BackgroundThe risk factors of bleeding related to dual or triple therapy in patients with atrial fibrillation after percutaneous coronary intervention (PCI) are not fully explored. We addressed this issue on patients enrolled in the MANJUSRI trial.MethodsData of patients assigned to the dual therapy group (ticagrelor + warfarin, Dual group) and the triple group (clopidogrel + aspirin + warfarin, Triple group) in the MANJUSRI trial were analyzed. Multivariate regression analysis was used to determine the risk factors of bleeding among enrolled patients.ResultsThe incidence of overall bleeding at 6 months was 36.49% in the dual group and 35.62% in the triple group (P > 0.05). Multivariate cox regression analysis showed that alcohol consumption was positively correlated with overall bleeding in the total cohort (OR = 3.905, P = 0.001) and in the dual therapy group (OR = 4.643, P = 0.034). Age was positively associated with overall bleeding risk (OR = 1.059, P = 0.032), while body mass index was negatively associated with overall bleeding risk (OR = 0.911, P = 0.048) in the triple therapy group.ConclusionsAlcohol consumption increased the risk of overall bleeding after PCI in atrial fibrillation patients, especially in patients treated with warfarin and ticagrelor. Aging also increased bleeding risk in the whole cohort. Lower body weight contributed significantly to increased risk of overall bleeding in AF patients post PCI receiving combined clopidogrel, aspirin and warfarin medications. Above factors should be considered in terms of individualized anticoagulation management in AF patients post PCI aiming to reduce their bleeding risk.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT02206815, identifier NCT02206815.

Modulating the balance between pro- and anti-inflammatory monocyte subsets holds therapeutic promise in acute myocardial infarction (AMI); however, effective and selective strategies are still lacking. In this study, we are the first to identify Ten-Eleven-Translocation 3 (TET3) expression in circulating monocytes as an independent predictor of AMI occurrence and patient prognosis in a clinical cohort. Building on this novel insight, we engineered a monocyte-targeted RNAi delivery system designed to silence TET3 expression selectively. The platform employs periodic mesoporous silica nanoparticles (PMS) loaded with siTET3, and is surface-modified with polyethylenimine (PEI) and polyethylene glycol (PEG) to enhance cellular uptake. Critically, we further functionalized the system with a CD14 receptor-recognizing transmembrane peptide (Cys-Gly-Trp-Arg-Arg-Arg-NH₂), enabling precise monocyte targeting and internalization. Our targeted nanotherapeutic successfully reprogrammed inflammatory monocytes in vitro, leading to attenuated pro-inflammatory phenotypes. In vivo, treatment with siTET3-loaded nanoparticles markedly reduced infarct size and myocardial fibrosis in murine AMI models. Importantly, translational validation in a porcine AMI model demonstrated substantial suppression of cardiac inflammation and improved post-infarction outcomes following systemic administration of the nanotherapeutic.

Exercise exerts cardioprotective effects, with prior research implicating exosomal miR-17-3p as a critical mediator in attenuating myocardial ischemia-reperfusion injury (MIRI). The present study aimed to elucidate the influence of exercise on exosomal miR-17-3p and to delineate the underly mechanisms by which it mitigates MIRI. A MIRI model was established using C57BL/6 mice. Exosomes were isolated and their impact on programmed necrosis, cardiac function, infarct size, inflammatory factors (LDH, TNF-α), as well as proteins associated with ventricular remodeling, was evaluated. Complementary in vitro experiments employed primary cardiomyocytes to further investigate these effects. The regulatory relationship between miR-17-3p and calcium/calmodulin-dependent protein kinase II (CAMK II) was examined. Additionally, the contribution of brown adipose tissue (BAT) as the source of exosomal miR-17-3p was assessed. Findings demonstrated that exercise enhanced cardiac function and reduced infarct size in MIRI mice through exosome-mediated mechanisms. Mechanistically, exosomal miR-17-3p directly targeted CAMKII, leading to inhibition of the RIPK3/MLKL pathway, thereby attenuating cardiomyocyte necrosis and inflammation and reversing pathological ventricular remodeling. BAT was identified as the principal origin of exosomal miR-17-3p, and ablation of BAT abrogated the cardioprotective effects conferred by exercise. Collectively, these results suggest that exercise confers protection against MIRI by promoting the uptake of BAT-derived exosomal miR-17-3p uptake by cardiomyocytes, which in turn supresses CAMKII activity and programmed necrosis. This study reveals a novel exercise-induced cardioprotective pathway and identifies potential therapeutic targets for MIRI.

