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Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary...
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Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 38596

Special Issue Editors

Dr. Anindita Das

E-Mail Website
Guest Editor
Pauley Heart Center, Department of Internal Medicine, Cardiology Division, Virginia Commonwealth University, Richmond, VA, USA
Interests: myocardial infarction; cardiac hypertrophy; heart failure; anti-cancer drug-induced cardiotoxicity; cardiomyocyte; inflammation; necrosis; apoptosis; autophagy; cardioprotecton by pharmacological agents; pre- and post-conditioning; cardioprotective mechanism in diabetic heart; breast cancer; prostate cancer; nitric oxide; phosphodiesterase-5 inhibitors; protein kinase G; mTOR signaling; STAT3 signaling; p53 signaling; long-non-coding RNA; microRNA
Special Issues, Collections and Topics in MDPI journals
Dr. Arun Samidurai

E-Mail Website
Guest Editor
Pauley Heart Center, Department of Internal Medicine, Cardiology Division, Virginia Commonwealth University, Richmond, VA, USA
Interests: cellular signaling; myocardial infarction; ischemia reperfusion injury; heart failure; epigenetics; non-coding RNA; microRNA; pulmonary hypertension; lung fibrosis; vascular remodeling; phosphodiesterase; mTOR signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular and lung diseases are among the leading causes of premature death worldwide. Emerging research evidence indicates that chronic respiratory and cardiovascular disease frequently coexist, which adversely affect the prognosis of patients and contribute to all-cause mortality. Therefore, a dire need to identify the novel targets and early biomarkers to advancing therapeutics for treating the patients afflicted with these diseases appears urgent. To alleviate the damage from heart and lung diseases and reduce mortality, the scientists aim to understand the signaling pathways/mechanisms and the molecular interactions in cells of the heart, blood vessel or lung tissue and their impact in various physiological and pathological settings. To achieve this goal, this special issue in Cells will highlight the state-of-the-art research articles, which could advance our knowledge regarding the potential cellular and molecular mechanistic insight in cardiovascular and lung diseases.

The editors of this Special Issue of Cells welcome original research articles, reviews, meta-analyses/systematic reviews, or shorter perspective articles as well novel technological approaches on all aspects related to the pathophysiological, molecular aspects and treatment options of Cardiovascular Diseases (including coronary artery disease, arrhythmia, dilated cardiomyopathy, hypertrophic cardiomyopathy, diabetic cardiomyopathy, myocardial infarction, heart failure, congestive heart failure, congenital heart disease, valvular heart disease, hypertension etc.) and Pulmonary Diseases (chronic obstructive pulmonary disease (COPD), Pulmonary Arterial Hypertension (PAH), Pulmonary Fibrosis, Lung Cancer, Lung infection (pneumonia), Acute respiratory distress syndrome  (ARDS), etc.).

We are looking forward to your contributions to this Special Issue.

Dr. Anindita Das
Dr. Arun Samidurai
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Biomarkers,
  • Cell Signaling,
  • Epigenetic Regulation of Gene Expression
  • Gene Targets and Therapy,
  • Heart Diseases,
  • Inflammation,
  • Ischemia/Reperfusion Injury,
  • miRNA-long-non-coding RNA-target protein
  • Lung Cancer,
  • Pulmonary Diseases

Published Papers (15 papers)

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26 pages, 3989 KiB  
Article
Integrated Analysis of lncRNA–miRNA–mRNA Regulatory Network in Rapamycin-Induced Cardioprotection against Ischemia/Reperfusion Injury in Diabetic Rabbits
by Arun Samidurai, Amy L. Olex, Ramzi Ockaili, Donatas Kraskauskas, Sean K. Roh, Rakesh C. Kukreja and Anindita Das
Cells 2023, 12(24), 2820; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12242820 - 12 Dec 2023
Viewed by 1117
Abstract
The inhibition of mammalian target of rapamycin (mTOR) with rapamycin (RAPA) provides protection against myocardial ischemia/reperfusion (I/R) injury in diabetes. Since interactions between transcripts, including long non-coding RNA (lncRNA), microRNA(miRNA) and mRNA, regulate the pathophysiology of disease, we performed unbiased miRarray profiling in [...] Read more.
