulating cardiomyocyte apoptosis. RESULTS: Myocardial apoptosis were observed in MI rat, and more EAT was found in the MI group in vivo. The conditioned medium prepared by EAT (EAT-CM) significantly reduced the activity of H9c2 cells. The content of CFD in EAT was significantly increased, and CFD promoted cardiomyocyte apoptosis in vitro and CFD-IN1 (a selective inhibitor of CFD) could revised this effect. CFD induced poly ADP-ribosepolymerase-1 (PARP-1) overactivation. Furthermore, the addition of pan-caspase inhibitor Z-VAD in the SAT-CM + CFD group couldn't affect H9c2 cell apoptosis. CFD induced cell apoptosis via PARP-1 activation and PARP-1 inhibitor 3-Aminobenzamide could revise this effect. The injection of CFD-IN1 in MI rat model confirmed that inhibition of CFD activity alleviated cardiomyocytes apoptosis. CONCLUSION: Our findings indicate that EAT mediating cardiomyocyte apoptosis after MI through secretion of CFD and activation of PARP-1 activity.

Dynamic Characteristics and Damage Constitutive Model of Mudstone under Impact Loading.

The mechanical response characteristics of mudstone from the ingate roadway of the west ventilation shaft in Yuandian No. 2 coal mine, Huaibei City, Anhui Province, China to dynamic loads were quantified in single- and cyclic-impact compression tests, using the split-Hopkinson pressure bar test device. The dynamic stress-strain relationships and the failure characteristics of mudstone samples under different impact loads were analyzed systematically. Considering the "rate effect" of the mudstone dynamic strength, the dynamic strength criterion of mudstone was proposed, and the dynamic damage constitutive model of mudstone was established, based on the statistical damage theory. In response to single-impact loads, with increasing impact pressure, the mudstone peak stress and strain gradually increased, and the peak stress and average strain rate increased nonlinearly. In response to cyclic-impact loads, with an increasing number of impacts, the mudstone peak stress first increased and then decreased, and the peak strain increased gradually. With increasing impact pressure, the number of impacts to the samples' failure decreased gradually. By parameter identification and comparative analysis of the test results, the proposed dynamic damage constitutive model of mudstone was validated. The model can be used for stability analysis of roadway-surrounding rock under dynamic loads.

Theoretical Research on Diffusion Radius of Cement-Based Materials Considering the Pore Characteristics of Porous Media.

In engineering, loose sandy (gravelly) strata are often filled with cement-based grout to form a mixed material with a certain strength and impermeability, so as to improve the mechanical properties of sandy (gravelly) strata. The tortuosity effect of sandy (gravelly) strata and the time-varying viscosity of slurry play a key role in penetration grouting projects. In order to better understand the influence of the above factors on the penetration and diffusion mechanism of power-law slurry, based on the capillary laminar flow model, this research obtained the seepage motion equation of power-law slurry, the time-varying constitutive equations of tortuosity and power-law fluid viscosity were introduced, and the spherical diffusion equation of penetration grouting considering both the tortuosity of porous media and time-varying slurry viscosity was established, which had already been verified by existing experiments. In addition, the time-varying factors of grouting pressure, the physical parameters of the injected soil layer, and slurry viscosity on penetration grouting diffusion law and the influencing factors were analyzed. The results show that considering the tortuosity of sandy (gravelly) strata and the time-varying of slurry viscosity at the same time, the error is smaller than the existing theoretical error, only 13~19%. The diffusion range of penetration grouting in the sandy (gravelly) strata is controlled by the tortuosity of sandy (gravelly) strata, the water-cement ratio of slurry, and grouting pressure. The tortuosity of sandy (gravelly) strata is inversely proportional to the diffusion radius of the slurry, and the water-cement ratio of slurry and grouting pressure are positively correlated with the diffusion radius. In sandy (gravelly) strata with a smaller particle size, the tortuosity effect of porous media dominates the slurry pressure attenuation. When the particle size is larger, the primary controlling factor of slurry pressure attenuation is the tortuosity effect of porous media in the initial stage and the time-varying viscosity of slurry in the later stage. The research results are of great significance to guide the penetration grouting of sandy (gravelly) strata.

Secretory products from epicardial adipose tissue induce adverse myocardial remodeling after myocardial infarction by promoting reactive oxygen species accumulation.

Adverse myocardial remodeling, manifesting pathologically as myocardial hypertrophy and fibrosis, often follows myocardial infarction (MI) and results in cardiac dysfunction. In this study, an obvious epicardial adipose tissue (EAT) was observed in the rat model of MI and the EAT weights were positively correlated with cardiomyocyte size and myocardial fibrosis areas in the MI 2- and 4-week groups. Then, rat cardiomyocyte cell line H9C2 and primary rat cardiac fibroblasts were cultured in conditioned media generated from EAT of rats in the MI 4-week group (EAT-CM). Functionally, EAT-CM enlarged the cell surface area of H9C2 cells and reinforced cardiac fibroblast activation into myofibroblasts by elevating intracellular reactive oxygen species (ROS) levels. Mechanistically, miR-134-5p was upregulated by EAT-CM in both H9C2 cells and primary rat cardiac fibroblasts. miR-134-5p knockdown promoted histone H3K14 acetylation of manganese superoxide dismutase and catalase by upregulating lysine acetyltransferase 7 expression, thereby decreasing ROS level. An in vivo study showed that miR-134-5p knockdown limited adverse myocardial remodeling in the rat model of MI, manifesting as alleviation of cardiomyocyte hypertrophy and fibrosis. In general, our study clarified a new pathological mechanism involving an EAT/miRNA axis that explains the adverse myocardial remodeling occurring after MI.