Biology subjects

Zhou, L.

Publications and source records attributed to Zhou, L..

At least 271 records · Page 15Linked to original sources

bioRxiv2020

Clustered Rapid Induction of Apoptosis Limits ZIKV and DENV-2 Proliferation in the Midguts of Aedes aegypti

Inter-host transmission of pathogenic arboviruses such as dengue virus (DENV) and Zika virus (ZIKV) requires systemic infection of the mosquito vector. Successful systemic infection requires initial viral entry and proliferation in the midgut cells of the mosquito followed by dissemination to secondary tissues and eventual entry into salivary glands1. Lack of arbovirus proliferation in midgut cells has been observed in several Aedes aegypti strains2, but the midgut antiviral responses underlying this phenomenon are not yet fully understood. We report here that there is a rapid induction of apoptosis (RIA) in the Aedes aegypti midgut epithelium within 2 hours of infection with DENV-2 or ZIKV in both in vivo blood-feeding and ex vivo midgut infection models. Inhibition of RIA led to increased virus proliferation in the midgut, implicating RIA as an innate immune mechanism mediating midgut infection in this mosquito vector.

microbiology↗

bioRxiv2020

Co-infection of influenza A virus enhances SARS-CoV-2 infectivity

The upcoming flu season in the northern hemisphere merging with the current COVID-19 pandemic raises a potentially severe threat to public health. Through experimental co-infection of IAV with either pseudotyped or SARS-CoV-2 live virus, we found that IAV pre-infection significantly promoted the infectivity of SARS-CoV-2 in a broad range of cell types. Remarkably, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice co-infected with IAV in vivo. Moreover, such enhancement of SARS-CoV-2 infectivity was not seen with several other viruses probably due to a unique IAV segment as an inducer to elevate ACE2 expression. This study illustrates that IAV has a special nature to aggravate SARS-CoV-2 infection, and prevention of IAV is of great significance during the COVID-19 pandemic.

microbiology↗

bioRxiv2020

A Genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms

The regulatory mechanisms of circadian rhythms have been studied primarily at the level of the transcription-translation feedback loops of protein coding genes. Regulatory modules involving non-coding RNAs are less thoroughly understood. In particular, emerging evidence has revealed the important role of miRNAs in maintaining the robustness of the circadian system. To identify miRNAs that have the potential to modulate circadian rhythms, we conducted a genome-wide miRNA screen using U2OS luciferase reporter cells. Among 989 miRNAs in the library, 120 changed the period length in a dosage-dependent manner. We further validated the circadian regulatory function of a miRNA cluster, miR-183/96/182, both in vitro and in vivo. We found that all three members of this miRNA cluster can modulate circadian rhythms. Particularly, miR-96 directly targeted a core circadian clock gene, PER2. The knockout of the miR-183/96/182 cluster in mice showed tissue-specific effects on circadian parameters and altered circadian rhythms at the behavioral level. This study identified a large number of miRNAs, including the miR-183/96/182 cluster, as circadian modulators. We provide a resource for further understanding the role of miRNAs in the circadian network and highlight the importance of miRNAs as a novel genome-wide layer of circadian clock regulation. Significance StatementAlthough miRNAs are emerging as important regulators of diverse physiological and pathological processes, our knowledge of their potential role in regulation of circadian rhythms is still limited. We deployed a cell-based genome-wide screening approach, and successfully identified mature miRNAs as cell-autonomous circadian modulators. We then specifically focused on the miR-183/96/182 cluster among the candidate miRNA hits and revealed their circadian function both in vitro and in vivo from the unbiased screen. This study provides resources for further understanding the role of miRNAs in the circadian network. It also highlights the importance of miRNAs as a novel genome-wide layer of circadian clock regulation.

molecular biology↗

bioRxiv2020

lncRNA-RMST functioned as a SOX2 transcription co-regulator to regulate miR-1251 in the progression of Hirschsprung's disease