The inhibition of mammalian target of rapamycin (mTOR) with rapamycin (RAPA) provides protection against myocardial ischemia/reperfusion (I/R) injury in diabetes. Since interactions between transcripts, including long non-coding RNA (lncRNA), microRNA(miRNA) and mRNA, regulate the pathophysiology of disease, we performed unbiased miRarray profiling in the heart of diabetic rabbits following I/R injury with/without RAPA treatment to identify differentially expressed (DE) miRNAs and their predicted targets of lncRNAs/mRNAs. Results showed that among the total of 806 unique miRNAs targets, 194 miRNAs were DE after I/R in diabetic rabbits. Specifically, eight miRNAs, including miR-199a-5p, miR-154-5p, miR-543-3p, miR-379-3p, miR-379-5p, miR-299-5p, miR-140-3p, and miR-497-5p, were upregulated and 10 miRNAs, including miR-1-3p, miR-1b, miR-29b-3p, miR-29c-3p, miR-30e-3p, miR-133c, miR-196c-3p, miR-322-5p, miR-499-5p, and miR-672-5p, were significantly downregulated after I/R injury. Interestingly, RAPA treatment significantly reversed these changes in miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated the participation of miRNAs in the regulation of several signaling pathways related to I/R injury, including MAPK signaling and apoptosis. Furthermore, in diabetic hearts, the expression of lncRNAs, HOTAIR, and GAS5 were induced after I/R injury, but RAPA suppressed these lncRNAs. In contrast, MALAT1 was significantly reduced following I/R injury, with the increased expression of miR-199a-5p and suppression of its target, the anti-apoptotic protein Bcl-2. RAPA recovered MALAT1 expression with its sponging effect on miR-199-5p and restoration of Bcl-2 expression. The identification of novel targets from the transcriptome analysis in RAPA-treated diabetic hearts could potentially lead to the development of new therapeutic strategies for diabetic patients with myocardial infarction. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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19 pages, 8501 KiB  
Article
Role of Pellino-1 in Inflammation and Cardioprotection following Severe Sepsis: A Novel Mechanism in a Murine Severe Sepsis Model †
by Mahesh Thirunavukkarasu, Santosh Swaminathan, Andrew Kemerley, Seetur R. Pradeep, Sue Ting Lim, Diego Accorsi, Rickesha Wilson, Jacob Campbell, Ibnalwalid Saad, Siu-Pok Yee, J. Alexander Palesty, David W. McFadden and Nilanjana Maulik
Cells 2023, 12(11), 1527; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12111527 - 01 Jun 2023
Viewed by 2342
Abstract
Objectives: Intra-abdominal sepsis is commonly diagnosed in the surgical population and remains the second most common cause of sepsis overall. Sepsis-related mortality remains a significant burden in the intensive care unit despite advances in critical care. Nearly a quarter of the deaths in [...] Read more.
Objectives: Intra-abdominal sepsis is commonly diagnosed in the surgical population and remains the second most common cause of sepsis overall. Sepsis-related mortality remains a significant burden in the intensive care unit despite advances in critical care. Nearly a quarter of the deaths in people with heart failure are caused by sepsis. We have observed that overexpression of mammalian Pellino-1 (Peli1), an E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Given these manifold applications, we investigated the role of Peli1 in sepsis using transgenic and knockout mouse models specific to this protein. Therefore, we aimed to explore further the myocardial dysfunction seen in sepsis through its relation to the Peli 1 protein by using the loss of function and gain-of-function strategy. Methods: A series of genetic animals were created to understand the role of Peli1 in sepsis and the preservation of heart function. Wild-type, global Peli1 knock out (Peli1−/−), cardiomyocyte-specific Peli1 deletion (CP1KO), and cardiomyocyte-specific Peli1 overexpressing (alpha MHC (αMHC) Peli1; AMPEL1Tg/+) animals were divided into sham and cecal ligation and puncture (CLP) surgical procedure groups. Cardiac function was determined by two-dimensional echocardiography pre-surgery and at 6- and 24-h post-surgery. Serum IL-6 and TNF-alpha levels (ELISA) (6 h), cardiac apoptosis (TUNEL assay), and Bax expression (24 h) post-surgery were measured. Results are expressed as mean ± S.E.M. Results: AMPEL1Tg/+ prevents sepsis-induced cardiac dysfunction assessed by echocardiographic analysis, whereas global and cardiomyocyte-specific deletion of Peli1 shows significant deterioration of cardiac functions. Cardiac function was similar across the sham groups in all three genetically modified mice. ELISA assay displayed how Peli 1 overexpression decreased cardo-suppressive circulating inflammatory cytokines (TNF-alpha, IL-6) compared to both the knockout groups. The proportion of TUNEL-positive cells varied according to Peli1 expression, with overexpression (AMPEL1Tg/+) leading to a significant reduction and Peli1 gene knockout (Peli1−/− and CP1KO) leading to a significant increase in their presence. A similar trend was also observed with Bax protein expression. The improved cellular survival associated with Peli1 overexpression was again shown with the reduction of oxidative stress marker 4-Hydroxy-2-Nonenal (4-HNE). Conclusion: Our results indicate that overexpression of Peli1 is a novel approach that not only preserved cardiac function but reduced inflammatory markers and apoptosis following severe sepsis in a murine genetic model. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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16 pages, 1941 KiB  
Article
Circulatory Serum Krebs von Den Lungen-6 and Surfactant Protein-D Concentrations Predict Interstitial Lung Disease Progression and Mortality
by Meghna Rai, Ashwaghosha Parthasarathi, Narasimha M. Beeraka, Mohammed Kaleem Ullah, Sowmya Malamardi, Sunag Padukudru, Jayaraj Biligere Siddaiah, Chinnappa A. Uthaiah, Prashant Vishwanath, Sindaghatta Krishnarao Chaya, Subramanian Ramaswamy, Swapna Upadhyay, Koustav Ganguly and Padukudru Anand Mahesh
Cells 2023, 12(9), 1281; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12091281 - 28 Apr 2023
Cited by 2 | Viewed by 1513
Abstract
There is a need for biomarkers to predict outcomes, including mortality, in interstitial lung disease (ILD). Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are associated with lung damage and fibrosis in all ILDs and are related to important clinical outcomes. [...] Read more.
