Inhibition of MRTF-A Ameliorates Pathological Remodeling of the Pressure-loaded Right Ventricle.

Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions where RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor - beta-1 (TGF-ß1) signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. Here we investigated whether MRTF-A inhibition improves RV pro-fibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure-loading. Rats were assigned into either 1) sham or 2) PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75mg/kg in a subset of PAB animals. Echocardiography and pressure-volume hemodynamics were obtained at a terminal experiment 6-weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and pro-fibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, while diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ). We also confirmed using a second-generation MRTF-A inhibitor CCG-203971 that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to TGF-ß1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of pro-fibrotic signaling in RV pressure-loading, and as potential targets to improve RV pro-fibrotic remodeling.

Single-nucleus analysis reveals microenvironment-specific neuron and glial cell enrichment in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complicated neurodegenerative disease. Neuron-glial cell interactions are an important but not fully understood process in the progression of AD. We used bioinformatic methods to analyze single-nucleus RNA sequencing (snRNA-seq) data to investigate the cellular and molecular biological processes of AD. METHOD: snRNA-seq data were downloaded from Gene Expression Omnibus (GEO) datasets and reprocessed to identify 240,804 single nuclei from healthy controls and patients with AD. The cellular composition of AD was further explored using Uniform Manifold Approximation and Projection (UMAP). Enrichment analysis for the functions of the DEGs was conducted and cell development trajectory analyses were used to reveal underlying cell fate decisions. iTALK was performed to identify ligand-receptor pairs among various cell types in the pathological ecological microenvironment of AD. RESULTS: Six cell types and multiple subclusters were identified based on the snRNA-seq data. A subcluster of neuron and glial cells co-expressing lncRNA-SNHG14, myocardin-related transcription factor A (MRTFA), and MRTFB was found to be more abundant in the AD group. This subcluster was enriched in mitogen-activated protein kinase (MAPK)-, immune-, and apoptosis-related pathways. Through molecular docking, we found that lncRNA-SNHG14 may bind MRTFA and MRTFB, resulting in an interaction between neurons and glial cells. CONCLUSIONS: The findings of this study describe a regulatory relationship between lncRNA-SNHG14, MRTFA, and MRTFB in the six main cell types of AD. This relationship may contribute to microenvironment remodeling in AD and provide a theoretical basis for a more in-depth analysis of AD.

The Mediator Med23 controls a transcriptional switch for muscle stem cell proliferation and differentiation in muscle regeneration.

Muscle stem cells (MuSCs) contribute to a robust muscle regeneration process after injury, which is highly orchestrated by the sequential expression of multiple key transcription factors. However, it remains unclear how key transcription factors and cofactors such as the Mediator complex cooperate to regulate myogenesis. Here, we show that the Mediator Med23 is critically important for MuSC-mediated muscle regeneration. Med23 is increasingly expressed in activated/proliferating MuSCs on isolated myofibers or in response to muscle injury. Med23 deficiency reduced MuSC proliferation and enhanced its precocious differentiation, ultimately compromising muscle regeneration. Integrative analysis revealed that Med23 oppositely impacts Ternary complex factor (TCF)-targeted MuSC proliferation genes and myocardin-related transcription factor (MRTF)-targeted myogenic differentiation genes. Consistently, Med23 deficiency decreases the ETS-like transcription factor 1 (Elk1)/serum response factor (SRF) binding at proliferation gene promoters but promotes MRTF-A/SRF binding at myogenic gene promoters. Overall, our study reveals the important transcriptional control mechanism of Med23 in balancing MuSC proliferation and differentiation in muscle regeneration.

Myeloid sarcoma with RBM15::MRTFA (MKL1) mimicking vascular neoplasm.

