Biology subjects

Yao, P.

Publications and source records attributed to Yao, P..

22 records · Page 2Linked to original sources

bioRxiv2021

FAM114A1 Influences Cardiac Fibrosis by Regulating Angiotensin II Signaling in Cardiac Fibroblasts

Cardiac fibrosis, a primary contributor to heart failure (HF) and sudden death, is considered as an important target for HF therapy. However, the signaling pathways that govern cardiac fibroblast (CF) function during cardiac fibrosis have not been fully elucidated. Here, we found that a functionally unannotated human myocardial infarction (MI) associated gene, family with sequence similarity 114 member A1 (FAM114A1), is induced in failing human and mouse hearts compared to non-failing hearts. Homozygous knockout of Fam114a1 (Fam114a1-/-) in the mouse genome reduces cardiac hypertrophy and fibrosis while significantly restores cardiac function in angiotensin (Ang) II- and MI-induced HF mouse models. Fam114a1 deletion antagonizes Ang II induced inflammation and oxidative stress. Using isolated mouse primary CFs in wild type and Fam114a1-/- mice, we found that FAM114A1 is a critical autonomous factor for CF proliferation, activation, and migration. We discovered that FAM114A1 interacts with angiotensin receptor associated protein (AGTRAP) and regulates the expression of angiotensin type 1 receptor (AT1R) and downstream Ang II signaling transduction, and subsequently influences pro-fibrotic response. Using RNA-Seq in mouse primary CFs, we identified differentially expressed genes including extracellular matrix proteins such as Adamts15. RNAi-mediated inactivation of Adamts15 attenuates CF activation and collagen deposition. Our results indicate that FAM114A1 regulates Ang II signaling and downstream pro-fibrotic and pro-inflammatory gene expression, thereby activating cardiac fibroblasts and augmenting pathological cardiac remodeling. These findings provide novel insights into regulation of cardiac fibrosis and identify FAM114A1 as a new therapeutic target for treatment of cardiac disease. SignificanceCardiac fibrosis is a hallmark of heart failure and angiotensin II signaling promotes pro-fibrotic response in the heart. This study is a pioneering investigation of the role of a functionally unknown protein FAM114A1. We show that FAM114A1 expression is induced in human and mouse failing hearts. Genetic ablation of FAM114A1 can effectively reduce cardiac fibrosis and pathological remodeling. Isolated cardiac fibroblasts from Fam114a1 knockout mice show reduced response to Ang II stimulation and compromised myofibroblast activation. Mechanistically, FAM114A1 binds to AGTRAP and influences AT1R protein expression, thereby enhancing angiotensin II signaling and pro-fibrotic response. Thus, FAM114A1 is a novel factor that modulates cardiac fibrosis and pharmacological inhibition of FAM114A1 may be a therapeutic strategy for the treatment of heart disease.

pathology↗

bioRxiv2021

High variation in immune responses and parasite phenotypes in naturally acquired Trypanosoma cruzi infection in a captive non-human primate breeding colony in Texas, USA

Trypanosoma cruzi, the causative agent of human Chagas disease, is endemic to the southern region of the United States where it routinely infects many host species. The indoor/outdoor housing configuration used in many non-human primate research and breeding facilities in the southern U.S. provides the opportunity for infection by T. cruzi and thus provides source material for in-depth investigation of host and parasite dynamics in a natural host species under highly controlled and restricted conditions. For cynomolgus macaques housed at such a facility, we used a combination of serial blood quantitative PCR (qPCR) and hemoculture to confirm infection in >92% of seropositive animals, although each method alone failed to detect infection in >20% of cases. Parasite isolates obtained from 43 of the 64 seropositive macaques were of 2 broad genetic types (discrete typing units, (DTUs) I and IV); both within and between these DTU groupings, isolates displayed a wide variation in growth characteristics and virulence, elicited host immune responses, and susceptibility to drug treatment in a mouse model. Likewise, the macaques displayed a diversity in T cell and antibody response profiles that rarely correlated with parasite DTU type, length of infection, or age of the primate. This study reveals the complexity of infection dynamics, parasite phenotypes, and immune response patterns that can occur in a primate group, despite being housed in a uniform environment at a single location, and the limited time period over which the T. cruzi infections were established. Author SummaryWe evaluated naturally occurring infections of Trypanosoma cruzi, the causative agent of human Chagas disease, in an indoor/outdoor primate colony at a breeding facility in Texas, USA. Using serial quantitative PCR and hemoculture, we confirmed infection in 92% of the 64 seropositive animals, but neither of these two methods confirmed more than 80% of the cases. Parasites by hemoculture fell into two genetic groups (discrete typing units I and IV), and displayed large variation in growth characteristics, elicited cellular and humoral immune responses as well as virulence and drug susceptibility when tested in mice. EKG abnormalities were found in 13 out of 51 qPCR-positive macaques. Our results demonstrate the complexity of these infection parameters in this colony in spite of the uniform and geographically constrained housing conditions of the macaques.

microbiology↗

bioRxiv2020

MicroRNA-574 Regulates FAM210A Expression and Influences Pathological Cardiac Remodeling