There is a need for biomarkers to predict outcomes, including mortality, in interstitial lung disease (ILD). Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are associated with lung damage and fibrosis in all ILDs and are related to important clinical outcomes. Though these two biomarkers have been associated with ILD outcomes, there are no studies that have evaluated their predictive potential in combination. This study aims to determine whether KL-6 and SP-D are linked to poor disease outcomes and mortality. Additionally, we plan to examine whether changes in KL-6 and SP-D concentrations correspond with changes in lung function and whether serial measurements improve their predictive potential to identify disease progression and mortality. Forty-four patients with ILD participated in a prospective 6-month longitudinal observational study. ILD patients who succumbed had the highest KL-6 levels (3990.4 U/mL (3490.0–4467.6)) and highest SP-D levels (256.1 ng/mL (217.9–260.0)), followed by those who deteriorated: KL-6 levels 1357.0 U/mL (822.6–1543.4) and SP-D levels 191.2 ng/mL (152.8–210.5). The generalized linear model (GLM) analysis demonstrated that changes in forced vital capacity (FVC), diffusing capacity of lungs for carbon monoxide (DLCO), forced expiratory volume in 1 s (FEV1), and partial pressure of arterial oxygen (PaO2) were correlated to changes in KL6 (p = 0.016, 0.014, 0.027, 0.047) and SP-D (p = 0.008, 0.012, 0.046, 0.020), respectively. KL-6 (odds ratio (OR): 2.87 (1.06–7.79)) and SPD (OR: 1.76 (1.05–2.97)) were independent predictors of disease progression, and KL-6 (hazard ratio (HR): 3.70 (1.46–9.41)) and SPD (HR: 2.58 (1.01–6.59)) were independent predictors of death by Cox regression analysis. Combined biomarkers (KL6 + SPD + CT + FVC) had the strongest ability to predict disease progression (AUC: 0.797) and death (AUC: 0.961), on ROC analysis. Elevated KL-6 and SPD levels are vital biomarkers for predicting the severity, progression, and outcomes of ILD. High baseline levels or an increase in levels over a six-month follow-up despite treatment indicate a poor prognosis. Combining KL6 and SPD with conventional measures yields a more potent prognostic indicator. Clinical studies are needed to test additional interventions, and future research will determine if this combined biomarker benefits different ethnicities globally. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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11 pages, 3087 KiB  
Communication
Inflammatory Cell Dynamics after Murine Femoral Artery Wire Injury: A Multi-Parameter Flow Cytometry-Based Analysis
by Vivek Pamulapati, Carla M. Cuda, Tracy L. Smith, Jonathan Jung, Liqun Xiong, Suchitra Swaminathan and Karen J. Ho
Cells 2023, 12(5), 689; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12050689 - 22 Feb 2023
Viewed by 1341
Abstract
An acute inflammatory response following arterial surgery for atherosclerosis, such as balloon angioplasty, stenting, and surgical bypass, is an important driver of neointimal hyperplasia after arterial injury, which leads to recurrent ischemia. However, a comprehensive understanding of the dynamics of the inflammatory infiltrate [...] Read more.