AIMS:Acute myocardial infarction results in significant mortality and chronic heart failure, with reperfusion frequently inducing myocardial ischaemia-reperfusion (IR) injury mediated by infiltrating monocytes and monocyte-derived macrophages (iMacs). The olfactory receptor 2 (Olfr2) is hypothesized to serve as a pivotal inflammatory mediator in this context. This study aimed to elucidate the regulatory role of Olfr2 in mitochondrial homeostasis and inflammation in iMacs during myocardial IR injury. METHODS AND RESULTS:The surface expression of OR6A2 (human ortholog of Olfr2) on monocyte subsets was assessed to determine its association with major adverse cardiovascular events (MACEs) in IR-injured patients. The mechanistic role of Olfr2 in modulating iMacs during myocardial IR injury was investigated using both in vivo and in vitro interventions targeting Olfr2. Elevated OR6A2 levels on human monocytes and octanal, an OR6A2 agonist, were significantly associated with an increased risk of MACEs and correlated with increased oxidative stress and pro-inflammatory responses in patients with IR injury. The genetic ablation of Olfr2 in mice demonstrated significant attenuation of mitochondrial reactive oxygen species (mtROS) and pro-inflammatory cytokine in iMacs, accompanied by diminished immune cell infiltration and reduced cardiomyocyte apoptosis, ultimately ameliorating myocardial IR injury. Mechanistically, Olfr2 activated nuclear receptor subfamily 4 group A member 1 (NR4A1) via cAMP/PKA signalling, promoting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which led to mitochondrial mtROS overproduction, mitochondrial membrane potential disruption, mitochondrial apoptosis, and the subsequent release of pro-inflammatory factors through NLRP3 inflammasome activation. Notably, monocyte/macrophage-specific NR4A1 overexpression in Olfr2 knockout mice negated the cardiovascular protection observed during IR injury. CONCLUSION:Elevated OR6A2 expression and octanal levels were significantly associated with an increased risk of MACEs. Our findings identified the Olfr2/cAMP/PKA/NR4A1 axis as a novel signalling pathway contributing to cardiac IR injury by promoting Drp1-mediated mitochondrial fission and subsequent production of pro-inflammatory cytokines.

Atherosclerotic disease is a substantial global burden, and existing treatments, such as statins, are recommended to lower low-density lipoprotein cholesterol (LDL-C) levels and inhibit the progression of atherosclerosis. However, side effects, including gastrointestinal unease, potential harm to the liver, and discomfort in the muscles, might be observed. In this study, we propose a novel method using periodic mesoporous silica nanoparticles (PMS) to create heparin-modified PMS (PMS-HP) with excellent biocompatibility, enabling selective removal of LDL-C from the blood. In vitro, through the introduction of PMS-HP into the plasma of mice, we observed that, compared to PMS alone, PMS-HP could selectively adsorb LDL-C while avoiding interference with valuable components such as plasma proteins and high-density lipoprotein cholesterol (HDL-C). Notably, further investigations revealed that the adsorption of LDL-C by PMS-HP could be well-fitted to quasi-first-order (R2 = 0.993) and quasi-second-order adsorption models (R2 = 0.998). Likewise, in vivo, intravenous injection of PMS-HP enabled targeted LDL-C adsorption (6.5 ± 0.73 vs. 8.6 ± 0.76 mM, p < 0.001) without affecting other plasma constituents, contributing to reducing intravascular plaque formation (3.66% ± 1.06% vs. 1.87% ± 0.79%, p < 0.05) on the aortic wall and inhibiting vascular remodeling (27.2% ± 6.55% vs. 38.3% ± 1.99%, p < 0.05). Compared to existing lipid adsorption techniques, PMS-HP exhibited superior biocompatibility and recyclability, rendering it valuable for both in vivo and in vitro applications.