Hirschsprungs disease (HSCR) is a congenital disorder characterized by the absence of enteric neural crest cells (ENCCs). Non-coding RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been authenticated as important regulators of biological functions. We conducted a microarray analysis and found lncRNA Rhabdomyosarcoma 2-associated transcript (RMST) was down-regulated in the stenotic segment of HSCR patients. MiR-1251 is transcribed from the intron region of RMST and was also low-expressed. When the expression of RMST or miR-1251 was reduced, the cell proliferation and migration were attenuated. However, RMST didnt affect the expression of miR-1251 directly found in this study. Through bioinformatic analysis, transcription factor SOX2 was predicted to bind to the promoter region of miR-1251 which was confirmed by CHIP assay. Herein, we demonstrated that RMST exerted as a co-regulator of SOX2 to regulate the expression of miR-1251. Furtherly, AHNAK was proved to be the target gene of miR-1251 in this study. Taken together, we revealed the role of RMST/SOX2/miR-1251/AHNAK pathway in the occurrence of Hirschsprungs disease and provided a potential therapeutic target for this disease. SUMMARY STATEMENTHirschsprung disease (HSCR) is characterized by a deficit in enteric neurons, however, the underlying mechanism remains unclear. This study revealed the role of lnc-RMST during the occurrence of HSCR.

cell biology↗

bioRxiv2020

Vitexin inhibited the invasion, metastasis, and progression of human melanoma cells by targeting STAT3 signaling pathway

In human melanoma cells, resistance to conventional chemotherapy and radiotherapy and rapid metastasis give melanoma a remarkable feature of the most aggressive and lethal. The low response rate of melanoma to existing treatment modalities is a substantial threat to patients and researchers. It is crucial to identify new therapeutic agents for the fatal malignancy melanoma. Vitexin is a flavonoid compound in many traditional Chinese medicines that exhibits antioxidant, anti-inflammatory and anti-tumour activities in many cancer cells. In our study, we elucidated the inhibitory effects of vitexin on invasion and metastasis in human melanoma A375 and C8161 cells in vitro. After vitexin treatment for 24 h or 48 h, the invasive ability and migration of melanoma cells were decreased in a dose- and time-dependent manners. In western blot analysis, we verified that vitexin inhibited the expression levels of MMP-2, MMP-9, vimentin, Slug and Twist which are known as the regulators of protein degradation and promote various cell behaviours such as migration and invasion. To further investigate the target signal that may be influenced by vitexin, immunofluorescence assay was performed to observe STAT3 localization and western blot results showed that vitexin decreased the expression of the phosphorylation of kinases that inducing STAT3 activation. Accordingly, we provide inspiring insight into the basic inhibition mechanism of vitexin, which will soon be an issue due to its scientific potential for further development as a novel anti-tumour agent for the clinical therapy of human melanoma.

cancer biology↗

bioRxiv2020

Polygenic Risk Scores for Kidney Function to the Circulating Proteome, and Incident Kidney Diseases: the Atherosclerosis Risk in Communities Study

Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. We developed a genome-wide polygenic risk score (PRS) using a weighted average of 1.2 million SNPs for eGFR using the LDpred algorithm, summary statistics generated by a European-ancestry (EA) meta-analysis of the CKDGen Consortium (N=558,423) and UK Biobank GWAS for eGFR (90% of the cohort; N=289,432), followed by best parameter selection using data from the remaining 10% of the UK Biobank (N=32,159). We then tested the association of the PRS among 8,886 EA participants in the Atherosclerosis Risk in Communities (ARIC) study (mean age: 54{+/-}6 years, 53% female) with incident chronic kidney disease (CKD), end stage kidney disease (ESKD), kidney failure (KF), and acute kidney injury (AKI). We also examined 4,877 plasma proteins measured at two time points (visit 3 (1993-95) and visit 5 (2011-13)) in relation to the PRS and compared associations between the proteome and eGFR itself. All models were adjusted for age, sex, center, and the first 10 principal components of ancestry. The developed PRS had an R2 for eGFR of 0.07 in ARIC. Over 30 years of follow up, the number of incident CKD, ESKD, KF, and AKI were 2,959, 137, 470, and 1,723, respectively. The PRS showed significant associations with all outcomes: hazard ratios (95% CI) per 1 SD lower PRS were 1.33 (1.28, 1.39), 1.20 (1.00, 1.42), 1.17 (1.06, 1.28), and 1.07 (1.02, 1.12) for incident CKD, ESKD, KF, and AKI respectively. The PRS was significantly associated (Bonferroni threshold P<1.02 x 10-5) with 108 proteins at both time points. The strongest associations were with cystatin-C (a marker of kidney function used in clinical practice), collagen alpha-1 (XV) chain, and desmocollin-2. All significant correlations with the PRS were negative, except those of testican-2 and angiostatin. Correlations of proteins with eGFR were much stronger than those with the PRS. Overall, we demonstrated that the PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases as well as broadly influence the plasma proteome.

genetics↗

bioRxiv2020

Natural Killer cell activation, reduced ACE2, TMPRSS2, cytokines G-CSF, M-CSF and SARS-CoV-2-S pseudovirus infectivity by MEK inhibitor treatment of human cells

COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. In serum-deprived and stimulated cells treated with remdesivir and MEKi we observed correlations between pRB, pERK, and ACE2 expression further supporting role of proliferative state and MAPK pathway in ACE2 regulation. We show elevated cytokines in COVID-19-(+) patient plasma (N=9) versus control (N=11). TMPRSS2, inflammatory cytokines G-CSF, M-CSF, IL-1, IL-6 and MCP-1 are suppressed by MEKi alone or with remdesivir. We observed MEKi stimulation of NK-cell killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. Pseudotyped SARS-CoV-2 virus with a lentiviral core and SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope infected human bronchial epithelial cells, small airway epithelial cells, or lung cancer cells and MEKi suppressed infectivity of the pseudovirus. We show a drug class-effect with MEKi to stimulate NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells. MEKi may attenuate SARS-CoV-2 infection to allow immune responses and antiviral agents to control disease progression.

cell biology↗

bioRxiv2020

Molecular mechanisms of Cardiac Injury associated with myocardial SARS-CoV-2 infection

BackgroundCoronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world. Developing cardiac injury is a common condition in COVID-19 patients, but the pathogenesis remains unclear. MethodsThe RNA-Seq dataset (GES150392) compared expression profiling of mock human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and SARS-cov-2-infected hiPSC-CMs were obtained from Gene Expression Omnibus (GEO). We identified the differentially expressed genes (DEGs) between those two groups. Through gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and CLINVAR human diseases analysis to identify the main effect of SARS-CoV-2 on cardiomyocytes. A protein-protein interaction (PPI) network was constructed to visualize interactions and functions of the hub genes. ResultsA total of 1554 DEGs were identified (726 upregulated genes and 828 downregulated genes). Gene enrichment analysis shown that SARS-CoV-2 activate immuno-inflammatory responses via multiple signal pathways, including TNF, IL6-JAK-STAT3, IL2-STAT5, NF-{kappa}B, IL17, and Toll-like receptor signaling pathway in hiPSC-CMs. Whereas, the muscle contraction, cellular respiration and cell cycle of hiPSC-CMs were inhibited by SARS-CoV-2. CLINVAR human diseases analysis shown SRAS-Cov-2 infection was associated with myocardial infarction, cardiomyopathy and Limb-girdle muscular dystrophy. 15 hub genes were identified based on PPI network. Function analysis revealed that 11 upregulated hub genes were mainly enriched in cytokine activity, chemokine activity, Inflammatory response, leukocyte chemotaxis, and lipopolysaccharide-mediated signaling pathway. Furthermore, 4 downregulated hub genes were related to cell cycle regulation. ConclusionThe present study elucidates that the SARS-CoV-2 infection induced a strong defensive response in cardiomyocyte, leading to excessive immune inflammation, cell hypoxia, functional contractility reduction and apoptosis, ultimately result in myocardial injury.

molecular biology↗

bioRxiv2020

AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimers disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

neuroscience↗

bioRxiv2020

Single species RNA purification with DNA nanoswitches

We report a novel method to purify individual RNA species using programmable DNA nanoswitches to facilitate RNA capture, release, and isolation. We validate sequence-based purification of microRNA, rRNA, and an mRNA fragment from total RNA, demonstrate multiplexing with two different RNA species, and show an application with downstream LC/MS analysis to identify RNA modifications. The simplicity, low cost, and low sample requirements of our method make it suitable for easy adoption.Competing Interest StatementLZ, ARC, and KH have intellectual property related to DNA nanoswitches. All other authors declare no competing interests.View Full Text

molecular biology↗

bioRxiv2020

Numerical Model for Formation and Evolution of the Bleb

ABSTRACTThe bleb morphology and its changes are an important mechanism of cell’s amoeboid migration. By releasing bonds between the membrane and the cortex of a cell, the formation of bleb can be observed experimentally, but the mechanism that affects the size and shape of this kind of bleb is waiting for further study. In this paper, a two-dimensional fluid-solid coupling model is established to describe a cell with membrane, cortex and cytoplasm in a solution, and a numerical solving method for the fluid-solid coupling model is developed to simulate the behaviors of cell bleb. The effects of parameters, such as the number of broken bonds, the viscosity coefficient of the cortex, and the cell’s membrane modulus on the size and the shape of the bleb were investigated. Numerical results show that the model is effective to simulate the formation and evolution of cell’s bleb, and derive the contribution of several affecting factors to the bleb shape and size clearly.SIGNIFICANCE To understand the process of cell migration with bleb pseudopods in the amoeba cell migration, it is necessary to study the formation mechanism of cells protruding bleb. In this paper, we propose a reasonable and reliable cell numerical model. With this model we successfully simulate the bleb phenomenon consistent with the experimental phenomenon by changing the key impact factors. The method in this paper is applicable to the cell model of amoeba cell migration pattern, which helps to understand the important role of blebs in the process of cell migration.View Full Text

