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1.
Cells ; 11(8)2022 Apr 13.
Article in English | MEDLINE | ID: covidwho-1785544

ABSTRACT

Cardiovascular disease (CVD) is the leading cause of death worldwide. Current data suggest that patients with cardiovascular diseases experience more serious complications with coronavirus disease-19 (COVID-19) than those without CVD. In addition, severe COVID-19 appears to cause acute cardiac injury, as well as long-term adverse remodeling of heart tissue. Cardiac fibroblasts and myofibroblasts, being crucial in response to injury, may play a pivotal role in both contributing to and healing COVID-19-induced cardiac injury. The role of cardiac myofibroblasts in cardiac fibrosis has been well-established in the literature for decades. However, with the emergence of the novel coronavirus SARS-CoV-2, new cardiac complications are arising. Bursts of inflammatory cytokines and upregulation of TGF-ß1 and angiotensin (AngII) are common in severe COVID-19 patients. Cytokines, TGF-ß1, and Ang II can induce cardiac fibroblast differentiation, potentially leading to fibrosis. This review details the key information concerning the role of cardiac myofibroblasts in CVD and COVID-19 complications. Additionally, new factors including controlling ACE2 expression and microRNA regulation are explored as promising treatments for both COVID-19 and CVD. Further understanding of this topic may provide insight into the long-term cardiac manifestations of the COVID-19 pandemic and ways to mitigate its negative effects.


Subject(s)
COVID-19 , Cardiovascular Diseases , COVID-19/complications , Cardiovascular Diseases/metabolism , Fibroblasts/metabolism , Humans , Myocardium/metabolism , Myofibroblasts/metabolism , Pandemics , SARS-CoV-2 , Transforming Growth Factor beta1/metabolism
2.
Sci Rep ; 12(1): 965, 2022 01 19.
Article in English | MEDLINE | ID: covidwho-1638855

ABSTRACT

Hospitalized patients who die from Covid-19 often have pre-existing heart disease. The SARS-CoV-2 virus is dependent on the ACE2 receptor to be able to infect cells. It is possible that the strong link between cardiovascular comorbidities and a poor outcome following a SARS-CoV-2 infection is sometimes due to viral myocarditis. The aim was to examine the expression of ACE2 in normal hearts and hearts from patients with terminal heart failure. The ACE2 expression was measured by global quantitative proteomics and RT-qPCR in left ventricular (LV) tissue from explanted hearts. Immunohistochemistry was used to examine ACE2 expression in cardiomyocytes, fibroblasts and endothelial cells. In total, tissue from 14 organ donors and 11 patients with terminal heart failure were included. ACE2 expression was 2.6 times higher in 4 hearts from patients with terminal heart failure compared with 6 healthy donor hearts. The results were confirmed by immunohistochemistry where more than half of cardiomyocytes or fibroblasts showed expression of ACE2 in hearts from patients with terminal heart failure. In healthy donor hearts ACE2 was not expressed or found in few fibroblasts. A small subpopulation of endothelial cells expressed ACE2 in both groups. Upregulated ACE2 expression in cardiomyocytes may increase the risk of SARS-CoV-2 myocarditis in patients with heart failure.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Endothelial Cells/pathology , Fibroblasts/pathology , Heart Failure/pathology , Myocytes, Cardiac/pathology , Tissue Donors/supply & distribution , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Case-Control Studies , Endothelial Cells/metabolism , Female , Fibroblasts/metabolism , Heart Failure/genetics , Heart Failure/metabolism , Heart Failure/therapy , Heart Transplantation/methods , Humans , Male , Middle Aged , Myocytes, Cardiac/metabolism , Young Adult
3.
Cells ; 11(1)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1580996

