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48


An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract

Yamaguchi, Naoko; Chang, Ernest W; Lin, Ziyan; Shekhar, Akshay; Bu, Lei; Khodadadi-Jamayran, Alireza; Tsirigos, Aristotelis; Cen, Yiyun; Phoon, Colin K L; Moskowitz, Ivan P; Park, David S
BACKGROUND/UNASSIGNED:Conotruncal defects due to developmental abnormalities of the outflow tract (OFT) are an important cause of cyanotic congenital heart disease. Dysregulation of transcriptional programs tuned by NKX2-5 (NK2 homeobox 5), GATA6 (GATA binding protein 6), and TBX1 (T-box transcription factor 1) have been implicated in abnormal OFT morphogenesis. However, there remains no consensus on how these transcriptional programs function in a unified gene regulatory network within the OFT. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSIONS/UNASSIGNED:Our results using human and mouse models reveal an essential gene regulatory network of the OFT that requires an anterior second heart field enhancer to link GATA6 with NKX2-5-dependent rotation and septation gene programs.
PMID: 37772400
ISSN: 1524-4539
CID: 5606412

DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress

Yepuri, Gautham; Ramirez, Lisa M; Theophall, Gregory G; Reverdatto, Sergei V; Quadri, Nosirudeen; Hasan, Syed Nurul; Bu, Lei; Thiagarajan, Devi; Wilson, Robin; Díez, Raquel López; Gugger, Paul F; Mangar, Kaamashri; Narula, Navneet; Katz, Stuart D; Zhou, Boyan; Li, Huilin; Stotland, Aleksandr B; Gottlieb, Roberta A; Schmidt, Ann Marie; Shekhtman, Alexander; Ramasamy, Ravichandran
Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
PMCID:10616211
PMID: 37903764
ISSN: 2041-1723
CID: 5610492

mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy

Li, Fengqiao; Zhang, Xue-Qing; Ho, William; Tang, Maoping; Li, Zhongyu; Bu, Lei; Xu, Xiaoyang
Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.
PMCID:10349854
PMID: 37454146
ISSN: 2041-1723
CID: 5535342

Contrasting Ionic Mechanisms of Impaired Conduction in FHF1- and FHF2-Deficient Hearts [Letter]

Santucci, John; Park, David S; Shekhar, Akshay; Lin, Xianming; Bu, Lei; Yamaguchi, Naoko; Mintz, Shana; Chang, Ernest Whanwook; Khodadadi-Jamayran, Alireza; Redel-Traub, Gabriel; Goldfarb, Mitchell; Fishman, Glenn I
PMID: 35862854
ISSN: 1941-3084
CID: 5268322

Neural cell adhesion molecule is required for ventricular conduction system development

Delgado, Camila; Bu, Lei; Zhang, Jie; Liu, Fang-Yu; Sall, Joseph; Liang, Feng-Xia; Furley, Andrew J; Fishman, Glenn I
The most distal portion of the ventricular conduction system (VCS) contains cardiac Purkinje cells (PCs), which are essential for synchronous activation of the ventricular myocardium. Contactin-2 (CNTN2), a member of the immunoglobulin superfamily of cell adhesion molecules (IgSF-CAMs), was previously identified as a marker of the VCS. Through differential transcriptional profiling, we discovered two additional highly enriched IgSF-CAMs in the VCS: NCAM-1 and ALCAM. Immunofluorescence staining showed dynamic expression patterns for each IgSF-CAM during embryonic and early postnatal stages, but ultimately all three proteins became highly enriched in mature PCs. Mice deficient in NCAM-1, but not CNTN2 or ALCAM, exhibited defects in PC gene expression and VCS patterning, as well as cardiac conduction disease. Moreover, using ST8sia2 and ST8sia4 knockout mice, we show that inhibition of post-translational modification of NCAM-1 by polysialic acid leads to disrupted trafficking of sarcolemmal intercalated disc proteins to junctional membranes and abnormal expansion of the extracellular space between apposing PCs. Taken together, our data provide insights into the complex developmental biology of the ventricular conduction system.
PMID: 34100064
ISSN: 1477-9129
CID: 4899742

Identification of Key Genes and Candidated Pathways in Human Autosomal Dominant Polycystic Kidney Disease by Bioinformatics Analysis

Liu, Dongmei; Huo, Yongbao; Chen, Sixiu; Xu, Dechao; Yang, Bo; Xue, Cheng; Fu, Lili; Bu, Lei; Song, Shuwei; Mei, Changlin
BACKGROUND/AIMS/OBJECTIVE:Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic form of kidney disease. High-throughput microarray analysis has been applied for elucidating key genes and pathways associated with ADPKD. Most genetic profiling data from ADPKD patients have been uploaded to public databases but not thoroughly analyzed. This study integrated 2 human microarray profile datasets to elucidate the potential pathways and protein-protein interactions (PPIs) involved in ADPKD via bioinformatics analysis in order to identify possible therapeutic targets. METHODS:The kidney tissue microarray data of ADPKD patients and normal individuals were searched and obtained from NCBI Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified, and enriched pathways and central node genes were elucidated using related websites and software according to bioinformatics analysis protocols. Seven DEGs were validated between polycystic kidney disease and control kidney samples by quantitative real-time polymerase chain reaction. RESULTS:Two original human microarray datasets, GSE7869 and GSE35831, were integrated and thoroughly analyzed. In total, 6,422 and 1,152 DEGs were extracted from GSE7869 and GSE35831, respectively, and of these, 561 DEGs were consistent between the databases (291 upregulated genes and 270 downregulated genes). From 421 nodes, 34 central node genes were obtained from a PPI network complex of DEGs. Two significant modules were selected from the PPI network complex by using Cytotype MCODE. Most of the identified genes are involved in protein binding, extracellular region or space, platelet degranulation, mitochondrion, and metabolic pathways. CONCLUSIONS:The DEGs and related enriched pathways in ADPKD identified through this integrated bioinformatics analysis provide insights into the molecular mechanisms of ADPKD and potential therapeutic strategies. Specifically, abnormal decorin expression in different stages of ADPKD may represent a new therapeutic target in ADPKD, and regulation of metabolism and mitochondrial function in ADPKD may become a focus of future research.
PMID: 31330507
ISSN: 1423-0143
CID: 3986842