Extramedullary involvement of acute myeloid leukemia (AML), aka myeloid sarcoma, is a rare phenomenon in acute megakaryoblastic leukemia with RBM15:: MRTFA(MKL1) fusion, which might mimic non-hematologic malignancies. A 7-month-old infant presented with leukocytosis, hepatosplenomegaly, multiple lymphadenopathies, and a solid mass in the right thigh. Initially, the patient was diagnosed with a malignant vascular tumor regarding the expression of vascular markers from the biopsy of the right thigh lesion that was performed after the inconclusive bone marrow biopsy. The second bone marrow biopsy, which was performed due to the partial response to sarcoma treatment, showed hypercellular bone marrow with CD34 and CD61-positive spindle cell infiltration and > 20% basophilic blasts with cytoplasmic blebs. RNA sequencing of soft tissue biopsy revealed the presence of RBM15::MRTFA(MKL1) fusion. Based on these findings, myeloid sarcoma/AML with RBM15::MRTFA(MKL1) fusion diagnosis was made. AML with RBM15::MRTFA(MKL1) fusion can initially present as extramedullary lesions and might cause misdiagnosis of non-hematologic malignancies.

Multiplex Imaging Reveals Novel Subcellular, Microenvironmental, and Racial Patterns of MRTFA/B Activation in Invasive Breast Cancers and Metastases.

Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin related transcription factors A and B (MRTFA/B) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we used a combination of multiplexed immunofluorescence and bioinformatics analyses to show that MRTFA/B are concurrently activated in tumor cells, but they show distinct patterns of expression across different histological subtypes and in the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen presenting cells (APCs) and its expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR). These results provide unique insights into how MRTFA and MRTFB can promote metastasis in human cancer, into the racial disparities of their expression patterns, and their function within the complex breast cancer TME.

Gas6-Axl Signaling Induces SRF/MRTF-A Gene Transcription via MICAL2.

MICAL2 is an actin-regulatory protein that functions through redox modification of actin. Nuclear localized MICAL2 triggers the disassembly of nuclear actin, which subsequently leads to nuclear retention of the actin-binding transcriptional coregulator myocardin-related transcription factor-A (MRTF-A), which leads to the activation of serum response factor (SRF)/MRTF-A-dependent gene transcription. In this study, we show that the secreted signaling protein GAS6 (growth-arrest specific 6) and its cognate receptor Axl, a transmembrane tyrosine kinase, also induce the activation of SRF/MRTF-A and their downstream target genes. We find that serum-induced SRF/MRTF-A-dependent gene expression can be blocked, in part, by the inhibition of Axl signaling. Furthermore, we find that Gas6/Axl-induced SRF/MRTF-A-dependent transcription is dependent on MICAL2. Gas6/Axl promotes cell invasion, which is blocked by MICAL2 knockdown, suggesting that MICAL2 promotes cytoskeletal effects of the Gas6/Axl pathway. We find that Gas/6/Axl signaling promotes the nuclear localization of MICAL2, which may contribute to the ability of Gas6/SRF to augment SRF/MRTF-A-dependent gene transcription. The physiological significance of the Gas6/Axl-MICAL2 signaling pathway described here is supported by the marked gene expression correlation across a broad array of different cancers between MICAL2 and Axl and Gas6, as well as the coexpression of these genes and the known SRF/MRTF-A target transcripts. Overall, these data reveal a new link between Gas6/Axl and SRF/MRTF-A-dependent gene transcription and link MICAL2 as a novel effector of the Gas6/Axl signaling pathway.

Pharmacogenomic Analyses Implicate B Cell Developmental Status and MKL1 as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy.

Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG+ cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.

MRTF-A/SRF signaling suppresses invasion of oral squamous cell carcinoma.

BACKGROUND: Serum response factor (SRF) and myocardial-associated transcription factor-A (MRTF-A) had different regulatory effects on the tumorigenesis and development in different cancers. However, the role of MRTF-A/SRF in oral squamous cell carcinoma (OSCC) remains to be determined. METHODS: CCK-8 assay, cell scratch experiment, and transwell invasion assay were conducted to investigate the effects of MRTF-A/SRF on biological behavior of OSCC cells. The expression pattern and prognostic value of MRTF-A/SRF in OSCC were analyzed based on cBioPortal website and TCGA database. Protein-protein interaction network was visualized to identify protein functions. Go and KEGG pathway analyses were performed to investigate related pathways. The effect of MRTF-A/SRF on epithelial-mesenchymal transformation (EMT) of OSCC cells was explored by western blot assay. RESULTS: Overexpression of MRTF-A/SRF inhibited the proliferation, migration, and invasion of OSCC cells in vitro. High expression of SRF was related to better prognosis of OSCC patients on hard palate, alveolar ridge, and oral tongue. Besides, overexpression of MRTF-A/SRF inhibited the EMT of OSCC cells. CONCLUSION: SRF was closely related to the prognosis of OSCC. High expression of SRF and its co-activator MRTF-A inhibited proliferation, migration, and invasion of OSCC cells in vitro, possibly via EMT suppression.

