Search

Abstract Background Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell dysfunction plays a crucial role in the progression of atherosclerosis (AS). Although miR-125b-5p is known to be involved in cardiovascular and cerebrovascular disorders, its function in ox-LDL-induced endothelial injury is still not well understood. Methods An in vitro AS cell model was established by exposing human umbilical vein endothelial cells (HUVECs) to 100 µg/mL ox-LDL for 24 h. A series of functional assays, including CCK-8 assay, flow cytometry, MDA and SOD kits, capillary-like network formation assay and ELISA assay were performed in vitro. TNFSF4/TLR4/NF-κB pathway-related protein expressions were measured by Western blot. Molecular mechanisms were elucidated through quantitative real-time PCR, western blot analysis, and luciferase reporter assays. Results Our investigation revealed that exposure to ox-LDL led to a downregulation in miR-125b-5p, while upregulating the expression of tumor necrosis factor (ligand) superfamily, member 4 (TNFSF4), TLR4, p-p65 and p-IkBa in HUVECs in a dose-dependent manner. We confirmed TNFSF4 as a direct target of miR-125b-5p. Ox-LDL exposure led to decreased cell viability and angiogenic capacity, along with increased apoptosis, inflammation, and oxidative stress in HUVECs. These effects were reversed by overexpressing miR-125b-5p or knocking down TNFSF4. Overexpression of TNFSF4 significantly reversed the effects brought about by miR-125b-5p in HUVECs exposed to ox-LDL. Moreover, miR-125b-5p inactivated the TLR4/NF-κB signaling pathway by negatively regulating TNFSF4. Conclusions In summary, our findings demonstrate that miR-125b-5p possessed an anti-inflammatory and anti-apoptosis against ox-LDL-induced HUVEC injury by regulating the TNFSF4/TLR4/NF-κB signaling, indicating that miR-125b-5p may have an important therapeutic function for AS.

Abstract Mesenchymal stem cells-derived exosomes (MSCs-exosomes) reportedly possess cardioprotective effects. This study investigated the therapeutic potential and mechanisms of MSCs-exosomes on heart failure (HF). H9c2 cells were used to establish a cardiomyocyte hypertrophy model by angiotensin II (Ang II) treatment. Isolated MSCs-exosomes were identified by transmission electron microscope and CD63 detection. Apoptosis rate was measured by terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay. Levels of inflammatory factors [interleukin (IL)-1β, IL-4, IL-6, and tumor necrosis factor (TNF)-α] and brain natriuretic peptide (BNP) were determined by ELISA. Expression of apoptosis-related proteins [Bax, B-cell lymphoma-2 (Bcl-2), and caspase 3] and Hippo-Yes-associated protein (YAP) pathway-related proteins [YAP, phosphor (p)-YAP, and tafazzin (TAZ)] was detected by western blotting. Cardiomyocyte hypertrophy of H9c2 cells induced by Ang II was ameliorated by MSCs-exosomes treatment. MSCs-exosomes downregulated Bax and caspase 3 levels and upregulated Bcl-2 level in Ang II-induced H9c2 cells. MSCs-exosomes also reduced the levels of BNP, IL-1β, IL-4, IL-6, and TNF-α in Ang II-induced H9c2 cells. Meanwhile, p-YAP was downregulated and TAZ was upregulated after MSCs-exosomes administration. In conclusion, MSCs-exosomes alleviate the apoptosis and inflammatory response of cardiomyocyte via deactivating Hippo-YAP pathway in HF.

Objective: Exploring the effectiveness of miR-30b-5p-loaded PEG-PLGA nanoparticles (NPs) for the treatment of heart failure and the underlying mechanism.Methods: PEG-PLGA characteristics with different loading amounts were first examined to determine the loading, encapsulation, and release of miR-30b-5p from NPs. The effects of miR-30b-5p NPs on cardiac function and structure were assessed by immunofluorescence, echocardiography, HE/Masson staining, and TUNEL staining. The effects of NPs on the expression of factors related to cardiac hypertrophy and inflammation were examined by RT-PCR and western blotting, and the mechanism of miR-30b-5p treatment on heart failure was explored by dual luciferase reporter assay and RT-PCR.Results: The size of PEG-PLGA NPs with different loading amounts ranged from 200 to 300 nm, and the zeta potential of PEG-PLGA NPs was negative. The mean entrapment efficiency of the NPs for miR-30b-5p was high (81.8 ± 2.1%), and the release rate reached 5 days with more than 90% release. Distribution experiments showed that NPs were mainly distributed in the heart and had a protective effect on myocardial injury and cardiac function. Compared with a rat model of cardiac failure and miR-30b-5p-non-loaede NP groups, the expression of cardiac hypertrophy markers (ANP, BNPβ-MHC) and inflammatory factors (IL-1β, IL-6) were significantly decreased. Dual luciferase reporter assay assays indicated that miR-30b-5p exerted its effects mainly by targeting TGFBR2.Conclusion: PEG-PLGA NPs loaded with miR-30b-5p improved cardiac function, attenuated myocardial injury, and regulated the expression of factors associated with cardiac hypertrophy and inflammation by targeting TGFBR2.

