Journal of Cardiovascular Translational Research最新文献

Trimethylamine oxide (TMAO) is an intestinal flora metabolite associated with risk of cardiovascular diseases. Transient receptor potential vanilloid 4 (TRPV4) is a Ca²⁺-permeable ion channel that is essential for vasodilation and endothelial function. Currently, there are few studies on the effect of TMAO on TRPV4 channels. In the present study, Ca²⁺ imaging of vascular tissue showed that TMAO inhibited TRPV4-mediated Ca²⁺ influx into aortic endothelial cells in a dose-dependent manner. Furthermore, a whole-cell patch clamp assay showed that TMAO blocked TRPV4-mediated cation currents. Notably, results of aortic vascular tension measurement showed that TMAO impaired endothelium-dependent vasodilation in mouse aortic vessels through the TRPV4-NO pathway. Our results indicated that TMAO inhibited Ca²⁺ entry in endothelial cells and impaired vasodilation through the TRPV4-NO pathway in mice. These results provide scientific evidence for novel pathogenic mechanisms underlying the role of TMAO in cardiovascular disease.

Survival analysis is employed to scrutinize time-to-event data, with emphasis on comprehending the duration until the occurrence of a specific event. In this article, we introduce two novel survival prediction models: CosAttnSurv and CosAttnSurv $+$ DyACT. CosAttnSurv model leverages transformer-based architecture and a softmax-free kernel attention mechanism for survival prediction. Our second model, CosAttnSurv $+$ DyACT, enhances CosAttnSurv with Dynamic Adaptive Computation Time (DyACT) control, optimizing computation efficiency. The proposed models are validated using two public clinical datasets related to heart disease patients. When compared to other state-of-the-art models, our models demonstrated an enhanced discriminative and calibration performance. Furthermore, in comparison to other transformer architecture-based models, our proposed models demonstrate comparable performance while exhibiting significant reduction in both time and memory requirements. Overall, our models offer significant advancements in the field of survival analysis and emphasize the importance of computationally effective time-based predictions, with promising implications for medical decision-making and patient care.

A left ventricular assist device (LVAD) supports hemodynamics in heart failure patients. To deepen the understanding of hemodynamic changes and the movement of thrombi in the aorta, we examined three distinct LVAD blood flow rates across two implantation sites using the theory of computational fluid dynamics. Our findings revealed the complex dynamics of blood flow during cardiac systole under various scenarios. We also analyzed thrombi residence time and flow probabilities into aortic branches. Simulation results indicate that thrombi distribution in the aorta is significantly influenced by the location of the LVAD outflow graft and the flow rate. When the LVAD outflow graft is implanted into the ascending aorta, higher flow rates may reduce the risk of cerebral thrombosis. However, lower flow rates may reduce the risk of cerebral thrombosis while it is implanted into the descending aorta. The study may offer valuable insights into the LVAD implantation about the risk of cerebrovascular embolism.

Acute-phase inhibition of the pro-inflammatory alarmin S100A8/A9 improves cardiac function post-myocardial infarction (MI), but the mechanisms underlying the long-term benefits of this short-term treatment remain to be elucidated. Here, we assessed the effects of S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 on myocardial neovascularization in mice with induced MI. The treatment significantly reduced S100A9 and increased neovascularization in the myocardium, assessed by CD31 staining. Proteomic analysis by mass-spectrometry showed strong myocardial upregulation of the pro-angiogenic proteins filamin A (~ 10-fold) and reticulon 4 (~ 5-fold), and downregulation of the anti-angiogenic proteins Ras homolog gene family member A (RhoA, ~ 4.7-fold), neutrophilic granule protein (Ngp, ~ 4.0-fold), and cathelicidin antimicrobial peptide (Camp, ~ 4.4-fold) versus controls. In-vitro, ABR-238901 protected against apoptosis induced by recombinant human S100A8/A9 in human umbilical vein endothelial cells (HUVECs). In conclusion, S100A8/A9 blockade promotes post-MI myocardial neovascularization by favorably modulating pro-angiogenic proteins in the myocardium and by inhibiting endothelial cell apoptosis.