A magnetically responsive valve actuator inspired by the starfish shape and fabricated with hydrophilic and hydrophobic surfaces was developed. The surface morphology and wettability of the magnetically responsive colloidal crystal hydrogel actuator were characterized using scanning electron microscopy and contact angle measurements. The actuator, resembling a flower, consists of Poly(HEMA-co-AAm)/Fe3O4/PDMS, exhibiting distinct Janus wettability with hydrophobic Fe3O4/PDMS and hydrophilic Poly(HEMA-co-AAm) surfaces. The directional movement of water droplets on the V-shaped structured film confirmed the anisotropic wetting behavior, influenced by the film’s wettability and structural dimensions. Moreover, the actuator demonstrated responsive angular and positional adjustments under varying magnetic fields, facilitated by embedded Fe3O4 particles aligning with magnetic lines of force. In experimental setups simulating intravascular applications, the actuator exhibited controlled movement within tubes and demonstrated effective adhesion to heart valve injuries under magnetic guidance. Additionally, a layered inverse opal film within the actuator showed promising capabilities for unidirectional fluid permeation, enhancing its functional versatility. These findings underscore the potential of the magnetically responsive colloidal crystal hydrogel actuator for biomedical applications, particularly in minimally invasive cardiac interventions requiring precise actuation and adhesive functionalities.

The integration of the properties of silicon nano crystallinity with silica mesoporosity provides a wealth of new opportunities for emerging biomedicine. Cholesterol (CHO) and triglyceride (TG) levels have always been a challenge for cardiologists in the treatment of patients with chronic coronary artery disease (CAD). For patients with hyperlipidemia, statins and other lipid-lowering drugs are currently recommended. It should be noted, however, that significant side effects have been reported in the treatments, including liver damage, muscle pain, etc. We here found that our previously produced periodic mesoporous nanocrystalline silicon-silica, meso-ncSi/SiO2 (PMS), a nanocomposite material, has the properties of lowering CHO and TG, and is associated with better safety and biocompatibility compared to existing lipid-lowering drugs. After being incubated with PMS for 2 hours, CHO and TG levels in blood were significantly lower than before. In addition, CHO and TG adsorbed on with PMS could also be extracted and released, contributing to the recovery and recycling of PMS.

Current studies have suggested that miRNA is beneficial in inhibiting myocardial remodeling after myocardial infarction (AMI), however, its underlying mechanism is unclear. We aimed to investigate whether miR-150 can inhibit myocardial remodeling after myocardial infarction and whether this process is regulated by the miR-150/TET3 pathway. On the first day, C57BL/6 AMI mice(n = 15) were administrated with miR-150, and another 15 AMI mice were administrated with the same volume of control Agomir. Left ventricular ejection fraction (LVEF