The effect of allyl isothiocyanate on chondrocyte phenotype is matrix stiffness-dependent: Possible involvement of TRPA1 activation.

Osteoarthritis (OA) is a chronic joint disease with increasing prevalence. Chondrocytes (CHs) are highly differentiated end-stage cells with a secretory phenotype that keeps the extracellular matrix (ECM) balanced and the cartilage environment stable. Osteoarthritis dedifferentiation causes cartilage matrix breakdown, accounting for one of the key pathogenesis of osteoarthritis. Recently, the activation of transient receptor potential ankyrin 1 (TRPA1) was claimed to be a risk factor in osteoarthritis by causing inflammation and extracellular matrix degradation. However, the underlying mechanism is still unknown. Due to its mechanosensitive property, we speculated that the role of TRPA1 activation during osteoarthritis is matrix stiffness-dependent. In this study, we cultured the chondrocytes from patients with osteoarthritis on stiff vs. soft substrates, treated them with allyl isothiocyanate (AITC), a transient receptor potential ankyrin 1 agonist, and compared the chondrogenic phenotype, containing cell shape, F-actin cytoskeleton, vinculin, synthesized collagen profiles and their transcriptional regulatory factor, and inflammation-related interleukins. The data suggest that allyl isothiocyanate treatment activates transient receptor potential ankyrin 1 and results in both positive and harmful effects on chondrocytes. In addition, a softer matrix could help enhance the positive effects and alleviate the harmful ones. Thus, the effect of allyl isothiocyanate on chondrocytes is conditionally controllable, which could be associated with transient receptor potential ankyrin 1 activation, and is a promising strategy for osteoarthritis treatment.

Knockdown SENP1 Suppressed the Angiogenic Potential of Mesenchymal Stem Cells by Impacting CXCR4-Regulated MRTF-A SUMOylation and CCN1 Expression.

The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and prevented its translocation into the nucleus, leading to downregulation of the cytokine and angiogenic factor CCN1, which significantly impacted MSC-mediated angiogenesis and cell migration. Further studies showed that SENP1 knockdown also suppressed the expression of a chemokine receptor CXCR4, and overexpression of CXCR4 could partially abrogate MRTF-A SUMOylation and reestablish the CCN1 level. Mutation analysis confirmed that SUMOylation occurred on three lysine residues (Lys-499, Lys-576, and Lys-624) of MRTF-A. In addition, SENP1 knockdown abolished the synergistic co-activation of CCN1 between MRTF-A and histone acetyltransferase p300 by suppressing acetylation on histone3K9, histone3K14, and histone4. These results revealed an important signaling pathway to regulate MSC differentiation and angiogenesis by MRTF-A SUMOylation involving cytokine/chemokine activities mediated by CCN1 and CXCR4, which may potentially impact a variety of cellular processes such as revascularization, wound healing, and progression of cancer.

MRTF-A alleviates myocardial ischemia reperfusion injury by inhibiting the inflammatory response and inducing autophagy.

Myocardin-related transcription factor A (MRTF-A) has an inhibitory effect on myocardial infarction; however, the mechanism is not clear. This study reveals the mechanism by which MRTF-A regulates autophagy to alleviate myocardial infarct-mediated inflammation, and the effect of silent information regulator 1 (SIRT1) on the myocardial protective effect of MRTF-A was also verified. MRTF-A significantly decreased cardiac damage induced by myocardial ischemia. In addition, MRTF-A decreased NLRP3 inflammasome activity, and significantly increased the expression of autophagy protein in myocardial ischemia tissue. Lipopolysaccharide (LPS) and 3-methyladenine (3-MA) eliminated the protective effects of MRTF-A. Furthermore, simultaneous overexpression of MRTF-A and SIRT1 effectively reduced the injury caused by myocardial ischemia; this was associated with downregulation of inflammatory factor proteins and when upregulation of autophagy-related proteins. Inhibition of SIRT1 activity partially suppressed these MRTF-A-induced cardioprotective effects. SIRT1 has a synergistic effect with MRTF-A to inhibit myocardial ischemia injury through reducing the inflammation response and inducing autophagy.