KLF4 as a rheostat of osteolysis and osteogenesis in prostate tumors in the bone

Tassone, Evelyne; Bradaschia-Correa, Vivian; Xiong, Xiaozhong; Sastre-Perona, Ana; Josephson, Anne Marie; Khodadadi-Jamayran, Alireza; Melamed, Jonathan; Bu, Lei; Kahler, David J; Ossowski, Liliana; Leucht, Philipp; Schober, Markus; Wilson, Elaine L
We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.
PMID: 31239516
ISSN: 1476-5594
CID: 3953842

Action potential response of human induced-pluripotent stem cell derived cardiomyocytes to the 28 CiPA compounds: A non-core site data report of the CiPA study

Yu, Yankun; Zhang, Mengrong; Chen, Ren; Liu, Feng; Zhou, Pengfei; Bu, Lei; Xu, Ying; Zheng, Lei
We used the whole-cell current clamp technique to examine the response of our in-house hiPSC-CMs to the 28 CiPA-selected compounds, aiming to compare field potential via MEA from core-sites and action potential via current clamp measurement. Our blinded study showed that all seven high-risk test compounds, including bepridil, caused early afterdepolarizations (EADs) at mid-high and/or high concentration(s). All hERG channel blockers in the mid-risk category prolonged APD30 and APD90 at mid-high, and then led to EADs at their respective high concentrations; while chlorpromazine, clarithromycin and risperidone showed little effects. In addition, ranolazine was the only low-risk test compound to prolong APD30 and APD90 at mid-high, and then produce EADs at high concentration. In conclusion, our results generally agreed with data from all core-sites of the CiPA consortium using the MEA method. Moreover, our assay can successfully detect pro-arrhythmic risk of drug candidates such as bepridil with superior sensitivity.
PMID: 31022455
ISSN: 1873-488x
CID: 3925612

Cardiac Sca-1+ Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair

Zhang, Lu; Sultana, Nishat; Yan, Jianyun; Yang, Fan; Chen, Fuxue; Chepurko, Elena; Yang, Feng-Chun; Du, Qinghua; Zangi, Lior; Xu, Mingjiang; Bu, Lei; Cai, Chen-Leng
BACKGROUND:cells within the mouse heart have been widely recognized as a stem cell population with multipotency that can give rise to cardiomyocytes, endothelial cells, and smooth muscle cells in vitro and after cardiac grafting. However, the developmental origin and authentic nature of these cells remain elusive. METHODS:cells. RESULTS:cells are in fact a pure endothelial cell population. They retain endothelial properties and exhibit minimal cardiomyogenic potential during development, normal aging and upon ischemic injury. CONCLUSIONS:cells in heart repair need to be reassessed.
PMID: 30566018
ISSN: 1524-4539
CID: 3556602

ETV1 activates a rapid conduction transcriptional program in rodent and human cardiomyocytes

Shekhar, Akshay; Lin, Xianming; Lin, Bin; Liu, Fang-Yu; Zhang, Jie; Khodadadi-Jamayran, Alireza; Tsirigos, Aristotelis; Bu, Lei; Fishman, Glenn I; Park, David S
Rapid impulse propagation is a defining attribute of the pectinated atrial myocardium and His-Purkinje system (HPS) that safeguards against atrial and ventricular arrhythmias, conduction block, and myocardial dyssynchrony. The complex transcriptional circuitry that dictates rapid conduction remains incompletely understood. Here, we demonstrate that ETV1 (ER81)-dependent gene networks dictate the unique electrophysiological characteristics of atrial and His-Purkinje myocytes. Cardiomyocyte-specific deletion of ETV1 results in cardiac conduction abnormalities, decreased expression of rapid conduction genes (Nkx2-5, Gja5, and Scn5a), HPS hypoplasia, and ventricularization of the unique sodium channel properties that define Purkinje and atrial myocytes in the adult heart. Forced expression of ETV1 in postnatal ventricular myocytes (VMs) reveals that ETV1 promotes a HPS gene signature while diminishing ventricular and nodal gene networks. Remarkably, ETV1 induction in human induced pluripotent stem cell-derived cardiomyocytes increases rapid conduction gene expression and inward sodium currents, converting them towards a HPS phenotype. Our data identify a cardiomyocyte-autonomous, ETV1-dependent pathway that is responsible for specification of rapid conduction zones in the heart and demonstrate that ETV1 is sufficient to promote a HPS transcriptional and functional program upon VMs.
PMCID:6028599
PMID: 29967479
ISSN: 2045-2322
CID: 3185592