Dysregulated RBM24 phosphorylation impairs APOE translation underlying psychological stress-induced cardiovascular disease.

Psychological stress contributes to cardiovascular disease (CVD) and sudden cardiac death, yet its molecular basis remains obscure. RNA binding protein RBM24 plays a critical role in cardiac development, rhythm regulation, and cellular stress. Here, we show that psychological stress activates RBM24 S181 phosphorylation through eIF4E2-GSK3β signaling, which causally links psychological stress to CVD by promoting APOE translation (apolipoprotein E).

Lysosomal membrane protein TMEM106B modulates hematopoietic stem and progenitor cell proliferation and differentiation by regulating LAMP2A stability.

Hematopoietic stem and progenitor cells (HSPCs) are successfully employed for hematological transplantations, and impaired HSPC function causes hematological diseases and aging. HSPCs maintain the lifelong homeostasis of blood and immune cells through continuous self-renewal and maintenance of the multilineage differentiation potential. TMEM106B is a transmembrane protein localized on lysosomal membranes and associated with neurodegenerative and cardiovascular diseases; however, its roles in HSPCs and hematopoiesis are unknown.

14-3-3ε/YWHAE regulates the transcriptional expression of cardiac sodium channel Na1.5.

Background: Cardiac voltage-gated sodium channel alpha subunit 5 (Na1.5) encoded by SCN5A is associated with arrhythmia disorders. However, the molecular mechanism underlying Na1.

Specifies Hemangioblasts at the Top of Regulatory Hierarchy via and mTOR-S6K-Emp2-ERK Signaling.

Background: Hemangioblasts are mesoderm-derived multipotent stem cells for differentiation of all hematopoietic and endothelial cells in the circulation system. However, the underlying molecular mechanism is poorly understood.

Methods: CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (type II CRISPR RNA-guided endonuclease) editing was used to develop and knockout zebra fish.

AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling.

Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1 mice, and β-aminopropionitrile-treated mice).

Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1.

Background: Skeletal muscle atrophy is a common condition without a pharmacologic therapy. AGGF1 encodes an angiogenic factor that regulates cell differentiation, proliferation, migration, apoptosis, autophagy and endoplasmic reticulum stress, promotes vasculogenesis and angiogenesis and successfully treats cardiovascular diseases. Here, we report the important role of AGGF1 in the pathogenesis of skeletal muscle atrophy and attenuation of muscle atrophy by AGGF1.

Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and liver fibrosis through the IGF1R/EGR1/PDGF-BB signaling pathway.

Background: Liver fibrogenesis is orchestrated by the paracrine signaling interaction between several resident cell types regulating the activation of hepatic stellate cells (HSCs). However, the molecular mechanisms underlying paracrine regulation are largely unknown. The aim of this study is to elucidate the role of Ninjurin2 in the crosstalk between hepatocytes and HSCs and better understand the implications of Ninjurin2 in liver fibrosis.

NINJ2 deficiency inhibits preadipocyte differentiation and promotes insulin resistance through regulating insulin signaling.

Objective: Genetic variants in ninjurin-2 (NINJ2; nerve injury-induced protein 2) confer risk of ischemic strokes and coronary artery disease as well as endothelial activation and inflammation. However, little is known about NINJ2's in vivo functions and underlying mechanisms.

Methods: The phenotypes of NINJ2 knockout mice were analyzed, and mechanisms of NINJ2 that regulate body weight, insulin resistance, and glucose homeostasis and lipogenesis were investigated in vivo and in vitro.

Two Novel Functional Mutations in Promoter Region of Gene Associated with Atrial Fibrillation.

The sodium voltage-gated channel beta subunit 3 (SCN3B) plays a crucial role in electrically excitable cells and conduction tissue in the heart. Some previous studies have established that genetic modification in sodium voltage-channel genes encoding for the cardiac β-subunits, such as SCN1B, SCN2B, SCN3B and SCN4B, can result in atrial fibrillation (AF). In the current study, we identified two rare variants in 5′UTR (NM_018400.

Gene therapy targeting protein trafficking regulator MOG1 in mouse models of Brugada syndrome, arrhythmias, and mild cardiomyopathy.

Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. encodes cardiac sodium channel Na1.5 and causes 25 to 30% of BrS cases.

Identification and characterization of a special type of subnuclear structure: AGGF1-coated paraspeckles.

AGGF1 is an angiogenic factor with G-Patch and FHA domains 1 described by our group. Gain-of-function mutations in AGGF1 cause Klippel-Trenaunay syndrome, whereas somatic loss-of-function mutations cause cancer. Paraspeckles are small membraneless subnuclear structures with a diameter of 0.

Mog1 deficiency promotes cardiac contractile dysfunction and isoproterenol-induced arrhythmias associated with cardiac fibrosis and Cx43 remodeling.

Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes.

Hyperlipidemia patients carrying LDLR splicing mutation c.1187-2A>G respond favorably to rosuvastatin and PCSK9 inhibitor evolocumab.