ABSTRACT

Patients with COPD may be at an increased risk for severe illness from COVID-19 because of ACE2 upregulation, the entry receptor for SARS-CoV-2. Chronic exposure to cigarette smoke, the main risk factor for COPD, increases pulmonary ACE2. How ACE2 expression is controlled is not known but may involve HuR, an RNA binding protein that increases protein expression by stabilizing mRNA. We hypothesized that HuR would increase ACE2 protein expression. We analyzed scRNA-seq data to profile ELAVL1 expression in distinct respiratory cell populations in COVID-19 and COPD patients. HuR expression and cellular localization was evaluated in COPD lung tissue by multiplex immunohistochemistry and in human lung cells by imaging flow cytometry. The regulation of ACE2 expression was evaluated using siRNA-mediated knockdown of HuR. There is a significant positive correlation between ELAVL1 and ACE2 in COPD cells. HuR cytoplasmic localization is higher in smoker and COPD lung tissue; there were also higher levels of cleaved HuR (CP-1). HuR binds to ACE2 mRNA but knockdown of HuR does not change ACE2 protein levels in primary human lung fibroblasts (HLFs). Our work is the first to investigate the association between ACE2 and HuR. Further investigation is needed to understand the mechanistic underpinning behind the regulation of ACE2 expression.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , ELAV-Like Protein 1/genetics , Gene Expression Regulation , Lung/metabolism , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , ELAV-Like Protein 1/metabolism , Female , Fibroblasts/metabolism , Gene Expression Profiling/methods , Humans , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/virology , RNA Interference , RNA-Seq/methods , SARS-CoV-2/physiology , Single-Cell Analysis/methods
4.
Mitochondrion ; 61: 147-158, 2021 11.
Article in English | MEDLINE | ID: covidwho-1500157

ABSTRACT

The COVID-19 pandemic prompted the FDA to authorize a new nucleoside analogue, remdesivir, for emergency use in affected individuals. We examined the effects of its active metabolite, remdesivir triphosphate (RTP), on the activity of the replicative mitochondrial DNA polymerase, Pol γ. We found that while RTP is not incorporated by Pol γ into a nascent DNA strand, it remains associated with the enzyme impeding its synthetic activity and stimulating exonucleolysis. In spite of that, we found no evidence for deleterious effects of remdesivir treatment on the integrity of the mitochondrial genome in human cells in culture.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , DNA Polymerase gamma/metabolism , DNA Replication/drug effects , DNA, Mitochondrial/biosynthesis , Fibroblasts/metabolism , SARS-CoV-2 , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , COVID-19/metabolism , Cells, Cultured , Humans
5.
Cells ; 10(10)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470800

ABSTRACT

Pulmonary epithelial cells are widely considered to be the first line of defence in the lung and are responsible for coordinating the innate immune response to injury and subsequent repair. Consequently, epithelial cells communicate with multiple cell types including immune cells and fibroblasts to promote acute inflammation and normal wound healing in response to damage. However, aberrant epithelial cell death and damage are hallmarks of pulmonary disease, with necrotic cell death and cellular senescence contributing to disease pathogenesis in numerous respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and coronavirus disease (COVID)-19. In this review, we summarise the literature that demonstrates that epithelial damage plays a pivotal role in the dysregulation of the immune response leading to tissue destruction and abnormal remodelling in several chronic diseases. Specifically, we highlight the role of epithelial-derived damage-associated molecular patterns (DAMPs) and senescence in shaping the immune response and assess their contribution to inflammatory and fibrotic signalling pathways in the lung.