An acute inflammatory response following arterial surgery for atherosclerosis, such as balloon angioplasty, stenting, and surgical bypass, is an important driver of neointimal hyperplasia after arterial injury, which leads to recurrent ischemia. However, a comprehensive understanding of the dynamics of the inflammatory infiltrate in the remodeling artery is difficult to attain due to the shortcomings of conventional methods such as immunofluorescence. We developed a 15-parameter flow cytometry method to quantitate leukocytes and 13 leukocyte subtypes in murine arteries at 4 time points after femoral artery wire injury. Live leukocyte numbers peaked at 7 days, which preceded the peak neointimal hyperplasia lesion at 28 days. Neutrophils were the most abundant early infiltrate, followed by monocytes and macrophages. Eosinophils were elevated after 1 day, while natural killer and dendritic cells gradually infiltrated over the first 7 days; all decreased between 7 and 14 days. Lymphocytes began accumulating at 3 days and peaked at 7 days. Immunofluorescence of arterial sections demonstrated similar temporal trends of CD45+ and F4/80+ cells. This method allows for the simultaneous quantitation of multiple leukocyte subtypes from small tissue samples of injured murine arteries and identifies the CD64+Tim4+ macrophage phenotype as being potentially important in the first 7 days post-injury. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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15 pages, 4301 KiB  
Article
TMEM43 Protects against Sepsis-Induced Cardiac Injury via Inhibiting Ferroptosis in Mice
by Zhen Chen, Zhe Cao, Feng Gui, Mengli Zhang, Xian Wu, Huan Peng, Bo Yu, Wei Li, Fen Ai and Jun Zhang
Cells 2022, 11(19), 2992; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11192992 - 26 Sep 2022
Cited by 17 | Viewed by 3332
Abstract
A previous study found that transmembrane protein 43 (TMEM43) was highly associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy. However, as a transmembrane protein, TMEM43 may be involved in ferroptosis in cardiovascular disease. In this study, we aimed to explore the role of TMEM43 in [...] Read more.
A previous study found that transmembrane protein 43 (TMEM43) was highly associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy. However, as a transmembrane protein, TMEM43 may be involved in ferroptosis in cardiovascular disease. In this study, we aimed to explore the role of TMEM43 in lipopolysaccharide (LPS)-induced cardiac injury and the underlying mechanism. Mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis. Mice were also subjected to AAV9-shTMEM43 to knock down TMEM43 or AAV9-TMEM43 to overexpress TMEM43 in hearts. H9c2 rat cardiomyocytes were also transfected with Ad-TMEM43 or TMEM43 siRNA to overexpress/knock down TMEM43. As a result, TMEM43 knockdown in hearts deteriorated LPS-induced mouse cardiac injury and dysfunction. LPS increased cardiac ferroptosis as assessed by malonaldehyde (MDA) and cardiac iron density, which were aggravated by TMEM43 knockdown. Moreover, TMEM43 overexpression alleviated LPS-induced cardiac injury, dysfunction, and ferroptosis. In vitro experiments showed that TMEM43 overexpression inhibited LPS-induced lipid peroxidation and cardiomyocyte injury while TMEM43 knockdown aggravated LPS-induced ferroptosis and injury in cardiomyocytes. Mechanistically, LPS increased the expression of P53 and ferritin but decreased the level of Gpx4 and SLC7A11. TMEM43 could inhibit the level of P53 and ferritin enhanced the level of Gpx4 and SLC7A11. Furthermore, ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, could protect against LPS-induced cardiac injury and also counteracted the deteriorating effects of TMEM43 silencing in the heart. Based on these findings, we concluded that TMEM43 protects against sepsis-induced cardiac injury via inhibiting ferroptosis in mice. By targeting ferroptosis in cardiomyocytes, TMEM43 may be a therapeutic strategy for preventing sepsis in the future. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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21 pages, 6503 KiB  
Article
Identification of Cardiovascular Disease-Related Genes Based on the Co-Expression Network Analysis of Genome-Wide Blood Transcriptome
by Taesic Lee, Sangwon Hwang, Dong Min Seo, Ha Chul Shin, Hyun Soo Kim, Jang-Young Kim and Young Uh
Cells 2022, 11(18), 2867; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11182867 - 14 Sep 2022
Cited by 2 | Viewed by 2183
Abstract
Inference of co-expression network and identification of disease-related modules and gene sets can help us understand disease-related molecular pathophysiology. We aimed to identify a cardiovascular disease (CVD)-related transcriptomic signature, specifically, in peripheral blood tissue, based on differential expression (DE) and differential co-expression (DcoE) [...] Read more.
