Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.

Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.

Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P-CUL7FBXW8-ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.

A gene cluster encoding a nonribosomal peptide synthetase-like enzyme catalyzes γ-aromatic butenolides.

Sea cucumber-derived fungi have attracted much attention due to their capacity to produce an incredible variety of secondary metabolites. Genome-wide information on Aspergillus micronesiensis H39 obtained using third-generation sequencing technology (PacBio-SMRT) showed that the strain contains nonribosomal peptide synthetase (NRPS)-like gene clusters, which aroused our interest in mining its secondary metabolites. 11 known compounds (1-11), including two γ-aromatic butenolides (γ-AB) and five cytochalasans, were isolated from A. micronesiensis H39. The structures of the compounds were determined by NMR and ESIMS, and comparison with those reported in the literature. From the perspective of biogenetic origins, the γ-butyrolactone core of compounds 1 and 2 was assembled by NRPS-like enzyme. All of the obtained compounds showed no inhibitory activity against drug-resistant bacteria and fungi, as well as compounds 1 and 2 had no anti-angiogenic activity against zebrafish.

Photoinduced Pd-Catalyzed Dearomative 2,5-Difunctionalizition of Furans via Cascade C-C/C-O Bond Formation.

We report an efficient and mild approach for radical dearomatization via photoinduced palladium-catalyzed reaction of three components (i.e., furans, alcohols, and bromoalkanes). In this strategy, various functionalized spiro-heterocycles were prepared from furans in one step via cascade C-C/C-O bond formation under redox neutral conditions.

Bioinspired Conductive Enhanced Polyurethane Ionic Skin as Reliable Multifunctional Sensors.

Ionogels prepared from ionic liquid (IL) have the characteristics of nonevaporation and stable performance relative to traditional hydrogels. However, the conductivities of commonly used ionogels are at very low relative to traditional hydrogels because the large sizes of the cation and anion in an IL impedes ion migration in polymer networks. In this study, ultradurable ionogels with suitable mechanical properties and high conductivities are prepared by impregnating IL into a safe, environmentally friendly water-based polyurethane (WPU) network by mimicking the ion transport channels in the phospholipid bilayer of the cell membrane. The increase in electrical conductivity is attributed to the introduction of carboxylic acid in the hard segment of WPU; this phenomenon regularly arranges hard segment structural domains by hydrogen bonding, forming ionic conduction channels. The conductivities of their ionogels are >28-39 mS cm-1 . These ionogels have adjustable mechanical properties that make the Young's modulus value (0.1-0.6 MPa) similar to that of natural skin. The strain sensor has an ultrahigh sensitivity that ranges from 0.99 to 1.35, with a wide sensing range of 0.1%-200%. The findings are promising for various ionotronics requiring environmental stability and high conductivity characteristics.

Silk fibroin based wearable electrochemical sensors with biomimetic enzyme-like activity constructed for durable and on-site health monitoring.

Flexible biomimetic sensors have encountered a bottleneck of sensitivity and durability, as the sensors must directly work within complex body fluid with ultra-trace biomarkers. In this work, a wearable electrochemical sensor on a modified silk fibroin substrate is developed using gold nanoparticles hosted into N-doped porous carbonizated silk fibroin (AuNPs@CSF) as active materials. Taking advantage of the inherent biocompatibility and flexibility of CSF, and the high stability and enzyme-like catalytic activity of AuNPs, AuNPs@CSF-based sensor exhibits durable stability and superior sensitivity to monitor H2O2 released from cancer cell (4T1) and glucose in sweat. The detection limits for H2O2 and glucose are low to be 1.88 µM and 23 µM respectively, and the sensor can be applied in succession within 30 days at room temperature. Further, physical cross-linking of polyurethane (PU) with SF well matches with the skin tissue mechanically and provides a flexible, robust and stable electrode-tissue interface. AuNPs@CSF is applied successfully for wearable electrochemical monitoring of glucose in human sweat.The present AuNPs@CSF will possess a potential application in clinical diagnosing of H2O2- or glucose-related diseases in future.

A Matrix-Metalloproteinase-Responsive Hydrogel System for Modulating the Immune Microenvironment in Myocardial Infarction.