Subject(s)
COVID-19/immunology , Epithelium/immunology , Idiopathic Pulmonary Fibrosis/immunology , Lung/immunology , Alarmins , Animals , Cellular Senescence , Coculture Techniques , Epithelial Cells/cytology , Epithelial Cells/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Fibrosis/metabolism , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Immunity , Inflammation/metabolism , Ligands , Necroptosis , Necrosis/pathology , Pulmonary Disease, Chronic Obstructive , SARS-CoV-2 , Signal Transduction
6.
mBio ; 12(4): e0157221, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1349194

ABSTRACT

Tissue- and cell-specific expression patterns are highly variable within and across individuals, leading to altered host responses after acute virus infection. Unraveling key tissue-specific response patterns provides novel opportunities for defining fundamental mechanisms of virus-host interaction in disease and the identification of critical tissue-specific networks for disease intervention in the lung. Currently, there are no approved therapeutics for Middle East respiratory syndrome coronavirus (MERS-CoV) patients, and little is understood about how lung cell types contribute to disease outcomes. MERS-CoV replicates equivalently in primary human lung microvascular endothelial cells (MVE) and fibroblasts (FB) and to equivalent peak titers but with slower replication kinetics in human airway epithelial cell cultures (HAE). However, only infected MVE demonstrate observable virus-induced cytopathic effect. To explore mechanisms leading to reduced MVE viability, donor-matched human lung MVE, HAE, and FB were infected, and their transcriptomes, proteomes, and lipidomes were monitored over time. Validated functional enrichment analysis demonstrated that MERS-CoV-infected MVE were dying via an unfolded protein response (UPR)-mediated apoptosis. Pharmacologic manipulation of the UPR in MERS-CoV-infected primary lung cells reduced viral titers and in male mice improved respiratory function with accompanying reductions in weight loss, pathological signatures of acute lung injury, and times to recovery. Systems biology analysis and validation studies of global kinetic transcript, protein, and lipid data sets confirmed that inhibition of host stress pathways that are differentially regulated following MERS-CoV infection of different tissue types can alleviate symptom progression to end-stage lung disease commonly seen following emerging coronavirus outbreaks. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe atypical pneumonia in infected individuals, but the underlying mechanisms of pathogenesis remain unknown. While much has been learned from the few reported autopsy cases, an in-depth understanding of the cells targeted by MERS-CoV in the human lung and their relative contribution to disease outcomes is needed. The host response in MERS-CoV-infected primary human lung microvascular endothelial (MVE) cells and fibroblasts (FB) was evaluated over time by analyzing total RNA, proteins, and lipids to determine the cellular pathways modulated postinfection. Findings revealed that MERS-CoV-infected MVE cells die via apoptotic mechanisms downstream of the unfolded protein response (UPR). Interruption of enzymatic processes within the UPR in MERS-CoV-infected male mice reduced disease symptoms, virus-induced lung injury, and time to recovery. These data suggest that the UPR plays an important role in MERS-CoV infection and may represent a host target for therapeutic intervention.


Subject(s)
Acute Lung Injury/pathology , Apoptosis/physiology , Coronavirus Infections/pathology , Unfolded Protein Response/physiology , Acute Lung Injury/virology , Animals , Cell Line , Endothelial Cells/metabolism , Endothelial Cells/virology , Female , Fibroblasts/metabolism , Fibroblasts/virology , Humans , Male , Mice , Middle East Respiratory Syndrome Coronavirus/immunology
7.
Mol Ther ; 29(10): 3042-3058, 2021 10 06.
Article in English | MEDLINE | ID: covidwho-1331299

ABSTRACT

Reprogramming non-cardiomyocytes (non-CMs) into cardiomyocyte (CM)-like cells is a promising strategy for cardiac regeneration in conditions such as ischemic heart disease. Here, we used a modified mRNA (modRNA) gene delivery platform to deliver a cocktail, termed 7G-modRNA, of four cardiac-reprogramming genes-Gata4 (G), Mef2c (M), Tbx5 (T), and Hand2 (H)-together with three reprogramming-helper genes-dominant-negative (DN)-TGFß, DN-Wnt8a, and acid ceramidase (AC)-to induce CM-like cells. We showed that 7G-modRNA reprogrammed 57% of CM-like cells in vitro. Through a lineage-tracing model, we determined that delivering the 7G-modRNA cocktail at the time of myocardial infarction reprogrammed ∼25% of CM-like cells in the scar area and significantly improved cardiac function, scar size, long-term survival, and capillary density. Mechanistically, we determined that while 7G-modRNA cannot create de novo beating CMs in vitro or in vivo, it can significantly upregulate pro-angiogenic mesenchymal stromal cells markers and transcription factors. We also demonstrated that our 7G-modRNA cocktail leads to neovascularization in ischemic-limb injury, indicating CM-like cells importance in other organs besides the heart. modRNA is currently being used around the globe for vaccination against COVID-19, and this study proves this is a safe, highly efficient gene delivery approach with therapeutic potential to treat ischemic diseases.