To improve the observation accuracy and robustness of the sensorless control of an interior permanent magnet synchronous motor (IPMSM), a sliding mode observer based on the super twisting algorithm (STA-SMO) with adaptive parameters estimation control is proposed, as parameter mismatches are considered. First, the conventional sliding mode observer (CSMO) is analyzed. The conventional exponential approach law produces a large chattering phenomenon in the back EMF estimation, which causes a large observation error when filtering the chattering through the low-pass filter. Second, a high-order approach law of the super twisting algorithm is introduced to observe the rotor position and speed estimation, which uses the integral function to eliminate the chattering of the sliding mode. Third, an adaptive parameter estimation control (APEC) is presented to enhance the observation accuracy caused by parameter mismatches; the motor parameter adaptive law of the APEC is designed by Lyapunov’s stability law. Finally, the proposed method not only reduces both the chattering and the low-pass filter, but it also enhances accuracy and robustness against parameter mismatches, as discussed through simulations and experiments.

Heart failure (HF) is a major global cause of morbidity and mortality. This study aimed to elucidate the role of secreted protein acidic and rich in cysteinerelated modular calcium-binding protein 2 (SMOC2) in HF development and its underlying mechanism. Using a rat HF model, SMOC2 expression was examined and then knocked down via transfection to assess its impact on cardiac function and damage. The study also evaluated the effects of SMOC2 knockdown on autophagy-related molecules and the transforming growth factor beta 1 (TGF-β1)/SMAD family member 3 (Smad3) signaling pathway. Intraperitoneal injection of the TGF-β agonist (SRI-011381) into the HF rat model was performed to explore the SMOC2-TGF-β1/Smad3 pathway relationship. SMOC2 expression was elevated in HF rats, while its downregulation improved cardiac function and damage. SMOC2 knockdown reversed alterations in the LC3-II/I ratio, Beclin-1, and p62 levels in HF rats. Through transmission electron microscope, we observed that SMOC2 knockdown restored autophagosome levels. Furthermore, SMOC2 downregulation inhibited the TGF-β1/Smad3 signaling pathway, which was counteracted by SRI-011381. In conclusion, SMOC2 knockdown inhibits HF development by modulating TGF-β1/Smad3 signaling-mediated autophagy, suggesting its potential as a therapeutic target for HF. [ABSTRACT FROM AUTHOR]

Previously, we reported that heat shock protein (HSP)65 impairs the effects of high-density lipoprotein on macrophages. We also showed that immune response activation adversely affects reverse cholesterol transport (RCT). In this study, we investigated the effects of the Src family kinase lymphocyte-specific protein tyrosine kinase (Lck) and elucidated the mechanismunderlying HSP65-regulated cholesterol efflux in T cells.We evaluated cell proliferation, Lck expression, and inflammatory cytokine production in Jurkat cells and CD4+ T cells. HSP65-mediated inhibition of RCTwas assessed by evaluating ABCA1, ABCG1, SR-BI, PPAR-γ, and liver X receptor-a expression. A dose-dependent relationship was found between the levels of these proteins and the suppression of cholesterol efflux. Stimulation of Lck-silenced T cells with ionomycin resulted in a decrease in intracellular calcium levels. Treatment of Jurkat cells with PP2, an inhibitor of Src family kinase, inhibited calcium-induced, but not PMA-induced, ERK phosphorylation. NF-κB activation in response to PMA was minimally inhibited in cells stimulated with PP2. HSP65 failed to trigger downstream ERK or JNK phosphorylation or to activate NF-κB or protein kinase C-γ in Lck-silenced cells. Additionally, elevation of intracellular calcium was also impaired. However, HSP65 significantly enhanced cholesterol efflux and decreased cellular cholesterol content by inducing the expression of cholesterol transport proteins in Lck-silenced cells. The treatment of Jurkat cells with PP2 also inhibited cell proliferation and promoted RCT. In conclusion, Lck is a key molecule in the TCR signaling cascade that inhibits cholesterol efflux and upregulates intracellular cholesterol ester content in T cells. Our results demonstrate that the immune response plays a previously unrecognized role in RCT. [ABSTRACT FROM AUTHOR]