Aberrant synthesis of mitochondrial proteins impairs cardiac function and causes heart disease. However, the mechanism of regulation of mitochondria encoded protein expression during cardiac disease remains underexplored. Here, we have shown that multiple pathogenic cardiac stressors induce the expression of miR-574 guide and passenger strands (miR-574-5p/3p) in both humans and mice. miR-574 knockout mice exhibit severe cardiac disorder under heart disease-triggering stresses. miR-574-5p/3p mimics that are delivered systematically using nanoparticles reduce cardiac pathogenesis under disease insults. Transcriptome analysis of miR-574-null hearts uncovers FAM210A as a common target mRNA for both strands of miR-574. The interactome capture and translational state analyses suggest that FAM210A interacts with mitochondrial translation factors and regulates the protein expression of mitochondrial encoded electron transport chain genes. Using a human cardiomyocyte cell culture system, we discover that miR-574 regulates FAM210A expression and modulates mitochondrial encoded protein expression, which influences cardiac remodeling in heart failure.

pathology↗

bioRxiv2019

EPRS Regulates Proline-rich Pro-fibrotic Protein Synthesis during Cardiac Fibrosis

RationaleIncreased protein synthesis of pro-fibrotic genes is a common feature of cardiac fibrosis, a major manifestation of heart failure. Despite this important observation, critical factors and molecular mechanisms for translational control of pro-fibrotic genes during cardiac fibrosis remain unclear.\n\nObjectiveThis study aimed to test the hypothesis that cardiac stress-induced expression of a bifunctional aminoacyl-tRNA synthetase (ARS), glutamyl-prolyl-tRNA synthetase (EPRS), is preferentially required for the translation of proline codon-rich (PRR) pro-fibrotic mRNAs in cardiac fibroblasts during cardiac fibrosis.\n\nMethods and ResultsBy analyses of multiple available unbiased large-scale screening datasets of human and mouse heart failure, we have discovered that EPRS acts as an integrated node among all the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at both mRNA and protein level ([~]1.5-2.5 fold increase) in failing hearts compared with non-failing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele of Eprs globally (Eprs+/-) using CRISPR-Cas9 technology or in a myofibroblast-specific manner (Eprsflox/+; PostnMCM/+) strongly reduces cardiac fibrosis ([~]50% reduction) in isoproterenol- and transverse aortic constriction-induced heart failure mouse models. Inhibition of EPRS by a prolyl-tRNA synthetase (PRS)-specific inhibitor, halofuginone (Halo), significantly decreased the translation efficiency of proline-rich collagens in cardiac fibroblasts. Furthermore, using transcriptome-wide RNA-Seq and polysome profiling-Seq in Halo-treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 and Sulf1, which are translationally regulated by EPRS. As a major EPRS downstream effector, SULF1 is highly enriched in human and mouse myofibroblast. siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition.\n\nConclusionsOur results indicate that EPRS preferentially controls the translational activation of proline codon-rich pro-fibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling.\n\nNovelty and SignificanceO_ST_ABSWhat is known?C_ST_ABSO_LITGF-{beta} and IL-11 increase synthesis of pro-fibrotic proteins during cardiac fibrosis.\nC_LIO_LIMany pro-fibrotic genes contain Pro genetic codon rich motifs such as collagens.\nC_LIO_LIEPRS is an essential house-keeping enzyme required for ligating Pro to tRNAPro for the synthesis of Pro-containing proteins.\nC_LI\n\nWhat New Information Does This Article Contribute?O_LIThis study is a pioneering investigation of translational control mechanisms of pro-fibrotic gene expression in cardiac fibrosis.\nC_LIO_LIEPRS mRNA and protein expression are induced in failing human hearts and mouse hearts undergoing pathological cardiac remodeling.\nC_LIO_LIThe first demonstration of the in vivo function of EPRS in cardiac remodeling. Heterozygous Eprs global knockout and myofibroblast-specific tamoxifen-inducible Eprs conditional knockout mice show reduced pathological cardiac fibrosis under stress, suggesting that the reduction of EPRS is cardioprotective.\nC_LIO_LIIdentification of novel preferential translational target genes of EPRS. We found that EPRS regulates translation of Pro-rich (PRR) transcripts, which comprise most of the ECM and secretory signaling molecules. Among those targets, we identified multiple novel PRR genes such as LTBP2 and SULF1.\nC_LIO_LISULF1 is validated as a myofibroblast marker protein in human and mouse heart failure and a potential anti-fibrosis target gene.\nC_LI\n\nIn cardiac fibroblasts, the synthesis of pro-fibrotic proteins is upregulated by cardiac stressors to activate extracellular matrix deposition and impair cardiac function. In this study, we have discovered an EPRS-PRR gene axis that influences translational homeostasis of pro-fibrotic proteins and promotes pathological cardiac remodeling and fibrosis. EPRS is identified as a common node downstream of multiple cardiac stressors and a novel regulatory factor that facilitates pro-fibrotic mRNA translation in cardiac fibrosis. Global and myofibroblast-specific genetic ablation of EPRS can effectively reduce cardiac fibrosis. This study reveals a novel translational control mechanism that modulates cardiac fibrosis and heart function. Mild inhibition of PRR mRNA translation could be a general therapeutic strategy for the treatment of heart disease. These findings provide novel insights into the translational control mechanisms of cardiac fibrosis and will promote the development of novel therapeutics by inhibiting pro-fibrotic translation factors or their downstream effectors.

pathology↗