Cardiac fibrosis following myocardial infarction (MI) seriously affects the prognosis and survival rate of patients. This study aimed to determine the effect and regulation mechanism of the dedicator of cytokinesis 2 (DOCK2) during this process. Experiments were carried out in mice in vivo, and in Ang II treated cardiac fibroblasts (CFs) in vitro. DOCK2 was increased in mouse myocardial tissues after MI and Ang II-treated CFs. In MI mice, DOCK2 silencing improved cardiac function, and ameliorated cardiac fibrosis. DOCK2 knockdown suppressed the activation of CFs and decreased the expression of α-SMA, collagen I, and collagen III. Suppression of DOCK2 mitigated Ang II induced migration of CFs. DOCK2 inhibition reduced the activity of the PI3K/Akt and Wnt/β-catenin pathways, while this change could be reversed by the pathway activators, SC79 and SKL2001. In summary, DOCK2 suppression improves cardiac dysfunction and attenuates cardiac fibrosis after MI via attenuating PI3K/Akt and Wnt/β-catenin pathways.

Methylation modification is a crucial epigenetic alteration encompassing RNA methylation, DNA methylation, and histone methylation. Ferroptosis represents a newly discovered form of programmed cell death (PCD) in 2012, which is characterized by iron-dependent lipid peroxidation. The comprehensive investigation of ferroptosis is therefore imperative for a more profound comprehension of the pathological and pathophysiological mechanisms implicated in a wide array of diseases. Researches show that methylation modifications can exert either promotive or inhibitory effects on cell ferroptosis. Consequently, this review offers a comprehensive overview of the pivotal role played by methylation in ferroptosis, elucidating its associated factors and underlying mechanisms.

To investigate the impacts of circ_0069094 on acute coronary syndrome. Real-time polymerase chain reaction was used to detect the expression levels of circ_0069094, and its diagnostic performance was evaluated using ROC curve. Spearman's method was performed for correlation analysis. The levels of SOD, MDA, vWF in ACS rat models were assessed by commercial kits. The activities of H/R cell models were detected by CCK-8, Transwell, flow cytometry. The GO and KEGG were performed to analyze the function of targeted genes of miR-484. The concentration of circ_0069094 was decreased in patients with ACS, ACS rat models and H/R HUVEC models. The dysfunction of SOD, MDA, vWF, LVIDs, LVDD, and LVEF in the ACS models was regulated by the increase of circ_0069094. The viability, migration, apoptosis of the H/R models were regulated by circ_0069094. MiR-484 was a ceRNA of circ_0069094 and mediated the function of circ_0069094.

Our objective was to determine the role of acetyl-Hsp90 and its relationship with the NF-κB p65 signaling pathway in CVDs. We investigated the effect of acetyl-Hsp90 on cardiac inflammation and apoptosis after ischemia-reperfusion injury (I/RI). The results showed that the induction of acetyl-Hsp90 occurred in the heart during I/R and in primary cardiomyocytes during oxygen-glucose deprivation/reoxygenation (OGD/R). Moreover, the nonacetylated mutant of Hsp90 (Hsp90-K284R), through the regulation of ATPase activities within its N-terminal domain (NTD), indirectly or directly increases its interaction with NF-κB p65. This led to a reduction in the activation of the NF-κB p65 pathway, thereby attenuating inflammation, apoptosis, and fibrosis, ultimately leading to an improvement in cardiac function. Furthermore, we demonstrated that recombinant human interleukin-37 (rIL-37) exerts a similar cardioprotective effect by reducing acetylation at K284 of Hsp90 after inhibiting the expression of KAT2A.

Hyperuricemia is a common metabolic disorder with severe complications. We aimed to develop a mouse model for spontaneous hyperuricemia. Uox^-/- mouse model was generated on C57BL/6J background by deleting exon 2-4 of Uox using the CRISPR/Cas9 system. The prototypic Uox ^-/-mice had 5.5-fold increased serum uric acid (1351.04±276.58μmol/L) as compared to the wild type mice (P<0.0001), but died by 4 weeks. After allopurinol (3ug/g) intervention, they all survived > 8 weeks. The serum uric acid was 612.55±146.98μmol/L in the 8-week-old allopurinol-rescued Uox ^-/-mice, which manifested multiple complications including severe renal insufficiency, hypertension, left ventricular remodeling and systolic dysfunction, aortic endothelial dysfunction, hepatic steatosis and elevated liver enzymes, as well as hyperglycemia and hypercholesteremia. The present Uox^-/- mice developed spontaneous hyperuricemia complicated with urate nephropathy, cardiovascular disease and cardiometabolic disorders, and may provide a novel tool to study hyperuricemia associated early-onset cardiovascular disorders in human.