Quantitative flow ratio (QFR) is a new method for the assessment of the extent of coronary artery stenosis. But it may be obscured by the cardiac remodeling and abnormal blood flow of the coronary artery when encountering atrial fibrillation (AF). The present study aimed to examine the impact of these changed structures and blood flow of coronary arteries on QFR results in AF patients. Methods and Results. We evaluated QFR in 223 patients (112 patients with AF; 111 non-AF patients served as controls) who had undergone percutaneous coronary intervention (PCI) due to severe stenoses in coronary arteries. QFR of the target coronary was determined according to the flow rate of the contrast agent. Results showed that AF patients had significantly higher QFR values than control (0.792 ± 0.118 vs. 0.685 ± 0.167, p<0.001). We further analyzed local QFR around the stenoses (0.858 ± 0.304 vs. 0.756 ± 0.146, p=0.002), residual QFR (0.958 ± 0.055 vs. 0.929 ± 0.093, p=0.005), and index QFR (0.807 ± 0.108 vs. 0.713 ± 0.152, p<0.001) in these two groups of patients with and without AF. Further analysis revealed that QFR in AF patients was negatively correlated with coronary flow velocity (R = −0.22, p=0.02) and area of stenosis (R = −0.70, p<0.001) but positively correlated with the minimum lumen area (MLA) (R = 0.47, p<0.001). Conclusion. AF patients with coronary artery stenosis have higher QFR values, which are associated with decreased blood flow velocity, smaller stenosis, and larger MLA in AF patients upon cardiac remodeling.

Endothelial-mesenchymal transition (EndoMT) is a complex biological process in which endothelial cells are transformed into mesenchymal cells, and dysregulated EndoMT causes a variety of pathological processes. Transforming growth factor beta (TGF-β) signaling effectively induces the EndoMT process in endothelial cells, and Smad2 is the critical protein of the TGF-β signaling pathway. However, whether small ubiquitin-like modifier modification (SUMOylation) is involved in EndoMT remains unclear. Here, we show that Smad2 is predominantly modified by SUMO1 at two major SUMOylation sites with PIAS2α as the primary E3 ligase, whereas SENP1 (sentrin/SUMO-specific protease 1) mediates the deSUMOylation of Smad2. In addition, we identified that SUMOylation significantly enhances the transcriptional activity and protein stability of Smad2, regulating the expression of downstream target genes. SUMOylation increases the phosphorylation of Smad2 and the formation of the Smad2-Smad4 complex, thus promoting the nuclear translocation of Smad2. Ultimately, the wildtype, but not SUMOylation site mutant Smad2 facilitated the EndoMT process. More importantly, TGF-β enhances the nuclear translocation of Smad2 by enhancing its SUMOylation and promoting the EndoMT process. These results demonstrate that SUMOylation of Smad2 plays a critical role in the TGF-β-mediated EndoMT process, providing a new theoretical basis for the treatment and potential drug targets of EndoMT-related clinical diseases.

Objective. Myocardial ischemia/reperfusion (I/R) injury can aggravate myocardial injury. Programmed necrosis plays a crucial role in this injury. However, the role of exosomal miRNAs in myocardial I/R injury remains unclear. Therefore, this study is aimed at exploring the function and mechanism of exosomal miR-17-3p in myocardial I/R injury. Methods. The myocardial I/R injury animal model was established in C57BL/6 mice. Exosomes were identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Programmed necrosis was detected by PI staining. Heart function and myocardial infarct size were evaluated using echocardiography and triphenyl tetrazolium chloride (TTC) staining, respectively. Histopathological changes were visualized by hematoxylin and eosin (H&E) and Masson staining. The regulation of TIMP3 expression by miR-17-3p was verified using a dual-luciferase reporter assay. Lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assays (ELISA). TIMP3 expression was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Results. We demonstrated that miR-17-3p was significantly downregulated in peripheral blood exosomes after cardiac I/R injury. Further analysis indicated that exosomal miR-17-3p attenuated H2O2-induced programmed necrosis in cardiomyocytes in vitro. Moreover, TIMP3 was a target for miR-17-3p. TIMP3 affected H2O2-induced programmed necrosis in cardiomyocytes. This effect was modulated by miR-17-3p in vitro. Furthermore, exosomal miR-17-3p greatly alleviated cardiac I/R injury in vivo. Conclusions. The present study demonstrated that exosomal miR-17-3p alleviated the programmed necrosis associated with cardiac I/R injury by regulating TIMP3 expression. These findings could represent a potential treatment for I/R injury.