Injectable hydrogels carrying therapeutic factors to modulate the infarct immune microenvironment show great potential in the treatment of myocardial infarction (MI). However, conventional injectable hydrogels release therapeutic factors in an uncontrolled manner, which leads to poor treatment efficacy and acute side effects on normal tissues. In this work, a matrix metalloproteinase (MMP)2/9-responsive hydrogel system (MPGC4) is developed, considering the characteristics of the post-MI microenvironment. MPGC4 consists of tetra-poly(ethylene glycol) (PEG) hydrogels and a composite gene nanocarrier (CTL4) that is composed of carbon dots (CDots) coupled with interleukin-4 plasmid DNA via electrostatic interactions. MPGC4 can be automatically triggered to release CTL4 on demand after MI to regulate the infarct immune microenvironment. In addition, due to the photoluminescence properties of CDots, a large amount of viscoelastic MPGC4 is found to be retained in situ after injection into the infarct region without leakage. The in vitro results demonstrate that CTL4 promotes proinflammatory M1 macrophage polarization to the anti-inflammatory M2 subtype and contributes to cardiomyocyte survival through macrophage transition. In a rat model of MI, MPGC4 clears MMPs and precisely targets CTL4 to the infarcted region. In particular, MPGC4 improves cardiac function by modulating macrophage transition to reduce early inflammatory responses and proangiogenic activity.

A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice.

OBJECTIVES: Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease that can range from hepatic steatosis to non-alcoholic steatohepatitis (NASH), which can lead to fibrosis and cirrhosis. Recently, ketogenic diet (KD), a low carbohydrate diet, gained popularity as a weight-loss approach, although it has been reported to induce hepatic insulin resistance and steatosis in animal model systems via an undefined mechanism. Herein, we investigated the KD metabolic benefits and its contribution to the pathogenesis of NASH. METHODS: Using metabolic, biochemical and omics approaches, we identified the effects of a KD on NASH and investigated the mechanisms by which KD induces hepatic insulin resistance and steatosis. RESULTS: We demonstrate that KD can induce fibrosis and NASH regardless of body weight loss compared to high-fat diet (HFD) fed mice at thermoneutrality. At ambient temperature (23 °C), KD-fed mice develop a severe hepatic injury, inflammation, and steatosis. In addition, KD increases liver cholesterol, IL-6, and p-JNK and aggravates diet induced-glucose intolerance and hepatic insulin resistance compared to HFD. Pharmacological inhibition of IL-6 and JNK reverses KD-induced glucose intolerance, and hepatic steatosis and restores insulin sensitivity. CONCLUSIONS: Our studies uncover a new mechanism for KD-induced hepatic insulin resistance and NASH potentially via IL-6-JNK signaling and provide a new NASH mouse model.

Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction.

BACKGROUND: Cardiac fibrosis is characterized by excessive extracellular matrix deposition that contributes to compromised cardiac function and potentially heart failure. Disruptor of telomeric silencing 1-like (Dot1L) is the catalytic enzyme required for histone H3K79 methylation which has been demonstrated to play a role in transcriptional activation. However, the functions of Dot1L in the process of cardiac fibrosis still remain unknown. RESULTS: In the present study, we found that endogenous Dot1L is upregulated in cardiac fibroblasts (CFs) treated with angiotensin II (Ang II) or transforming growth factor (TGF)-ß1, along with elevated extracellular matrix (ECM) such as fibronectin, collagen I and III. Silencing or inhibiting Dot1L mitigated Ang II-induced myofibroblast generation and fibrogenesis. We identified the transcription factor-forkhead box O (FoxO) 3a as a novel substrate of Dot1L, the transcriptional activating mark H3K79me3 level on the promoter of FoxO3a was increase in activated-CFs, and inhibition of Dot1L markedly decreased FoxO3a transcription accompanied by a significant decrease in the expression of fibrogenic gene. Knockdown of FoxO3a could alleviate ECM deposition induced by Ang II, on the contrary, overexpression FoxO3a resulting in CFs activation. Consistently, in vivo Dot1L ablation rescued myocardial ischemia-induced cardiac fibrosis and improved cardiac function. CONCLUSIONS: Our findings conclude that upregulation of Dot1L results in activation of the cardiac fibroblasts to promote profibrotic gene, eventually causes cardiac fibrosis. Pharmacological targeting for Dot1L might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.

SMYD3-PARP16 axis accelerates unfolded protein response and mediates neointima formation.