Inference of co-expression network and identification of disease-related modules and gene sets can help us understand disease-related molecular pathophysiology. We aimed to identify a cardiovascular disease (CVD)-related transcriptomic signature, specifically, in peripheral blood tissue, based on differential expression (DE) and differential co-expression (DcoE) analyses. Publicly available blood sample datasets for coronary artery disease (CAD) and acute coronary syndrome (ACS) statuses were integrated to establish a co-expression network. A weighted gene co-expression network analysis was used to construct modules that include genes with highly correlated expression values. The DE criterion is a linear regression with module eigengenes for module-specific genes calculated from principal component analysis and disease status as the dependent and independent variables, respectively. The DcoE criterion is a paired t-test for intramodular connectivity between disease and matched control statuses. A total of 21 and 23 modules were established from CAD status- and ACS-related datasets, respectively, of which six modules per disease status (i.e., obstructive CAD and ACS) were selected based on the DE and DcoE criteria. For each module, gene–gene interactions with extremely high correlation coefficients were individually selected under the two conditions. Genes displaying a significant change in the number of edges (gene–gene interaction) were selected. A total of 6, 10, and 7 genes in each of the three modules were identified as potential CAD status-related genes, and 14 and 8 genes in each of the two modules were selected as ACS-related genes. Our study identified gene sets and genes that were dysregulated in CVD blood samples. These findings may contribute to the understanding of CVD pathophysiology. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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22 pages, 3475 KiB  
Article
HIV and Schistosoma Co-Exposure Leads to Exacerbated Pulmonary Endothelial Remodeling and Dysfunction Associated with Altered Cytokine Landscape
by Sandra Medrano-Garcia, Daniel Morales-Cano, Bianca Barreira, Alba Vera-Zambrano, Rahul Kumar, Djuro Kosanovic, Ralph Theo Schermuly, Brian B. Graham, Francisco Perez-Vizcaino, Alistair Mathie, Rajkumar Savai, Soni Pullamseti, Ghazwan Butrous, Edgar Fernández-Malavé and Angel Cogolludo
Cells 2022, 11(15), 2414; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152414 - 04 Aug 2022
Cited by 1 | Viewed by 2213
Abstract
HIV and Schistosoma infections have been individually associated with pulmonary vascular disease. Co-infection with these pathogens is very common in tropical areas, with an estimate of six million people co-infected worldwide. However, the effects of HIV and Schistosoma co-exposure on the pulmonary vasculature [...] Read more.
HIV and Schistosoma infections have been individually associated with pulmonary vascular disease. Co-infection with these pathogens is very common in tropical areas, with an estimate of six million people co-infected worldwide. However, the effects of HIV and Schistosoma co-exposure on the pulmonary vasculature and its impact on the development of pulmonary vascular disease are largely unknown. Here, we have approached these questions by using a non-infectious animal model based on lung embolization of Schistosoma mansoni eggs in HIV-1 transgenic (HIV) mice. Schistosome-exposed HIV mice but not wild-type (Wt) counterparts showed augmented pulmonary arterial pressure associated with markedly suppressed endothelial-dependent vasodilation, increased endothelial remodeling and vessel obliterations, formation of plexiform-like lesions and a higher degree of perivascular fibrosis. In contrast, medial wall muscularization was similarly increased in both types of mice. Moreover, HIV mice displayed an impaired immune response to parasite eggs in the lung, as suggested by decreased pulmonary leukocyte infiltration, small-sized granulomas, and augmented residual egg burden. Notably, vascular changes in co-exposed mice were associated with increased expression of proinflammatory and profibrotic cytokines, including IFN-γ and IL-17A in CD4+ and γδ T cells and IL-13 in myeloid cells. Collectively, our study shows for the first time that combined pulmonary persistence of HIV proteins and Schistosoma eggs, as it may occur in co-infected people, alters the cytokine landscape and targets the vascular endothelium for aggravated pulmonary vascular pathology. Furthermore, it provides an experimental model for the understanding of pulmonary vascular disease associated with HIV and Schistosoma co-morbidity. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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14 pages, 1994 KiB  
Article
Monocyte Subsets in Patients with Chronic Heart Failure Treated with Cardiac Resynchronization Therapy
by Katarzyna Ptaszyńska-Kopczyńska, Andrzej Eljaszewicz, Marta Marcinkiewicz-Siemion, Emilia Sawicka-Śmiarowska, Ewa Tarasiuk, Anna Lisowska, Marlena Tynecka, Kamil Grubczak, Urszula Radzikowska, Adrian Janucik, Marcin Moniuszko, Karol Charkiewicz, Piotr Laudański, Bożena Sobkowicz and Karol A. Kamiński
Cells 2021, 10(12), 3482; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123482 - 09 Dec 2021
Cited by 3 | Viewed by 2187
Abstract
Background: The exact role of individual inflammatory factor in heart failure with reduced ejection fraction (HFrEF) remains elusive. The study aimed to evaluate three monocyte subsets (classical-CD14++CD16−, intermediate-CD14++CD16+, and nonclassical-CD14+CD16++) in [...] Read more.