Subject(s)
Cellular Reprogramming/genetics , Genetic Therapy/methods , Ischemia/therapy , Muscle, Skeletal/blood supply , Myocardial Infarction/therapy , Neovascularization, Physiologic/genetics , Regeneration/genetics , Transfection/methods , Animals , Animals, Newborn , Cells, Cultured , Disease Models, Animal , Female , Fibroblasts/metabolism , Humans , Male , Mice , Mice, Knockout, ApoE , Myocytes, Cardiac/metabolism , RNA, Messenger/genetics
9.
Commun Biol ; 4(1): 631, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1283664

ABSTRACT

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNß1 and subsequently IL7. IFNß1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.


Subject(s)
Interleukins/biosynthesis , Interleukins/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antiviral Agents/metabolism , Cell Culture Techniques , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Enterocytes/immunology , Enterocytes/metabolism , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Interleukins/immunology , Intestinal Mucosa/metabolism , Intestines/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organoids/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
10.
Eur J Immunol ; 51(9): 2330-2340, 2021 09.
Article in English | MEDLINE | ID: covidwho-1261763

ABSTRACT

The molecular mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein was characterized to identify novel therapies. The impact of tofacitinib, IL-6R Ab, or TNFi therapy was determined on Spike protein or LPS/IFN-γ-induced signaling, inflammation, and metabolic reprogramming in MΦs and/or rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS). ACE2 frequency was markedly expanded in MΦs compared to T cells and RA FLS. Tofacitinib suppresses Spike protein potentiated STAT1 signaling, whereas this function was unchanged by TNFi. Tofacitinib impairs IL-6/IFN/LPS-induced STAT1 and STAT3 phosphorylation in RA MΦs and FLS. Interestingly, tofacitinib had a broader inhibitory effect on the monokines, glycolytic regulators, or oxidative metabolites compared to IL-6R Ab and TNFi in Spike-protein-activated MΦs. In contrast, all three therapies disrupted IFN-α and IFN-ß secretion in response to Spike protein; nonetheless, the IFN-γ was only curtailed by tofacitinib or IL-6R Ab. While tofacitinib counteracted MΦ metabolic rewiring instigated by Spike protein, it was inconsequential on the glycolysis expansion mediated via HK2 and/or LDHA in the activated RA MΦ and FLS. Nevertheless, the potentiated inflammatory response and the diminished oxidative phosphorylation modulated by Spike protein and/or LPS/IFN-γ stimulation in MΦs or RA FLS were reversed by tofacitinib. In conclusion, tofacitinib suppresses MΦ inflammation and immunometabolism triggered by Spike protein and may provide a promising strategy for COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Macrophages/drug effects , Piperidines/pharmacology , Pyrimidines/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Arthritis, Rheumatoid/metabolism , COVID-19/metabolism , Cells, Cultured , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Interleukin-6/metabolism , Macrophages/metabolism , Receptors, Interleukin-6/metabolism , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolism
11.
BMC Med Genomics ; 14(1): 138, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1241103

ABSTRACT

BACKGROUND: Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. METHODS: Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2. RESULTS: Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. CONCLUSIONS: Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.