cell biology↗

bioRxiv2020

Altered Affective Behaviors in Casein Kinase 1 Epsilon Mutant Mice

Affective behaviors and mental health are profoundly affected by disturbances in circadian rhythms. Casein kinase 1 epsilon (CSNK1E) is an essential component of the core circadian clock. Mice with tau or null mutation of this gene have shortened and lengthened circadian period respectively. Here we examined anxiety-like, fear, and depressive-like behaviors in both male and female mice of these two different mutants. Compared with wild-type mice, we found reductions in fear and anxiety-like behaviors in both mutant lines and in both sexes, with the tau mutants exhibiting the greatest phenotypic changes. However, the depressive-like behaviors had distinct phenotypic patterns, with markedly less depressive-like behaviors in female null mutants, but not in tau mutants of either sex. To determine whether abnormal light entrainment of tau mutants to 24 hour light-dark cycles contributes to these phenotypic differences, we also examined these behaviors in tau mutants on a 20 hour light-dark cycle close to their endogenous circadian period. The normalized entrainment restored more wild-type-like behaviors for fear and anxiety, but it induced depressive-like behavior in tau mutant females. These data show that both mutations of Csnk1e broadly affect fear and anxiety-like behaviors, while the effects on depressive-like behavior vary with genetics, photoperiod, and sex, suggesting that the mechanisms by which Csnk1e affects fear and anxiety-like behaviors may be similar, but distinct from those affecting depressive-like behavior. Our study also provides experimental evidence in support of the hypothesis of beneficial outcomes from properly entrained circadian rhythms in terms of the anxiety-like and fear behaviors.

neuroscience↗

bioRxiv2020

Acquisition of hypoxia inducibility by oxygen sensing N-terminal cysteine oxidase in spermatophytes

N-terminal cysteine oxidases (NCOs) are enzymes that use molecular oxygen to oxidize the amino-terminal cysteine of specific proteins, thereby initiating the proteolytic N-degron pathway and thus conferring them oxygen-dependent instability. To expand the characterization of the plant family of NCOs (PCOs), we performed a phylogenetic analysis across different plant taxa in terms of sequence similarity and transcriptional regulation. Based on this survey, we propose a distinction of PCOs into two main groups: A-type and B-type sequences. A-type PCOs are conserved across all plant species and are generally unaffected at the mRNA level by oxygen availability. Instead, B-type PCOs differentiated in spermatophytes to acquire specific amino acid features and transcriptional regulation in response to hypoxia. Both groups of PCO proteins possess the ability to destabilize Cys-initiating proteins. Indeed, the inactivation of two A-type PCOs in Arabidopsis thaliana, PCO4 and PCO5, is sufficient to activate, at least partially, the anaerobic response in young seedlings, whereas the additional removal of B-type PCOs leads to a stronger induction of anaerobic genes and impairs plant growth and development. Our results show that both PCO types are required to regulate the anaerobic response in angiosperm. Therefore, while it is possible to distinguish two clades within the PCO family, separated by both amino acid features and transcriptional regulation, we conclude that they both contribute to restrain the anaerobic transcriptional program in normoxic conditions and together generate a molecular switch to toggle the hypoxic response in Arabidopsis.One sentence summary Hypoxic induction of Plant Cysteine Oxidases has been acquired and fixed in seed plants by ancestor proteins able to initiate the proteolysis of Cys-initiating protein substrates by the Arg/N-degron pathway.View Full Text

plant biology↗

bioRxiv2020

The Growth Rate Hypothesis as a predictive framework for microevolutionary adaptation to selection for high population growth: an experimental test under phosphorus rich and phosphorus poor conditions