Neointimal hyperplasia after vascular injury is a representative complication of restenosis. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is involved in the pathogenesis of vascular intimal hyperplasia. PARP16, a member of the poly(ADP-ribose) polymerases family, is correlated with the nuclear envelope and the ER. Here, we found that PERK and IRE1α are ADP-ribosylated by PARP16, and this might promote proliferation and migration of smooth muscle cells (SMCs) during the platelet-derived growth factor (PDGF)-BB stimulating. Using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) analysis, PARP16 was identified as a novel target gene for histone H3 lysine 4 (H3K4) methyltransferase SMYD3, and SMYD3 could bind to the promoter of Parp16 and increased H3K4me3 level to activate its host gene's transcription, which causes UPR activation and SMC proliferation. Moreover, knockdown either of PARP16 or SMYD3 impeded the ER stress and SMC proliferation. On the contrary, overexpression of PARP16 induced ER stress and SMC proliferation and migration. In vivo depletion of PARP16 attenuated injury-induced neointimal hyperplasia by mediating UPR activation and neointimal SMC proliferation. This study identified SMYD3-PARP16 is a novel signal axis in regulating UPR and neointimal hyperplasia, and targeting this axis has implications in preventing neointimal hyperplasia related diseases.

H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation.

[Figure: see text].

Histone methyltransferase Smyd3 is a new regulator for vascular senescence.

Endothelial cell senescence is one of the main risk factors contributing to vascular diseases. As increasing number of "epigenetic drugs" entering clinical trials, understanding the mechanism of epigenetic regulation in vascular aging has significant implications in finding targets to cure vascular diseases. However, the epigenetic regulation of endothelial senescence remains unclear. Based on the findings that increased protein level of histone H3 lysine 4 (H3K4) methyltransferase Smyd3 and elevated H3K4me3 modification happened in angiotensin II (Ang II)-induced senescence in rat endothelial cells, we are curious about whether and how Smyd3 can regulate endothelial senescence. We found that an increase of Smyd3 alone promoted senescence-associated phenotypes, while knockdown of Smyd3 blocked senescence in endothelial cells. Furthermore, Smyd3-specific inhibitor reversed vascular senescence-associated phenotypes at cellular level. Importantly, Ang II-induced vascular senescence can be greatly alleviated in Smyd3 knockout (KO) mice and those treated with Smyd3 inhibitor. Mechanistically, Smyd3 directly bound to the promoter region of Cdkn1a (coding for p21), then caused its increased H3K4me3 level and elevated gene expression, and ultimately gave rise to senescence-associated phenotypes. Intriguingly, Smyd3-mediated p21 upregulated expression also exists in human tissues of vascular disease, indicating it is probably an evolutionarily conserved mechanism in regulating vascular senescence. Thus, Smyd3 can act as a novel factor regulating endothelial senescence through transcriptionally promoting p21 expression. Blocking the Smyd3-p21 signaling axis may also have potential medical implications in treating diseases related to vascular aging.

Targeting JMJD3 histone demethylase mediates cardiac fibrosis and cardiac function following myocardial infarction.

Myocardial fibrosis is the pathological consequence of injury-induced fibroblastto-myofibroblast transition, resulting in increased stiffness and diminished cardiac function. Histone modification has been shown to play an important role in the pathogenesis of cardiac fibrosis. Here, we identified H3K27me3 demethylase JMJD3/KDM6B promotes cardiac fibrosis via regulation of fibrogenic pathways. Using neonatal rat cardiac fibroblasts (NRCF), we show that the expression of endogenous JMJD3 is induced by angiotensin II (Ang II), while the principle extracellular matrix (ECM) such as fibronectin, CTGF, collagen I and III are increased. We find that JMJD3 inhibition markedly enhances the suppressive mark (H3K27me3) at the beta (ß)-catenin promoter in activated cardiac fibroblasts, and then substantially decreases expression of fibrogenic gene. Both inhibition of ß-catenin-mediated transcription with ICG-001 and genetic loss of ß-catenin can prevent Ang II-induced ECM deposition. Most importantly, in vivo inhibition of JMJD3 rescues myocardial ischemia-induced cardiac fibrosis and cardiac dysfunction. Collectively, our findings are the first to report a novel role of histone demethylase JMJD3 in the pro-fibrotic cardiac fibroblast phenotype, pharmacological targeting of JMJD3 might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.

Jmjd3 regulates inflammasome activation and aggravates DSS-induced colitis in mice.