Cardiovascular disease (CVD) is a common disease caused by many factors, including atherosclerosis, congenital heart disease, heart failure, and ischemic cardiomyopathy. CVD has been regarded as one of the most common diseases and has a severe impact on the life quality of patients. The main features of CVD include high morbidity and mortality, which seriously threaten human health. SUMO proteins covalently conjugate lysine residues with a large number of substrate proteins, and SUMOylation regulates the function of target proteins and participates in cellular activities. Under certain pathological conditions, SUMOylation of proteins related to cardiovascular development and function are greatly changed. Numerous studies have suggested that SUMOylation of substrates plays critical roles in normal cardiovascular development and function. We reviewed the research progress of SUMOylation in cardiovascular development and function, and the regulation of protein SUMOylation may be applied as a potential therapeutic strategy for CVD treatment.

Leukemia is a malignant disease of hematopoietic tissue characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow. ERG (ETS-related gene) is an important member of the E26 transformation-specific (ETS) transcription factor family that plays a crucial role in physiological and pathological processes. However, the role of ERG and its modification in leukemia remains underexplored. In the present study, we stably knocked down or overexpressed ERG in leukemia cells and observed that ERG significantly promotes the proliferation and inhibits the differentiation of AML (acute myeloid leukemia) cells. Further experiments showed that ERG was primarily modified by SUMO2, which was deconjugated by SENP2. PML promotes the SUMOylation of ERG, enhancing its stability. Arsenic trioxide decreased the expression level of ERG, further promoting cell differentiation. Furthermore, the mutation of SUMO sites in ERG inhibited its ability to promote the proliferation and inhibit the differentiation of leukemia cells. Our results demonstrated the crucial role of ERG SUMOylation in the development of AML, providing powerful targeted therapeutic strategies for the clinical treatment of AML.

Spinal muscular atrophy (SMA), a degenerative motor neuron disease and a leading cause of infant mortality, is caused by loss of functional survival motor neuron (SMN) protein due to SMN1 gene mutation. Here, using mouse and cell models for behavioral and histological studies, we found that SENP2 (SUMO/sentrin-specific protease 2)-deficient mice developed a notable SMA-like pathology phenotype with significantly decreased muscle fibers and motor neurons. At the molecular level, SENP2 deficiency in mice did not affect transcription but decreased SMN protein levels by promoting the SUMOylation of SMN. SMN was modified by SUMO2 with the E3 PIAS2α and deconjugated by SENP2. SUMOylation of SMN accelerated its degradation by the ubiquitin–proteasome degradation pathway with the ubiquitin E1 UBA1 (ubiquitin-like modifier activating enzyme 1) and E3 ITCH. SUMOylation of SMN increased its acetylation to inhibit the formation of Cajal bodies (CBs). These results showed that SENP2 deficiency induced hyper-SUMOylation of the SMN protein, which further affected the stability and functions of the SMN protein, eventually leading to the SMA-like phenotype. Thus, we uncovered the important roles for hyper-SUMOylation of SMN induced by SENP2 deficiency in motor neurons and provided a novel targeted therapeutic strategy for SMA.

