scholarly journals Selective CDK9 inhibition resolves neutrophilic inflammation and enhances cardiac regeneration in larval zebrafish

Development ◽  
2021 ◽  
Author(s):  
Aryan Kaveh ◽  
Finnius A. Bruton ◽  
Magdalena E. M. Oremek ◽  
Carl S. Tucker ◽  
Jonathan M. Taylor ◽  
...  
Keyword(s):  
Cardiac Injury ◽  
Neutrophil Infiltration ◽  
Light Sheet ◽  
Cardiac Repair ◽  
Adverse Outcomes ◽  
Continuous Exposure ◽  
Neutrophilic Inflammation ◽  
Macrophage Polarisation ◽  
Larval Zebrafish ◽  
Cdk9 Inhibitor

Sustained neutrophilic inflammation is detrimental for cardiac repair and associated with adverse outcomes following myocardial infarction (MI). An attractive therapeutic strategy to treat MI is to reduce or remove infiltrating neutrophils to promote downstream reparative mechanisms. CDK9 inhibitor compounds enhance the resolution of neutrophilic inflammation, however, their effects on cardiac repair/regeneration are unknown. Our laboratory has devised a cardiac injury model to investigate inflammatory and regenerative responses in larval zebrafish using heartbeat-synchronised light sheet fluorescence microscopy. We used this model to test two clinically approved CDK9 inhibitors, AT7519 and Flavopiridol, examining their effects on neutrophils, macrophages and cardiomyocyte regeneration. We found AT7519 and Flavopiridol resolve neutrophil infiltration by inducing reverse migration from the cardiac lesion. While continuous exposure to AT7519 or Flavopiridol caused adverse phenotypes, transient treatment accelerated neutrophil resolution while avoiding these effects. Transient treatment with AT7519, but not Flavopiridol, augmented wound-associated macrophage polarisation, which enhanced macrophage-dependent cardiomyocyte number expansion and the rate of myocardial wound closure. Using cdk9−/- knockout mutants we showed AT7519 is a selective CDK9 inhibitor, revealing the potential of such treatments to promote cardiac repair/regeneration.

scholarly journals Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bas Molenaar ◽  
Louk T. Timmer ◽  
Marjolein Droog ◽  
Ilaria Perini ◽  
Danielle Versteeg ◽  
...  
Keyword(s):  
Single Cell ◽  
Communication Networks ◽  
Cardiac Remodeling ◽  
Cardiac Injury ◽  
Ischemic Injury ◽  
Cell Types ◽  
Repair Process ◽  
Cardiac Repair ◽  
Cellular Heterogeneity ◽  
Intercellular Signaling

AbstractThe efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair.

scholarly journals The Predictive Value of Myoglobin for COVID-19-Related Adverse Outcomes: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Chaoqun Ma ◽  
Dingyuan Tu ◽  
Jiawei Gu ◽  
Qiang Xu ◽  
Pan Hou ◽  
...  
Keyword(s):  
Troponin I ◽  
Meta Analysis ◽  
Severe Disease ◽  
Cardiac Injury ◽  
Case Fatality ◽  
Adverse Outcomes ◽  
Cardiac Biomarkers ◽  
Severe Illness ◽  
Poor Outcomes ◽  
Meta Analyses

Objective: Cardiac injury is detected in numerous patients with coronavirus disease 2019 (COVID-19) and has been demonstrated to be closely related to poor outcomes. However, an optimal cardiac biomarker for predicting COVID-19 prognosis has not been identified.Methods: The PubMed, Web of Science, and Embase databases were searched for published articles between December 1, 2019 and September 8, 2021. Eligible studies that examined the anomalies of different cardiac biomarkers in patients with COVID-19 were included. The prevalence and odds ratios (ORs) were extracted. Summary estimates and the corresponding 95% confidence intervals (95% CIs) were obtained through meta-analyses.Results: A total of 63 studies, with 64,319 patients with COVID-19, were enrolled in this meta-analysis. The prevalence of elevated cardiac troponin I (cTnI) and myoglobin (Mb) in the general population with COVID-19 was 22.9 (19–27%) and 13.5% (10.6–16.4%), respectively. However, the presence of elevated Mb was more common than elevated cTnI in patients with severe COVID-19 [37.7 (23.3–52.1%) vs.30.7% (24.7–37.1%)]. Moreover, compared with cTnI, the elevation of Mb also demonstrated tendency of higher correlation with case-severity rate (Mb, r = 13.9 vs. cTnI, r = 3.93) and case-fatality rate (Mb, r = 15.42 vs. cTnI, r = 3.04). Notably, elevated Mb level was also associated with higher odds of severe illness [Mb, OR = 13.75 (10.2–18.54) vs. cTnI, OR = 7.06 (3.94–12.65)] and mortality [Mb, OR = 13.49 (9.3–19.58) vs. cTnI, OR = 7.75 (4.4–13.66)] than cTnI.Conclusions: Patients with COVID-19 and elevated Mb levels are at significantly higher risk of severe disease and mortality. Elevation of Mb may serve as a marker for predicting COVID-19-related adverse outcomes.Prospero Registration Number:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020175133, CRD42020175133.