Subject(s)
COVID-19/genetics , COVID-19/virology , Gene Expression Regulation , Peptidyl-Dipeptidase A/genetics , Receptors, Pattern Recognition/genetics , Receptors, Virus/genetics , SARS-CoV-2/metabolism , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Child , Dermis/pathology , Fibroblasts/metabolism , Gene Expression Profiling , Humans , Middle Aged , RNA-Seq , Receptors, Virus/metabolism , Young Adult
12.
Clin Immunol ; 227: 108733, 2021 06.
Article in English | MEDLINE | ID: covidwho-1198654

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for many pathological processes, including altered vascular disease development, dysfunctional thrombosis and a heightened inflammatory response. However, there is limited work to determine the underlying cellular responses induced by exposure to SARS-CoV-2 structural proteins. Thus, our objective was to investigate how human arterial adventitial fibroblasts inflammation, thrombosis and diabetic disease markers are altered in response to Spike, Nucleocapsid and Membrane-Envelope proteins. We hypothesized that after a short-term exposure to SARS-CoV-2 proteins, adventitial fibroblasts would have a higher expression of inflammatory, thrombotic and diabetic proteins, which would support a mechanism for altered vascular disease progression. After incubation, the expression of gC1qR, ICAM-1, tissue factor, RAGE and GLUT-4 was significantly up-regulated. In general, the extent of expression was different for each SARS-CoV-2 protein, suggesting that SARS-CoV-2 proteins interact with cells through different mechanisms. Thus, SARS-CoV-2 protein interaction with vascular cells may regulate vascular disease responses.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/virology , Diabetes Mellitus/virology , Fibroblasts/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Thrombosis/virology , Aorta/cytology , Aorta/metabolism , Cardiovascular Diseases/complications , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Carrier Proteins/metabolism , Cell Survival/immunology , Cell Survival/physiology , Complement System Proteins/immunology , Coronavirus Envelope Proteins/immunology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Diabetes Mellitus/metabolism , Glucose Transporter Type 4/metabolism , Humans , Inflammation/metabolism , Inflammation/virology , Intercellular Adhesion Molecule-1/metabolism , Mitochondrial Proteins/metabolism , Receptor for Advanced Glycation End Products/metabolism , Thrombosis/complications , Thrombosis/metabolism
14.
Cell Rep ; 35(5): 109055, 2021 05 04.
Article in English | MEDLINE | ID: covidwho-1179291

ABSTRACT

Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Although infection initiates in the proximal airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type 2 (AT2) cells of the distal lung and associated inflammation. In this study, we develop primary human lung epithelial infection models to understand initial responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface (ALI) cultures of proximal airway epithelium and alveosphere cultures of distal lung AT2 cells are readily infected by SARS-CoV-2, leading to an epithelial cell-autonomous proinflammatory response with increased expression of interferon signaling genes. Studies to validate the efficacy of selected candidate COVID-19 drugs confirm that remdesivir strongly suppresses viral infection/replication. We provide a relevant platform for study of COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and emergent respiratory pathogens.


Subject(s)
Alveolar Epithelial Cells/virology , COVID-19/drug therapy , COVID-19/pathology , Lung/virology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adult , Aged , Alanine/analogs & derivatives , Alanine/pharmacology , Alveolar Epithelial Cells/metabolism , COVID-19/metabolism , COVID-19/virology , Child, Preschool , Drug Discovery/methods , Epithelial Cells/virology , Epithelium/metabolism , Epithelium/virology , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Lung/pathology , Male , Middle Aged , Models, Biological , Primary Cell Culture , Respiratory Mucosa/virology , SARS-CoV-2/physiology , Virus Replication/drug effects
15.
Biochim Biophys Acta Mol Basis Dis ; 1867(4): 166044, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1103717