Identification of ligustrazine-based analogs of piperlongumine as potential anti-ischemic stroke agents.

Piper longum has a specific aroma and spicy taste. In addition to edible value, current studies have shown that piper longum also has pharmacological activities such as anti-platelet aggregation, anti-inflammation, anti-cancer, anti-diabetes and anti-depression. Piperlongumine is an alkaloid isolated from Piper longum. Based on our previous studies, four Piperlongumine analogs were synthesized, and their anti-platelet aggregation activities were evaluated. Among them, compound 8 has the strongest anti-platelet aggregation activity. Therefore, compound 8 was docked with stroke-related protein targets, and it was found that compound 8 had good binding affinity to MRTF-A complex and Bcl-2. Through animal experiments, it was found that compound 8 could significantly improve the pathological damage of brain tissue after ischemia and could increase the expression of MRTF-A and Bcl-2 in cerebral cortex in rats. These results suggest that compound 8 may have a good inhibitory effect on apoptosis and tissue structurel disorders induced by cerebral ischemia-reperfusion, so as to reduce the injury caused by ischemic stroke.

WAVE2 Is a Vital Regulator in Myogenic Differentiation of Progenitor Cells through the Mechanosensitive MRTFA-SRF Axis.

Skeletal myogenesis is an intricate process involving the differentiation of progenitor cells into myofibers, which is regulated by actin cytoskeletal dynamics and myogenic transcription factors. Although recent studies have demonstrated the pivotal roles of actin-binding proteins (ABPs) as mechanosensors and signal transducers, the biological significance of WAVE2 (Wiskott-Aldrich syndrome protein family member 2), an ABP essential for actin polymerization, in myogenic differentiation of progenitor cells has not been investigated. Our study provides important insights into the regulatory roles played by WAVE2 in the myocardin-related transcription factor A (MRTFA)-serum response factor (SRF) signaling axis and differentiation of myoblasts. We demonstrate that WAVE2 expression is induced during myogenic differentiation and plays a pivotal role in actin cytoskeletal remodeling in C2C12 myoblasts. Knockdown of WAVE2 in C2C12 cells reduced filamentous actin levels, increased globular actin accumulation, and impaired the nuclear translocation of MRTFA. Furthermore, WAVE2 depletion in myoblasts inhibited the expression and transcriptional activity of SRF and suppressed cell proliferation in myoblasts. Consequently, WAVE2 knockdown suppressed myogenic regulatory factors (i.e., MyoD, MyoG, and SMYD1) expressions, thereby hindering the differentiation of myoblasts. Thus, this study suggests that WAVE2 is essential for myogenic differentiation of progenitor cells by modulating the mechanosensitive MRTFA-SRF axis.

MBNL1 and MRTF-A form a positive feedback loop in regulating the migration of esophageal cancer cells.

Background: Esophageal cancer is a serious human health threat with increasing incidence and poor prognosis. This study explored the effects and mechanisms of MBNL1 and MRTF-A in the migration of esophageal cancer cells. Materials and Methods: The analysis of relevant sequencing data showed the impact of MBNL1 expression on esophageal cancer. Western blotting and real-time polymerase chain reaction (PCR) were used to explore the expression levels MBNL1 and MRTF-A. Wound healing and Transwell invasion assays evaluated cancer cell migration. Molecular mechanisms were explored by RNA immunoprecipitation and luciferase and chromatin immunoprecipitation assays. Results: MBNL1 is highly expressed in esophageal cancer and associated with poor prognosis. MBNL1 promotes the migration of esophageal KYSE150 cancer cells by stabilizing MRTF-A mRNA. Moreover, MRTF-A activates transcription of the MBNL1 promoter, resulting in the upregulation of MBNL1 expression. Conclusions: MBNL1 may be an important regulator of metastasis and a factor associated with poor prognosis in esophageal cancer. Positive feedback regulation between MBNL1 and MRTF-A may be a potential therapeutic target for interrupting esophageal cancer migration. Generally, our results provide a theoretical basis for elucidating the molecular mechanisms of esophageal cancer cell migration.