Background: The exact role of individual inflammatory factor in heart failure with reduced ejection fraction (HFrEF) remains elusive. The study aimed to evaluate three monocyte subsets (classical-CD14++CD16−, intermediate-CD14++CD16+, and nonclassical-CD14+CD16++) in HFrEF patients and to assess the effect of the cardiac resynchronization therapy (CRT) on the changes in monocyte compartment. Methods: The study included 85 patients with stable HFrEF. Twenty-five of them underwent CRT device implantation with subsequent 6-month assessment. The control group consisted of 23 volunteers without HFrEF. Results: The analysis revealed that frequencies of non-classical-CD14+CD16++ monocytes were lower in HFrEF patients compared to the control group (6.98 IQR: 4.95–8.65 vs. 8.37 IQR: 6.47–9.94; p = 0.021), while CD14++CD16+ and CD14++CD16− did not differ. The analysis effect of CRT on the frequency of analysed monocyte subsets 6 months after CRT device implantation showed a significant increase in CD14+CD16++ (from 7 IQR: 4.5–8.4 to 7.9 IQR: 6.5–9.5; p = 0.042) and CD14++CD16+ (from 5.1 IQR: 3.7–6.5 to 6.8 IQR: 5.4–7.4; p = 0.017) monocytes, while the frequency of steady-state CD14++CD16− monocytes was decreased (from 81.4 IQR: 78–86.2 to 78.2 IQR: 76.1–81.7; p = 0.003). Conclusions: HFrEF patients present altered monocyte composition. CRT-related changes in the monocyte compartment achieve levels observed in controls without HFrEF. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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18 pages, 4280 KiB  
Article
Intermittent High Glucose Elevates Nuclear Localization of EZH2 to Cause H3K27me3-Dependent Repression of KLF2 Leading to Endothelial Inflammation
by Sumukh Thakar, Yash T Katakia, Shyam Kumar Ramakrishnan, Niyati Pandya Thakkar and Syamantak Majumder
Cells 2021, 10(10), 2548; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102548 - 26 Sep 2021
Cited by 10 | Viewed by 3442
Abstract
Epigenetic mechanisms have emerged as one of the key pathways promoting diabetes-associated complications. Herein, we explored the role of enhancer of zeste homolog 2 (EZH2) and its product histone 3 lysine 27 trimethylation (H3K27me3) in high glucose-mediated endothelial inflammation. To examine this, we [...] Read more.
Epigenetic mechanisms have emerged as one of the key pathways promoting diabetes-associated complications. Herein, we explored the role of enhancer of zeste homolog 2 (EZH2) and its product histone 3 lysine 27 trimethylation (H3K27me3) in high glucose-mediated endothelial inflammation. To examine this, we treated cultured primary endothelial cells (EC) with different treatment conditions—namely, constant or intermittent or transient high glucose. Intermittent high glucose maximally induced endothelial inflammation by upregulating transcript and/or protein-level expression of ICAM1 and P-selectin and downregulating eNOS, KLF2, and KLF4 protein levels. We next investigated the underlining epigenetic mechanisms responsible for intermittent hyperglycemia-dependent endothelial inflammation. Compared with other high glucose treatment groups, intermittent high glucose-exposed EC exhibited an increased level of H3K27me3 caused by reduction in EZH2 threonine 367 phosphorylation and nuclear retention of EZH2. Intermittent high glucose also promoted polycomb repressive complex-2 (PRC2) assembly and EZH2′s recruitment to histone H3. Abrupt enrichment of H3K27me3 on KLF2 and KLF4 gene promoters caused repression of these genes, further supporting endothelial inflammation. In contrast, reducing H3K27me3 through small molecule and/or siRNA-mediated inhibition of EZH2 rescued KLF2 level and inhibited endothelial inflammation in intermittent high glucose-challenged cultured EC and isolated rat aorta. These findings indicate that abrupt chromatin modifications cause high glucose-dependent inflammatory switch of EC. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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15 pages, 3462 KiB  
Article
Th17/Treg-Related Intracellular Signaling in Patients with Chronic Obstructive Pulmonary Disease: Comparison between Local and Systemic Responses
by Juliana D. Lourenço, Walcy R. Teodoro, Denise F. Barbeiro, Ana Paula P. Velosa, Larissa E. F. Silva, Júlia B. Kohler, Alyne R. Moreira, Marcelo V. Aun, Isadora C. da Silva, Frederico L. A. Fernandes, Elnara M. Negri, Jefferson L. Gross, Iolanda F. L. C. Tibério, Juliana T. Ito and Fernanda D. T. Q. S. Lopes
Cells 2021, 10(7), 1569; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071569 - 22 Jun 2021
Cited by 10 | Viewed by 2269
Abstract
Th17/Treg imbalance plays a pivotal role in COPD development and progression. We aimed to assess Th17/Treg-related intracellular signaling at different COPD stages in local and systemic responses. Lung tissue and/or peripheral blood samples were collected and divided into non-obstructed (NOS), COPD stages I [...] Read more.