ABSTRACT

Diabetes-associated morbidity and mortality is predominantly due to complications of the disease that may cause debilitating conditions, such as heart and renal failure, hepatic insufficiency, retinopathy or peripheral neuropathy. Fibrosis, the excessive and inappropriate deposition of extracellular matrix in various tissues, is commonly found in patients with advanced type 1 or type 2 diabetes, and may contribute to organ dysfunction. Hyperglycemia, lipotoxic injury and insulin resistance activate a fibrotic response, not only through direct stimulation of matrix synthesis by fibroblasts, but also by promoting a fibrogenic phenotype in immune and vascular cells, and possibly also by triggering epithelial and endothelial cell conversion to a fibroblast-like phenotype. High glucose stimulates several fibrogenic pathways, triggering reactive oxygen species generation, stimulating neurohumoral responses, activating growth factor cascades (such as TGF-ß/Smad3 and PDGFs), inducing pro-inflammatory cytokines and chemokines, generating advanced glycation end-products (AGEs) and stimulating the AGE-RAGE axis, and upregulating fibrogenic matricellular proteins. Although diabetes-activated fibrogenic signaling has common characteristics in various tissues, some organs, such as the heart, kidney and liver develop more pronounced and clinically significant fibrosis. This review manuscript summarizes current knowledge on the cellular and molecular pathways involved in diabetic fibrosis, discussing the fundamental links between metabolic perturbations and fibrogenic activation, the basis for organ-specific differences, and the promises and challenges of anti-fibrotic therapies for diabetic patients.


Subject(s)
Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 2/pathology , Animals , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Disease Progression , Epigenesis, Genetic , Fibroblasts/metabolism , Fibroblasts/pathology , Fibrosis , Glucose/genetics , Glucose/metabolism , Humans , Inflammation/genetics , Inflammation/metabolism , Inflammation/pathology , Signal Transduction
16.
Nature ; 588(7838): 466-472, 2020 12.
Article in English | MEDLINE | ID: covidwho-1075229

ABSTRACT

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.


Subject(s)
Myocardium/cytology , Single-Cell Analysis , Transcriptome , Adipocytes/classification , Adipocytes/metabolism , Adult , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Epithelial Cells/classification , Epithelial Cells/metabolism , Epithelium , Female , Fibroblasts/classification , Fibroblasts/metabolism , Gene Expression Profiling , Genome-Wide Association Study , Heart Atria/anatomy & histology , Heart Atria/cytology , Heart Atria/innervation , Heart Ventricles/anatomy & histology , Heart Ventricles/cytology , Heart Ventricles/innervation , Homeostasis/immunology , Humans , Macrophages/immunology , Macrophages/metabolism , Male , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Myocytes, Cardiac/classification , Myocytes, Cardiac/metabolism , Neurons/classification , Neurons/metabolism , Pericytes/classification , Pericytes/metabolism , Receptors, Coronavirus/analysis , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Stromal Cells/classification , Stromal Cells/metabolism
17.
Am J Physiol Lung Cell Mol Physiol ; 320(1): L152-L157, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1054733

ABSTRACT

The COVID-19 pandemic is associated with severe pneumonia and acute respiratory distress syndrome leading to death in susceptible individuals. For those who recover, post-COVID-19 complications may include development of pulmonary fibrosis. Factors contributing to disease severity or development of complications are not known. Using computational analysis with experimental data, we report that idiopathic pulmonary fibrosis (IPF)- and chronic obstructive pulmonary disease (COPD)-derived lung fibroblasts express higher levels of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 entry and part of the renin-angiotensin system that is antifibrotic and anti-inflammatory. In preclinical models, we found that chronic exposure to cigarette smoke, a risk factor for both COPD and IPF and potentially for SARS-CoV-2 infection, significantly increased pulmonary ACE2 protein expression. Further studies are needed to understand the functional implications of ACE2 on lung fibroblasts, a cell type that thus far has received relatively little attention in the context of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/pathology , Fibroblasts/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Adult , Animals , Female , Gene Expression Regulation/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Receptors, Virus/biosynthesis , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/metabolism , Smoke/adverse effects
18.
Exp Mol Med ; 52(12): 1871-1878, 2020 12.
Article in English | MEDLINE | ID: covidwho-1012677

ABSTRACT

Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFß) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.