Cell-cell contacts via N-cadherin induce a regulatory renin secretory phenotype in As4.1 cells.

The lack of a clonal renin-secreting cell line has greatly hindered the investigation of the regulatory mechanisms of renin secretion at the cellular, biochemical, and molecular levels. In the present study, we investigated whether it was possible to induce phenotypic switching of the renin-expressing clonal cell line As4.1 from constitutive inactive renin secretion to regulated active renin secretion. When grown to postconfluence for at least two days in media containing fetal bovine serum or insulin-like growth factor-1, the formation of cell-cell contacts via N-cadherin triggered downstream cellular signaling cascades and activated smooth muscle-specific genes, culminating in phenotypic switching to a regulated active renin secretion phenotype, including responding to the key stimuli of active renin secretion. With the use of phenotype-switched As4.1 cells, we provide the first evidence that active renin secretion via exocytosis is regulated by phosphorylation/dephosphorylation of the 20 kDa myosin light chain. The molecular mechanism of phenotypic switching in As4.1 cells described here could serve as a working model for full phenotypic modulation of other secretory cell lines with incomplete phenotypes.

Interrelation between α-Cardiac Actin Treadmilling and Myocardin-Related Transcription Factor-A Nuclear Shuttling in Cardiomyocytes.

Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics that are controlled by Rho GTPases. SRF is a ubiquitous transcription factor strongly expressed in muscular tissues. The depletion of SRF in the adult mouse heart leads to severe dilated cardiomyopathy associated with the down-regulation of target genes encoding sarcomeric proteins including α-cardiac actin. The regulatory triad, composed of SRF, its cofactor MRTFA and actin, plays a major role in the coordination of the nuclear transcriptional response to adapt actin filament dynamics associated with changes in cell shape, and contractile and migratory activities. Most of the knowledge on the regulation of the SRF-MRTF-Actin axis has been obtained in non-muscle cells with α-actin and smooth muscle cells with α-smooth actin. Here, we visualized for the first time by a time-lapse video, the nucleocytoplasmic shuttling of MRTFA induced by serum or pro-hypertrophic agonists such as angiotensin II, phenylephrine and endothelin-1, using an MRTFA-GFP adenovirus in cultures of neonatal rat cardiomyocytes. We showed that an inhibitor of the RhoA/ROCK signaling pathway leads to an α-cardiac actin polymerization disruption and inhibition of MRTFA nucleocytoplasmic shuttling. Moreover, inhibition of the PI3K/Akt signaling pathway also prevents the entry of MRTFA into the nuclei. Our findings point out a central role of the SRF-MRTFA-actin axis in cardiac remodeling.

SREBP1 regulates Lgals3 activation in response to cholesterol loading.

Aberrant smooth muscle cell (SMC) plasticity is etiological to vascular diseases. Cholesterol induces SMC phenotypic transition featuring high LGALS3 (galectin-3) expression. This proatherogenic process is poorly understood for its molecular underpinnings, in particular, the mechanistic role of sterol regulatory-element binding protein-1 (SREBP1), a master regulator of lipid metabolism. Herein we show that cholesterol loading stimulated SREBP1 expression in mouse, rat, and human SMCs. SREBP1 positively regulated LGALS3 expression (and vice versa), whereas Krüppel-like factor-15 (KLF15) acted as a negative regulator. Both bound to the Lgals3 promoter, yet at discrete sites, as revealed by chromatin immunoprecipitation-qPCR and electrophoretic mobility shift assays. SREBP1 and LGALS3 each abated KLF15 protein, and blocking the bromo/extraterminal domain-containing proteins (BETs) family of acetyl-histone readers abolished cholesterol-stimulated SREBP1/LGALS3 protein production. Furthermore, silencing bromodomain protein 2 (BRD2; but not other BETs) reduced SREBP1; endogenous BRD2 co-immunoprecipitated with SREBP1's transcription-active domain, its own promoter DNA, and that of L gals 3. Thus, results identify a previously uncharacterized cholesterol-responsive dyad-SREBP1 and LGALS3, constituting a feedforward circuit that can be blocked by BETs inhibition. This study provides new insights into SMC phenotypic transition and potential interventional targets.

p38MAPK silencing attenuates scar proliferation after cleft palate repair surgery in rats via MRTF-A/SRF pathway.