Mutations in the LDL receptor gene LDLR cause familial hypercholesterolemia (FH); however, the pharmacogenomics of specific LDLR mutations remains poorly understood. The goals of this study were to identify the genetic cause of a three-generation Chinese family affected with autosomal dominant FH, and to investigate the response of FH patients in the family to statin and evolocumab. Whole exome sequencing of the FH family with four patients and six unaffected members identified a heterozygous splicing mutation (c.

Angiogenic factor AGGF1 blocks neointimal formation after vascular injury via interaction with integrin α7 on vascular smooth muscle cells.

Angiogenic factor AGGF1 (AngioGenic factor with G-patch and FHA (Forkhead-Associated) domain 1) blocks neointimal formation (formation of a new or thickened layer of arterial intima) after vascular injury by regulating phenotypic switching of vascular smooth muscle cells (VSMCs). However, the AGGF1 receptor on VSMCs and the underlying molecular mechanisms of its action are unknown. In this study, we used functional analysis of serial AGGF1 deletions to reveal the critical AGGF1 domain involved in VSMC phenotypic switching.

Identification and functional analysis of two new de novo KCNMA1 variants associated with Liang-Wang syndrome.

Aim: Loss-of-function KCNMA1 variants cause Liang-Wang syndrome (MIM #618729), a newly identified multiple malformation syndrome with a broad spectrum of developmental and neurological phenotypes. However, the full spectrum of clinical features and underlying pathogenic mechanisms need full elucidation.

Methods: Exome sequencing was used to identify pathogenic variants.

Functional rare variant in a binding site in gene increases the risk of coronary artery disease.

Objective: regulates activation of vascular endothelial cells, and genome-wide association studies showed that variants in confer risk to stroke. However, whether variants in are associated with coronary artery disease (CAD) is unknown.

Methods: We genotyped rs34166160 in in two independent Chinese GeneID populations which included 2,794 CAD cases and 4,131 controls, and performed genetics association studies.

Mechanistic insights into the interaction of cardiac sodium channel Na1.5 with MOG1 and a new molecular mechanism for Brugada syndrome.

Background: Mutations in cardiac sodium channel Na1.5 cause Brugada syndrome (BrS). MOG1 is a chaperone that binds to Na1.

Genetic association analysis between IL9 and coronary artery disease in a Chinese Han population.

Interleukin-9 (IL-9) plays important role in coronary artery disease (CAD). However, the exact relationship between them is not explored yet. Here, four tag SNPs covering IL9 (rs31563, rs2069868, rs2069870 and rs31564) were selected to conduct case-control association analyses in a total of 3704 individuals from Chinese Han population (1863 CAD vs 1841 control).

Role of epigenetic m A RNA methylation in vascular development: mettl3 regulates vascular development through PHLPP2/mTOR-AKT signaling.

N -methyladenosine (m6A) methylation is the most prevalent RNA modification, and it emerges as an important regulatory mechanism of gene expression involved in many cellular and biological processes. However, the role of m A methylation in vascular development is not clear. The m A RNA methylation is regulated by dynamic interplay among methyltransferases, binding proteins, and demethylases.

Endothelial cell metabolic memory causes cardiovascular dysfunction in diabetes.

Aims: The aim of this study was to identify the molecular mechanism for hyperglycaemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes.

Methods And Results: Hyperglycaemia induces increased nuclear factor-κB (NF-κB) signalling, up-regulation of miR-27a-3p, down-regulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-β (TGF-β) signalling, down-regulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction. Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs.

Angiogenic factor AGGF1 acts as a tumor suppressor by modulating p53 post-transcriptional modifications and stability via MDM2.

Angiogenesis factors are widely known to promote tumor growth by increasing tumor angiogenesis in the tumor microenvironment, however, little is known whether their intracellular function is involved in tumorigenesis. Here we show that AGGF1 acts as a tumor suppressor by regulating p53 when acting inside tumor cells. AGGF1 antagonizes MDM2 function to inhibit p53 ubiquitination, increases the acetylation, phosphorylation, stability and expression levels of p53, activates transcription of p53 target genes, and regulates cell proliferation, cell cycle, and apoptosis.

Splice variants of lncRNA RNA ANRIL exert opposing effects on endothelial cell activities associated with coronary artery disease.

Each gene typically has multiple alternatively spliced transcripts. Different transcripts are assumed to play a similar biological role; however, some transcripts may simply lose their function due to loss of important functional domains. Here, we show that two different transcripts of lncRNA gene associated with coronary artery disease (CAD) play antagonizing roles against each other.

ADTRP regulates TFPI expression via transcription factor POU1F1 involved in coronary artery disease.

Genomic variants in both ADTRP and TFPI genes are associated with risk of coronary artery disease (CAD). ADTRP regulates TFPI expression and endothelial cell functions involved in the initiation of atherosclerotic CAD. ADTRP also specifies primitive myelopoiesis and definitive hematopoiesis by upregulating TFPI expression.