The intracellular NOD-like receptor nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) is a pivotal regulator of intestinal homeostasis through regulating a variety of inflammatory and autoimmune diseases. The Jumonji domain-containing 3 (Jmjd3) plays important role in inflammatory responses and thus has been proposed as a novel attractive epigenetic target for the treatment of inflammatory diseases. We here investigated whether targeting Jmjd3 regulates NLRP3 inflammasome during experimental colitis. Jmjd3 specific inhibitor GSK J4 or knocking down Jmjd3 significantly inhibited NLRP3 inflammasome activation in lipopolysaccharide (LPS) and nigericin-stimulated bone marrow-derived macrophages. Chromatin immunoprecipitation-PCR analysis validated that GSK J4 rescued the decreased repressive H3K27me3 recruitment level on the promotors of nuclear factor-erythroid 2-related factor 2 (Nrf2) in LPS plus nigericin-induced macrophages. Nrf2 knockdown abolished NLRP3 inflammasome activation. Notably, oral administration of GSK J4 attenuated the disease progression in dextran sodium sulfate-induced colitis mouse model, including reduced disease activity index, improved body weight, rescued bowel shortening and NLRP3 inflammasome activation. Overall, our study reveals that Jmjd3 is a potential epigenetic regulator for the treatment of inflammatory bowel disease (IBD), suggesting that Nrf2 is a potential target gene of Jmjd3 by mediating methylation status of trimethylated H3 lysine 27 (H3K27me3) in the promotor and is required for NLRP3 inflammasome activation, thereby providing the platform for potential future therapeutic interventions in IBD.

Solvation-Controlled Elastification and Shape-Recovery of Cellulose Nanocrystal-Based Aerogels.

Aerogels based on rod-like cellulose nanocrystals (CNCs) have been used in anisotropic materials, adsorbents and sensors, whereas they also suffer a low elasticity, leading to hard handling/processing in practical applications. Inspired by the sea cucumber, which transits from rigid to flexible when its cross-link network of collagen fibers is weakened by stiparin inhibitor, we cross-linked the CNCs with flexible poly ethylene glycol (PEG) to prepare an aerogel owning variable mechanical properties in different environments. This aerogel not only had a chemical-bond cross-link network, but also an H-bond one, which could be easily weakened by water. The results showed that the obtained CNC/PEG aerogel owned a high modulus of 0.80 MPa in a dry state and transited to an elastic state (modulus is 0.87 kPa) in a wet state. In the dry state, the shape change of the CNC/PEG aerogel could not recover when the strain was over 10%, when in the wet state the shape change could be reversible. Interestingly, the irreversible strain in the dry state could further transit to reversible in the wet state, and the wet aerogel could then transit back to rigid after freeze-drying. The mechanism study proved that this recovery came from the solvation-controlled weakening of the H-bond network between PEG and CNC. This work offered a simple but useful design of stimulation-response aerogels that can conduce to an elastification and shape recovery.

Hydrogen sulfide protects against DSS-induced colitis by inhibiting NLRP3 inflammasome.

Hydrogen sulfide (H2S), as the third gasotransmitter, has been shown to be effective in the prevention of inflammation. In addition, the NLRP3 inflammasome is a key player in the pathogenesis of dextran sulfate sodium (DSS)-induced colitis. Therefore, the aim of our research was to determine whether H2S exerts an anti-inflammatory effect on DSS-induced colitis by targeting NLRP3 inflammasome. Our data showed that DSS-induced colitis is attenuated by H2S, lessening the shortening of the colon lengths and colonic pathological damages. The cytokines TNF-α, IL-1ß, and IL-6 in colon samples were also significantly downregulated by H2S. Besides, H2S markedly suppressed the expression of NLRP3 and cleaved caspase-1 (p20) in colons from DSS-induced colitis mice. More importantly, CSE-/- mice were more susceptive to DSS-induced colitis when compared to wild-type (WT) mice. Our experimental results also suggested that H2S dose-dependently inhibits the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) by reducing the cleavage of caspase-1 and the secretion of IL-1ß. Furthermore, the inhibitory effect of H2S is due to a reduction in reactive oxygen species (ROS) generation and partly dependent on the disruption of nuclear erythroid 2-related factor-2 (Nrf2) activation. Collectively, our study confirms that H2S exerts its protective effect on DSS-induced mouse colitis at least partly by inhibiting the activation of NLRP3 inflammasome pathway.

Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

Vascular aging has a strong relationship with cardiovascular disease. Fos-related antigen 1 (Fra-1), also referred to as Fos-like antigen 1, is a transcription factor and has been reported to be involved in many pathologic processes. Here, we demonstrate that Fra-1 plays a critical role in angiotensin II (Ang II)-induced vascular senescence. Fra-1 expression is increased significantly in Ang II-induced rat aortic endothelial cell (RAEC) senescence and the arteries from Ang II-infused mice. Interestingly, silencing Fra-1 blocks Ang II-induced senescence phenotypes in RAECs, including decreased senescence-associated ß-galactosidase staining, and mitigated proliferation suppression and senescence-associated secretory phenotype. Further, knocking down Fra-1 inhibits vascular aging phenotypes in an Ang II-infused mice model. The up-regulated Fra-1 also exists in human atherosclerotic plaques and Ang II-induced vascular smooth muscle cells as well as in replicated senescence RAECs. Mechanistic studies reveal that Fra-1 preferentially associates with c-Jun and binds to the cyclin-dependent kinase inhibitor 1a (p21) and cyclin-dependent kinase inhibitor 2a (p16) promoter region, leading to elevated gene expression, which causes senescence-related phenotypes. In conclusion, our results identify that Fra-1 plays a novel and key role in promoting vascular aging by directly binding and transcriptionally activating p21 and p16 signaling, suggesting intervention of Fra-1 is a potential strategy for preventing aging-associated cardiovascular disorders.-Yang, D., Xiao, C., Long, F., Wu, W., Huang, M., Qu, L., Liu, X., Zhu, Y. Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis.