Th17/Treg imbalance plays a pivotal role in COPD development and progression. We aimed to assess Th17/Treg-related intracellular signaling at different COPD stages in local and systemic responses. Lung tissue and/or peripheral blood samples were collected and divided into non-obstructed (NOS), COPD stages I and II, and COPD stages III and IV groups. Gene expression of STAT3 and -5, RORγt, Foxp3, interleukin (IL)-6, -17, -10, and TGF-β was assessed by RT-qPCR. IL-6, -17, -10, and TGF-β levels were determined by ELISA. We observed increased STAT3, RORγt, Foxp3, IL-6, and TGF-β gene expression and IL-6 levels in the lungs of COPD I and II patients compared to those of NOS patients. Regarding the systemic response, we observed increased STAT3, RORγt, IL-6, and TGF-β gene expression in the COPD III and IV group and increased IL-6 levels in the COPD I and II group. STAT5 was increased in COPD III and IV patients, although there was a decrease in Foxp3 expression and IL-10 levels in the COPD I and II and COPD III and IV groups, respectively. We demonstrated that an increase in Th17 intracellular signaling in the lungs precedes this increase in the systemic response, whereas Treg intracellular signaling varies between the compartments analyzed in different COPD stages. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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11 pages, 1230 KiB  
Article
Red Blood Cell Peroxynitrite Causes Endothelial Dysfunction in Type 2 Diabetes Mellitus via Arginase
by Ali Mahdi, John Tengbom, Michael Alvarsson, Bernhard Wernly, Zhichao Zhou and John Pernow
Cells 2020, 9(7), 1712; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071712 - 16 Jul 2020
Cited by 39 | Viewed by 3352
Abstract
We recently showed that red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM-RBCs) induce endothelial dysfunction through a mechanism involving arginase I and reactive oxygen species. Peroxynitrite is known to activate arginase in endothelial cells. Whether peroxynitrite regulates arginase activity [...] Read more.
We recently showed that red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM-RBCs) induce endothelial dysfunction through a mechanism involving arginase I and reactive oxygen species. Peroxynitrite is known to activate arginase in endothelial cells. Whether peroxynitrite regulates arginase activity in RBCs, and whether it is involved in the cross-talk between RBCs and the vasculature in T2DM, is unclear and elusive. The present study was designed to test the hypothesis that endothelial dysfunction induced by T2DM-RBCs is driven by peroxynitrite and upregulation of arginase. RBCs were isolated from patients with T2DM and healthy age matched controls. RBCs were co-incubated with aortae isolated from wild type rats for 18 h in the absence and presence of peroxynitrite scavenger FeTTPS. Evaluation of endothelial function in organ chambers by cumulative addition of acetylcholine as well as measurement of RBC and vessel arginase activity was performed. In another set of experiments, RBCs isolated from healthy subjects (Healthy RBCs) were incubated with the peroxynitrite donor SIN-1 with subsequent evaluation of endothelial function and arginase activity. T2DM-RBCs, but not Healthy RBCs, induced impairment in endothelial function, which was fully reversed by scavenging of RBC but not vascular peroxynitrite with FeTPPS. Arginase activity was up-regulated by the peroxynitrite donor SIN-1 in Healthy RBCs, an effect that was inhibited by FeTTPS. Healthy RBCs co-incubated with aortae in the presence of SIN-1 caused impairment of endothelial function, which was inhibited by FeTTPS or the arginase inhibitor ABH. T2DM-RBCs induced up-regulation of vascular arginase, an effect that was fully inhibited by FeTTPS. Collectively, our data indicate that RBCs impair endothelial function in T2DM via an effect that is driven by a peroxynitrite-mediated increase in arginase activity. This mechanism may be targeted in patients with T2DM for improvement in endothelial function. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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Review

Jump to: Research, Other

10 pages, 1416 KiB  
Review
Methodological Progress of Stereology in Cardiac Research and Its Application to Normal and Pathological Heart Development
by Christian Mühlfeld and Julia Schipke
Cells 2022, 11(13), 2032; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132032 - 26 Jun 2022
Cited by 4 | Viewed by 1946
Abstract
Design-based stereology is the gold standard for obtaining unbiased quantitative morphological data on volume, surface area, and length, as well as the number of tissues, cells or organelles. In cardiac research, the introduction of a stereological method to unbiasedly estimate the number of [...] Read more.