The vascular eendothelial cells are highly heterogeneous and associated with numerous diseases. Thymosin β4 (Tβ4) plays pleiotropic roles in endothelial cell differentiation, migration and angiogenesis. However, the underlying mechanisms played by Tβ4 in the regulation of endothelial cells have not yet been well investigated. In the present study, Tβ4 -GFP adenovirus, transfected into human umbilical vein endothelial cells (HUVECs), and cell morphology were analyzed by fluorescence microscopy. ELISA was used to determine the concentration of Tβ4 expression. Furthermore, the effects of Tβ4 overexpression on HUVECs proliferation, apoptosis and migration were investigated. Real-time quantitative PCR and western blot were conducted to examine mRNA and protein expression in HUVECs with Tβ4 overexpression. Moreover, the underlying molecular mechanism of Tβ4 in HUVECs function was tested through treatment with LY294002, a PI3K/AKT inhibitor. Overexpression of Tβ4 increased the cell ability of HUVECs, and up-regulated the expression of the proliferation markers PCNA and Cyclin D1. In addition, overexpression of Tβ4 reduced HUVECs apoptosis, both under normoxic and hypoxic conditions. Moreover, overexpression of Tβ4 increased the ability of HUVECs to migrate through the membrane and up-regulated levels of MMP-2 and MMP-9. The use of LY294002 decreased the p-AKT (Ser473) level, which was induced by Tβ4 overexpression. Importantly, LY294002 reduced Tβ4-induced HUVECs proliferation and migration. In conclusion, our results suggest that Tβ4 is a major regulator of HUVECs function by activating the AKT signaling pathway.

Background: Warfarin, along with aspirin and clopidogrel, has long been recommended for patients with atrial fibrillation (AF) who are undergoing percutaneous coronary intervention with a drug-eluting stent (PCI-DES). However, this triple therapy has been known to increase the risk of bleeding complications. Meanwhile, there is no evidence from prospective trials on the use of ticagrelor in a dual therapy. We here aimed to compare the antiplatelet drug ticagrelor as a dual antithrombotic agent to aspirin and clopidogrel in bleeding events.Methods: In this multicenter, active-controlled, open-label, randomized trial, patients with AF taking warfarin who had undergone PCI-DES were randomly assigned to the ticagrelor therapy group (Dual group) or the clopidogrel plus aspirin therapy group (Triple group). The primary and secondary endpoints were overall bleeding events and major bleeding events, respectively, according to the Thrombolysis in Myocardial Infarction (TIMI) criteria at 6 months. Cardiovascular events [re-PCI, surgical bypass, myocardial infarction (MI), heart failure, rehospitalization due to angina pectoris, stent thrombosis and death due to cardiovascular causes] at 6 months were also recorded.Results: A total of 296 patients from 12 medical centers in China were randomized after PCI-DES to either the Dual therapy group (n = 148) or the Triple group (n = 146) for 6 months. The overall incidence of bleeding events at 6 months was 36.49% in the Dual therapy group and 35.62% in the Triple group [hazard ratio, 0.930; 95% confidence interval (CI), 0.635 to 1.361; P = 0.7088]. The incidence of the secondary endpoint over 6 months was 4.73% in the Dual therapy group and 1.37% in the Triple group (hazard ratio, 0.273; 95% CI, 0.057 to 1.315; P = 0.1056). Cardiovascular event occurrence was also comparable in both groups at 6 months (18.24 vs. 16.44%; hazard ratio, 0.845; 95% CI, 0.488 to 1.465; P = 0.5484).Conclusions: The incidence of total bleeding events in AF patients treated with ticagrelor was comparable to that in patients treated with clopidogrel plus aspirin at 6 month; Meanwhile, the incidence of cardiovascular events were also comparable between the groups.Clinical Trial Registration: MANJUSRI, ClinicalTrials.gov# NCT02206815, 2014, August 1st