Cystathionine-γ-lyase (CSE), an enzyme associated with hydrogen sulfide (H2S) production, is an important endogenous regulator of inflammation. Jumonji domain-containing protein 3 (JMJD3) is implicated in the immune response and inflammation. Here, we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis (RA). Upregulated CSE and JMJD3 were identified in synovial fibroblasts (SFs) from RA patients as well as in the joints of arthritic mice. Knocking down CSE augmented inflammation in IL-1ß-induced SFs by increasing JMJD3 expression. In addition, CSE-/- mice with collagen-induced arthritis (CIA) developed severe joint inflammation and bone erosion. Conversely, overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1ß-treated SFs. Furthermore, JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1ß-treated SFs, mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes. GSK-J4 markedly attenuated the severity of arthritis in CIA mice. In conclusion, suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.

Critical role of histone demethylase Jumonji domain-containing protein 3 in the regulation of neointima formation following vascular injury.

Aims: Jumonji domain-containing protein 3 (JMJD3), also called lysine specific demethylase 6B (KDM6b), is an inducible histone demethylase which plays an important role in many biological processes, however, its function in vascular remodelling remains unknown. We aim to demonstrate that JMJD3 mediates vascular neointimal hyperplasia following carotid injury, and proliferation and migration in platelet-derived growth factor BB (PDGF-BB)-induced vascular smooth muscle cells (VSMCs). Methods and results: By using both genetic and pharmacological approaches, our study provides the first evidence that JMJD3 controls PDGF-BB-induced VSMCs proliferation and migration. Furthermore, our in vivo mouse and rat intimal thickening models demonstrate that JMJD3 is a novel mediator of neointima formation based on its mediatory effects on VSMCs proliferation, migration, and phenotypic switching. We further show that JMJD3 ablation by small interfering RNA or inhibitor GSK J4 can suppress the expression of NADPH oxidase 4 (Nox4), which is correlated with H3K27me3 enrichment around the gene promoters. Besides, deficiency of JMJD3 and Nox4 prohibits autophagic activation, and subsequently attenuates neointima and vascular remodelling following carotid injury. Above all, the increased expression of JMJD3 and Nox4 is further confirmed in human atherosclerotic arteries plaque specimens. Conclusions: JMJD3 is a novel factor involved in vascular remodelling. Deficiency of JMJD3 reduces neointima formation after vascular injury by a mechanism that inhibits Nox4-autophagy signalling activation, and suggesting JMJD3 may serve as a perspective target for the prevention and treatment of vascular diseases.

GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by abnormal inflammation, angiogenesis, and cartilage destruction. In RA, neoangiogenesis is an early and crucial event to promote the formation of pannus, causing further inflammatory cell infiltration. The transcription factor GATA4 is a critical regulator of cardiac differentiation-specific gene expression. We find that a higher level of GATA4 exists in synovium of rheumatoid arthritis (RA) patients, but the function of GATA4 in RA remains unclear. In the present study, IL-1ß induces inflammation in fibroblast-like synoviocytes (FLS) MH7A, which is accompanied with the increased expression of GATA4 and VEGF production. Through application of GATA4 loss-of-function assays, we confirm the requirement of GATA4 expression for inflammation induced by IL-1ß in FLS. In addition, we demonstrate for the first time that GATA4 plays key roles in regulating VEGF secretion from RA FLS to promote cellular proliferation, induce cell migration, and angiogenic tube formation of endothelial cells. GATA4 induces the angiogenic factors VEGFA and VEGFC, by directly binding to the promoter and enhancing transcription. The knockdown of GATA4 attenuates the development of collagen-induced arthritis (CIA) and prevents RA-augmented angiogenesis in vivo, which are accompanied with decreased VEGF level. These results reveal a previously unrecognized function for GATA4 as a regulator of RA angiogenesis and we provide experimental data validating the therapeutic target of GATA4 in RA mice.