The growth rate hypothesis, a central concept of Ecological Stoichiometry, explains the frequently observed positive association between somatic growth rate and somatic phosphorus content (Psom) in organisms across a broad range of taxa. Here, we explore its potential in predicting intraspecific microevolutionary adaptation. For this, we subjected zooplankton populations to selection for fast population growth (PGR) in either a P-rich (HP) or P-poor (LP) food environment. With common garden transplant experiments we demonstrate evolution in HP populations towards increased PGR concomitant with an increase in Psom. In contrast we show that LP populations evolved higher PGR independently of Psom. We conclude that the GRH hypothesis has considerable value for predicting microevolutionary change, but that its application may be contingent on stoichiometric context. Our results highlight the potential of cryptic evolution in determining the performance response of field populations to elemental limitation of their food resources.

ecology↗

bioRxiv2020

Arhopalus rusticus (Coleoptera: Cerambycidae): a new vector for pine wood nematode, Bursaphelenchus xylophilus (Nematoda: Aphelenchoididae)

In the study on the transmission of pine wood nematodes by Arhopalus rusticus, we research the ability and characteristics of Arhopalus rusticus to transmit pine wood nematodes. A total of 288 Arhopalus rusticus (female 142, male 146) were collected and 20 (female 8, male 12) of them were able to carry pine wood nematodes. Results shown that 12 beetles can transmit pine wood nematodes. Arhopalus rusticus does not eat the pine bark, but eat the pine needles. Pine wood nematodes are transmitted through the feeding bite mark on the pine needles. In addition experiments further confirmed that pine wood nematodes could transmit through pine needles.

zoology↗

bioRxiv2020

Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice

Microglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and the development of neuropathic pain in vivo remains incompletely understood. To address this issue, we applied chemogenetic approach by using CX3CR1creER/+:R26LSL-hM4Di/+ transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) exclusively in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain initiation and maintenance. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1{beta}). Using in vivo spinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after peripheral nerve injury. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.

neuroscience↗

bioRxiv2020

ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection

Purpose Conjunctival signs and symptoms are observed in a subset of patients with COVID-19, and SARS-CoV-2 has been detected in tears, raising concerns regarding the eye both as a portal of entry and carrier of the virus. The purpose of this study was to determine whether ocular surface cells possess the key factors required for cellular susceptibility to SARS-CoV-2 entry/infection.Methods We analyzed human post-mortem eyes as well as surgical specimens for the expression of ACE2 (the receptor for SARS-CoV-2) and TMPRSS2, a cell surface-associated protease that facilitates viral entry following binding of the viral spike protein to ACE2.Results Across all eye specimens, immunohistochemical analysis revealed expression of ACE2 in the conjunctiva, limbus, and cornea, with especially prominent staining in the superficial conjunctival and corneal epithelial surface. Surgical conjunctival specimens also showed expression of ACE2 in the conjunctival epithelium, especially prominent in the superficial epithelium, as well as the substantia propria. All eye and conjunctival specimens also expressed TMPRSS2. Finally, western blot analysis of protein lysates from human corneal epithelium obtained during refractive surgery confirmed expression of ACE2 and TMPRSS2.Conclusions Together, these results indicate that ocular surface cells including conjunctiva are susceptible to infection by SARS-CoV-2, and could therefore serve as a portal of entry as well as a reservoir for person-to-person transmission of this virus. This highlights the importance of safety practices including face masks and ocular contact precautions in preventing the spread of COVID-19 disease.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2020

Mesenchymal stem cells with overexpression of Angiotensin-converting enzyme-2 improved the microenvironment and cardiac function in a rat model of myocardial infarction

BackgroundAngiotensin-converting enzyme-2 (ACE2) overexpression improves left ventricular remodeling and function in diabetic cardiomyopathy; however, the effect of ACE2-overexpressed mesenchymal stem cells (MSCs) on myocardial infarction (MI) remains unexplored. This study aimed to investigate the effect of ACE2-overexpression on the function of MSCs and the therapeutic efficacy of MSCs for MI. MethodsMSCs were transfected with Ace2 gene using lentivirus, and then transplanted into the border zone of ischemic heart. The renin-angiotensin system (RAS) expression, nitric oxide synthase (NOS) expression, paracrine factors, anti-hypoxia ability, tube formation of MSCs, and heart function were determined. ResultsMSCs expressed little ACE2. ACE2-overexpression decreased the expression of AT1 and VEGF apparently, up-regulated the paracrine of HGF, and increased the synthesis of Angiotensin 1-7 in vitro. ACE2-overexpressed MSCs showed a cytoprotective effect on cardiomyocyte, and an interesting tube formation ability, decreased the heart fibrosis and infarct size, and improved the heart function. ConclusionTherapies employing MSCs with ACE2 overexpression may represent an effective treatment for improving the myocardium microenvironment and the cardiac function after MI.

pharmacology and toxicology↗