Design-based stereology is the gold standard for obtaining unbiased quantitative morphological data on volume, surface area, and length, as well as the number of tissues, cells or organelles. In cardiac research, the introduction of a stereological method to unbiasedly estimate the number of cardiomyocytes has considerably increased the use of stereology. Since its original description, various modifications to this method have been described. A particular field in which this method has been employed is the normal developmental life cycle of cardiomyocytes after birth, and particularly the question of when, during postnatal development, cardiomyocytes lose their capacity to divide and proliferate, and thus their inherent regenerative ability. This field is directly related to a second major application of stereology in recent years, addressing the question of what consequences intrauterine growth restriction has on the development of the heart, particularly of cardiomyocytes. Advances have also been made regarding the quantification of nerve fibers and collagen deposition as measures of heart innervation and fibrosis. In the present review article, we highlight the methodological progress made in the last 20 years and demonstrate how stereology has helped to gain insight into the process of normal cardiac development, and how it is affected by intrauterine growth restriction. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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20 pages, 1732 KiB  
Review
Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis
by I-Chen Chen, Yi-Ching Liu, Yen-Hsien Wu, Shih-Hsing Lo, Zen-Kong Dai, Jong-Hau Hsu and Yu-Hsin Tseng
Cells 2022, 11(9), 1543; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091543 - 04 May 2022
Cited by 5 | Viewed by 2968
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and it has a worse prognosis than non-small cell lung cancer. The pathomechanism of IPF is not fully understood, but it has been suggested that repeated microinjuries of epithelial cells [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and it has a worse prognosis than non-small cell lung cancer. The pathomechanism of IPF is not fully understood, but it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts. These activated myofibroblasts express α smooth muscle actin and release extracellular matrix to promote matrix deposition and tissue remodeling. Under physiological conditions, the remodeling process stops once wound healing is complete. However, in the lungs of IPF patients, myofibroblasts re-main active and deposit excess extracellular matrix. This leads to the destruction of alveolar tissue, the loss of lung elastic recoil, and a rapid decrease in lung function. Some evidence has indicated that proteasomal inhibition combats fibrosis by inhibiting the expressions of extracellular matrix proteins and metalloproteinases. However, the mechanisms by which proteasome inhibitors may protect against fibrosis are not known. This review summarizes the current research on proteasome inhibitors for pulmonary fibrosis, and provides a reference for whether proteasome inhibitors have the potential to become new drugs for the treatment of pulmonary fibrosis. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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27 pages, 713 KiB  
Review
Developmental Pathways Underlying Lung Development and Congenital Lung Disorders
by Inês Caldeira, Hugo Fernandes-Silva, Daniela Machado-Costa, Jorge Correia-Pinto and Rute Silva Moura
Cells 2021, 10(11), 2987; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112987 - 02 Nov 2021
Cited by 17 | Viewed by 3542
Abstract
Lung organogenesis is a highly coordinated process governed by a network of conserved signaling pathways that ultimately control patterning, growth, and differentiation. This rigorously regulated developmental process culminates with the formation of a fully functional organ. Conversely, failure to correctly regulate this intricate [...] Read more.
Lung organogenesis is a highly coordinated process governed by a network of conserved signaling pathways that ultimately control patterning, growth, and differentiation. This rigorously regulated developmental process culminates with the formation of a fully functional organ. Conversely, failure to correctly regulate this intricate series of events results in severe abnormalities that may compromise postnatal survival or affect/disrupt lung function through early life and adulthood. Conditions like congenital pulmonary airway malformation, bronchopulmonary sequestration, bronchogenic cysts, and congenital diaphragmatic hernia display unique forms of lung abnormalities. The etiology of these disorders is not yet completely understood; however, specific developmental pathways have already been reported as deregulated. In this sense, this review focuses on the molecular mechanisms that contribute to normal/abnormal lung growth and development and their impact on postnatal survival. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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Other

Jump to: Research, Review

8 pages, 835 KiB  
Brief Report
Association of Clonal Hematopoiesis of Indeterminate Potential with Inflammatory Gene Expression in Patients with COPD
by Stefan Kuhnert, Siavash Mansouri, Michael A. Rieger, Rajkumar Savai, Edibe Avci, Gabriela Díaz-Piña, Manju Padmasekar, Mario Looso, Stefan Hadzic, Till Acker, Stephan Klatt, Jochen Wilhelm, Ingrid Fleming, Natascha Sommer, Norbert Weissmann, Claus Vogelmeier, Robert Bals, Andreas Zeiher, Stefanie Dimmeler, Werner Seeger and Soni S. Pullamsettiadd Show full author list remove Hide full author list
Cells 2022, 11(13), 2121; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132121 - 05 Jul 2022
Cited by 5 | Viewed by 2646
Abstract
Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its [...] Read more.
Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (~20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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