Subject(s)
Inflammation/etiology , Inflammation/metabolism , Interleukin-11/metabolism , Respiratory Tract Diseases/etiology , Respiratory Tract Diseases/metabolism , Signal Transduction , Animals , Biomarkers , Cellular Senescence/genetics , Cellular Senescence/immunology , Cytokines/metabolism , Disease Susceptibility , Fibroblasts/metabolism , Fibrosis , Humans , Inflammation/diagnosis , Inflammation Mediators/metabolism , MAP Kinase Signaling System , Respiratory Function Tests , Respiratory Tract Diseases/diagnosis
19.
Eur Rev Med Pharmacol Sci ; 24(23): 12609-12622, 2020 12.
Article in English | MEDLINE | ID: covidwho-995022

ABSTRACT

OBJECTIVE: In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease. MATERIALS AND METHODS: PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm. RESULTS: The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed. CONCLUSIONS: The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.


Subject(s)
Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Cardiomyopathies/metabolism , Cytokine Release Syndrome/metabolism , Endothelium, Vascular/physiopathology , Liver Cirrhosis/metabolism , Systemic Inflammatory Response Syndrome/metabolism , Thrombosis/metabolism , Angiotensin I/metabolism , Atrial Fibrillation/metabolism , Atrial Fibrillation/physiopathology , Blood Coagulation , COVID-19/pathology , COVID-19/physiopathology , Capillary Permeability , Cardiomyopathies/pathology , Cardiomyopathies/physiopathology , Cytokine Release Syndrome/physiopathology , Cytokines/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Fibrosis , Humans , Liver Cirrhosis/pathology , Liver Cirrhosis/physiopathology , Myocarditis/metabolism , Myocarditis/pathology , Myocarditis/physiopathology , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , SARS-CoV-2/metabolism , Systemic Inflammatory Response Syndrome/physiopathology , Thrombosis/physiopathology , Virus Internalization
20.
Int J Mol Sci ; 21(23)2020 Dec 03.
Article in English | MEDLINE | ID: covidwho-965280

ABSTRACT

Glucocorticoids are drugs of choice in Duchenne muscular dystrophy (DMD), prolonging patients' ambulation. Their mode of action at the protein level is not completely understood. In DMD, muscle tissue is replaced by fibrotic tissue produced by fibroblasts, reducing mobility. Nuclear factor of activated T-cells 5 (NFAT5) is involved in fibroblast proliferation. By treating one DMD fibroblast cell culture and one of unaffected skeletal muscle fibroblasts with methylprednisolone (MP) or hydrocortisone (HC) for 24 h or 12 d, the antiproliferative properties of glucocorticoids could be unraveled. NFAT5 localization and expression was explored by immunocytochemistry (ICC), Western blotting (WB) and RT-qPCR. NFAT5 and glucocorticoid receptor (GR) colocalization was measured by ImageJ. GR siRNA was used, evaluating GR's influence on NFAT5 expression during MP and HC treatment. Cell proliferation was monitored by IncuCyte ZOOM. In DMD fibroblasts, treatment with MP for 24 h induced dots (ICC) positive for NFAT5 and colocalizing with GR. After 12 d of MP or HC in DMD fibroblasts, NFAT5 expression was decreased (RT-qPCR and WB) and growth arrest was observed (Incucyte ZOOM), whereas NFAT5 expression and cell growth remained unchanged in unaffected skeletal muscle fibroblasts. This study may help understand the antiproliferative properties of glucocorticoids in DMD fibroblasts.


Subject(s)
Fibroblasts/drug effects , Fibroblasts/metabolism , Glucocorticoids/pharmacology , Receptors, Glucocorticoid/metabolism , Transcription Factors/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Fluorescent Antibody Technique , Humans , Hydrocortisone/pharmacology , Methylprednisolone/pharmacology , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/metabolism , Protein Binding
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