Quantitative Flow Ratio (QFR) is now a new method for the assessment of the extent of coronary artery stenosis but may be obscured by involvement of the mutated status of anatomical structure and blood flow in the coronary artery when encountering Atrial Fibrillation (AF). In this study, we aimed to expose the effect of mutated status of anatomical structure and blood flow on QFR results in AF patients. Methods and results: We evaluated QFR on 223 patients (112 patients with AF; 111non-AF patients served as control) who had undergone PCI-ES due to severe stenoses in coronary arteries. QFR of the target coronary was determined according to the flow rate of the contrast agent, results showed that AF patients with significantly higher QFR value than control group (0.792 ± 0.011 vs. 0.685 ± 0.016, p＜0.001). Then we further analyzed the local QFR around the stenoses (0.858 ± 0.0287 vs. 0.756 ± 0.014, p=0.002), residual QFR (0.958 ± 0.005 vs. 0.929 ± 0.009, p=0.005), index QFR (0.807 ± 0.010vs. 0.713 ± 0.014, p<0.0001) in these two groups of patients with and without AF. Further analysis revealed that AF patients accompanied with relatively lower blood flow velocity (0.130 ± 0.006 m/s vs. 0.153 ± 0.005 m/s, p=0.003) in the diseased coronary artery as compared to the control. Meanwhile we observed that AF patients with higher minimum lumen area (MLA, mm 2 ) (1.65 ± 0.097 vs. 1.11 ± 0.062, p＜0.001) and decreased maximum lesion distorted angle (28.14°± 1.16°vs. 31.95°± 1.23°, p=0.025) compared to the control. Conclusion: Mutated status of anatomical structure and blood flow in the coronary artery of AF patients may enlarge the value of QFR, this may be ascribed to the lower blood flow velocity and decreased maximum lesion distorted angle in AF patients.

Post-translational modification by SUMO (small ubiquitin-like modifier) proteins has been shown to regulate a variety of functions of proteins, including protein stability, chromatin organization, transcription, DNA repair, subcellular localization, protein-protein interactions, and protein homeostasis. SENP (sentrin/SUMO-specific protease) regulates precursor processing and deconjugation of SUMO to control cellular mechanisms. SENP3, which is one of the SENP family members, deconjugates target proteins to alter protein modification. The effect of modification via SUMO and SENP3 is crucial to maintain the balance of SUMOylation and guarantee normal protein function and cellular activities. SENP3 acts as an oxidative stress-responsive molecule under physiological conditions. Under pathological conditions, if the SUMOylation process of proteins is affected by variations in SENP3 levels, it will cause a cellular reaction and ultimately lead to abnormal cellular activities and the occurrence and development of human diseases, including cardiovascular diseases, neurological diseases, and various cancers. In this review, we summarized the most recent advances concerning the critical roles of SENP3 in normal physiological and pathological conditions as well as the potential clinical implications in various diseases. Targeting SENP3 alone or in combination with current therapies might provide powerful targeted therapeutic strategies for the treatment of these diseases.

Coronary collaterals can effectively improve myocardial blood supply to the area of CTO (chronic total coronary occlusion) and can, thus, reduce infarct size. LUNAR1(leukemia-induced noncoding activator RNA-1) is a specific LncRNA regulated by Notch signaling that not only can enhance the expression of IGFR-1 but also can promote angiogenesis and cell survival. Here, we investigated the relationship between LncRNA-LUNAR1 levels in peripheral plasma and the formation of coronary collaterals. In total, 172 patients with CTO were enrolled and followed up for 12 months. Coronary collaterals were scored according to the Rentrop scoring system. Preclinical tests of tube formation were used to address the mechanisms behind the association between LncRNA-LUNAR1 and development of collaterals. Clinical data and inflammatory factors, including comorbidity, CD14++CD16− monocytes, and CCL2 (chemokine motif ligand 2), were compared and analyzed. Real-time PCR was used to detect the expression of LncRNA-LUNAR1 in peripheral blood plasma. The Rentrop score was positively correlated with LncRNA-LUNAR1 levels in patients with CTO (R = 0.47, p < 0.001). Tube formation assay proved the direct association between LncRNA-LUNAR1 and development of collaterals (p = 0.011). The univariate Kaplan–Meier analysis revealed that patients with low LncRNA-LUNAR1 expression exhibited worse clinical outcomes than those with high LncRNA-LUNAR1 levels (p = 0.008). Receiver operating characteristic (ROC) curve and correlation analysis further confirmed that LncRNA-LUNAR1 expression was closely related to chronic inflammatory diseases, especially diabetes (area = 0.644, p = 0.001; 95% CI, 0.562–0.726). Furthermore, both CD14++CD16− monocytes (r = − 0.37; p < 0.001) and CCL2 levels (r = − 0.35; p < 0.001) negatively affected the expression of LncRNA-LUNAR1. LncRNA-LUNAR1 expression was positively correlated with coronary collaterals in patients with CTO. Inflammatory factors, including CD14++CD16− monocytes and CCL2, may be risk factors affecting LncRNA-LUNAR1 expression.