Scarring is the primary factor of maxilla growth restriction among people who have undergone cleft palate repair surgery. p38 mitogen-activated protein kinase (p38MAPK) promotes fibrosis in a variety of organs. However, its role in post-surgery scarring on the hard palate has not been fully understood. This study is designed to investigate the role of p38MAPK in scar formation and maxilla growth of rats. We removed the mucosa on the hard palate of rats and applied the p38MAPK silencing adenovirus vector on it two weeks after surgery. Then the scarring tissue and maxilla growth were evaluated by histological and morphological examination. The effect of p38MAPK silencing on scarring-related genes in fibroblasts was also studied. We found that local injection of Ad-p38MAPK-1 in vivo effectively reduces the expression of p38MAPK and scarring-related proteins and weakens the impact of scarring on the width of the hard palate. Mechanistically, p38MAPK silencing inhibits the expression of α-smooth muscle actin (α-SMA) via mediating the production and nuclear localization of myocardin-related transcription factor A (MRTF-A) in fibroblasts. These results reveal a molecular pathway of scar formation involving p38MAPK/MRTF-A stimulation and support targeting p38MAPK as a potentially effective treatment for post-surgery scarring on the hard palate.

MRTF-A-mediated protection against amyloid-ß-induced neuronal injury correlates with restoring autophagy via miR-1273g-3p/mTOR axis in Alzheimer models.

Myocardia-Related Transcription Factors-A (MRTF-A), which is enriched in the hippocampus and cerebral cortex, has been shown to have a protective function against ischemia hypoxia-induced neuronal apoptosis. However, the function of MRTF-A on ß-amyloid peptide (Aß)-induced neurotoxicity and autophagy dysfunction in Alzheimer's disease is still unclear. This study shows that the expression of MRTF-A in the hippocampus of Tg2576 transgenic mice is reduced, and the overexpression of MRTF-A mediated by lentiviral vectors carrying MRTF-A significantly reduces the accumulation of hippocampal ß-amyloid peptide and reduces cognition defect. Overexpression of MRTF-A inhibits neuronal apoptosis, increases the protein levels of microtubule-associated protein 1 light chain 3-II (MAP1LC3/LC3-II) and Beclin1, reduces the accumulation of SQSTM1/p62 protein, and promotes autophagosomes-Lysosomal fusion in vivo and in vitro. Microarray analysis and bioinformatics analysis show that MRTF-A reverses Aß-induced autophagy impairment by up-regulating miR-1273g-3p level leading to negative regulation of the mammalian target of rapamycin (mTOR), which is confirmed in Aß1-42-treated SH-SY5Y cells. Further, overexpression of MRTF-A reduces Aß1-42-induced neuronal apoptosis. And the effect was abolished by miR-1273g-3p inhibitor or MHY1485 (mTOR agonist), indicating that the protection of MRTF-A on neuronal damage is through targeting miR-1273g-3p/mTOR axis. Targeting this signaling may be a promising approach to protect against Aß-induced neuronal injury.

Interdependence of Angiogenesis and Arteriogenesis in Development and Disease.

The structure of arterial networks is optimized to allow efficient flow delivery to metabolically active tissues. Optimization of flow delivery is a continuous process involving synchronization of the structure and function of the microcirculation with the upstream arterial network. Risk factors for ischemic cardiovascular diseases, such as diabetes mellitus and hyperlipidemia, adversely affect endothelial function, induce capillary regression, and disrupt the micro- to macrocirculation cross-talk. We provide evidence showing that this loss of synchronization reduces arterial collateral network recruitment upon arterial stenosis, and the long-term clinical outcome of current revascularization strategies in these patient cohorts. We describe mechanisms and signals contributing to synchronized growth of micro- and macrocirculation in development and upon ischemic challenges in the adult organism and identify potential therapeutic targets. We conclude that a long-term successful revascularization strategy should aim at both removing obstructions in the proximal part of the arterial tree and restoring "bottom-up" vascular communication.