BACKGROUND:Ly6Chigh monocytes are inflammatory cells that accumulate in an infarcted myocardium, and Ly6Clow monocytes are believed to be reparative and curb myocardial remodeling. NR4A1 is a novel target for modulating the inflammatory phenotype of monocytes during atherogenesis.OBJECTIVES:We aimed to investigate whether MSCs can contribute to the heterogeneity of Ly6Chigh monocytes differentiated into Ly6Clow monocytes and whether this regulation is related to nuclear receptor NR4A1.METHODS:Ly6Chigh/low monocytes were first cocultured with MSCs. C57BL/6CX3CR1-/- mice and C57BL/6 wild-type mice were then used to construct AMI models, and survival functions in the two groups were further compared. Ly6Chigh/low monocytes in circulation and in MI tissue of C57BL/6CX3CR1-/- AMI mice with or without MSC transplantation were determined by flow cytometry at day 1 and day 3. NR4A1 expression was further determined by Western blot. Apoptosis of cardiac myocytes in the infarct border zone at day 3 and day 7 was identified by TUNEL kits. Angiogenesis in the AMI heart at day 7 and day 21 was determined through immunohistochemistry by CD31.RESULTS:We first demonstrated that the percentage of Ly6Clow monocytes increased greatly after 3 days of coculture with MSCs (12.8% ± 3.77% vs. 3.69% ± 0.74%, p < 0.001). The expression of NR4A1 in Ly6Chigh/low monocytes was also significantly elevated at that time (1.81 ± 0.46 vs. 0.43 ± 0.09, p < 0.001). Following AMI, the percentage of circulating Ly6Clow monocytes in C57BL/6CX3CR1-/- mice was significantly lower than that in C57BL/6 wild-type mice (4.36% ± 1.27% vs. 12.17% ± 3.81%, p < 0.001). The survival rate of C57BL/6CX3CR1-/- mice (25%) was significantly lower than that of C57BL/6 wild-type mice (56.3%) after AMI (χ 2 = 4.343, p = 0.037). After MSCs were transplanted, we observed a significant increase in Ly6Clow monocytes both in circulation (16.7% ± 3.67% vs. 3.22% ± 0.44%, p < 0.001) and in the MI heart (3.31% ± 0.69% vs. 0.42% ± 0.21%, p < 0.001) of C57BL/6CX3CR1-/- mice. Western blot analysis further showed that the expression level of NR4A1 in the MI hearts of C57BL/6CX3CR1-/- mice increased significantly under MSC transplantation (0.39 ± 0.10 vs. 0.11 ± 0.04, p < 0.001). We also found significantly decreased TUNEL+ cardiac myocytes (15.45% ± 4.42% vs. 22.78% ± 6.40%, p < 0.001) in mice with high expression levels of NR4A1 compared to mice with low expression levels. Meanwhile, we further identified increased capillary density in the infarct zones of mice with high expression levels of NR4A1 (0.193 ± 0.036 vs. 0.075 ± 0.019, p < 0.001) compared to mice with low expression levels 21 days after AMI.CONCLUSIONS:MSCs can control the heterogeneity of Ly6Chigh monocyte differentiation into Ly6Clow monocytes and further reduce inflammation after AMI. The underlying mechanism might be that MSCs contribute to the increased expression of NR4A1 in Ly6Chigh/low monocytes.