Abstract 15: Limiting GRK2 in the Ischemic Heart can Promote Cardiac Regeneration

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Maria Cecilia Scimia ◽  
Lin Zuo ◽  
Kate E Sydnes ◽  
Daniel A Zuppo ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Cardiac Repair ◽  
Functional Improvement ◽  
Coronary Artery Ligation ◽  
Therapeutic Effects ◽  
Artery Ligation ◽  
C Terminus ◽  
Independent Effects

The detrimental role of G protein-coupled receptor (GPCR) kinase (GRK2) following cardiac injury/stress has been documented over the last two decades. Importantly, our lab has shown that inhibition or deletion of GRK2 in cardiomyocytes can prevent and also rescue heart failure (HF) phenotypes. Its role in GPCR desensitization including regulation of β-adrenergic receptors (βARs) during HF development has been well characterized. However, recently our lab and others have found that GRK2 can have novel GPCR-independent effects in the heart that appear to contribute to its pathological effects and thus, inhibition of these actions of GRK2 may contribute to therapeutic effects seen. In this study we explored whether the cardiac repair observed with lower myocardial GRK2 might involve regenerative processes. In cardiac-specific GRK2 knockout (KO) mice and also transgenic mice with cardiac-targeted expression of the βARKct, a peptide inhibitor of GRK2 activation via Gβγ sequestration, we induced HF via coronary artery ligation and subsequent myocardial infarction (MI) and measured aspects of cardiac repair including potential regeneration indices. Post-MI mice (GRK2 KO, βARKct mice and wild-type and non-transgenic control mice) were treated with 5-ethynyl-2’-deoxyuridine (EdU) or Bromodeoxyuridine (BrDU) to examine indices of DNA proliferation in myocytes as well as Ki67 staining. We also quantitated c-kit+ cells and myocytes in the post-MI hearts to compare how either loss of GRK2 expression or inhibition via its C-terminus altered potential regeneration mechanisms compared to control mice with endogenous GRK2 levels and activity. We found significantly more BrDU positive myocytes in post-MI hearts with lower GRK2 and this correlated with increased myocytes that were also cKit+. Thus, it appears that the myocardial functional improvement seen in the post-MI heart with targeted lowering of GRK2 involves, to at least a certain extent, regenerative mechanisms. This adds novel insight into the therapeutic potential of GRK2 inhibition for HF.

scholarly journals Covering and Re-Covering the Heart: Development and Regeneration of the Epicardium

2018 ◽  
Vol 6 (1) ◽  
pp. 3 ◽  
Author(s):  
Yingxi Cao ◽  
Jingli Cao
Keyword(s):  
Heart Development ◽  
Progenitor Cell ◽  
Recent Progress ◽  
Cardiac Injury ◽  
Vital Role ◽  
Cardiac Repair ◽  
Heart Regeneration ◽  
Epicardial Cells ◽  
Cell Source ◽  
Signaling Center

The epicardium, a mesothelial layer that envelops vertebrate hearts, has become a therapeutic target in cardiac repair strategies because of its vital role in heart development and cardiac injury response. Epicardial cells serve as a progenitor cell source and signaling center during both heart development and regeneration. The importance of the epicardium in cardiac repair strategies has been reemphasized by recent progress regarding its requirement for heart regeneration in zebrafish, and by the ability of patches with epicardial factors to restore cardiac function following myocardial infarction in mammals. The live surveillance of epicardial development and regeneration using zebrafish has provided new insights into this topic. In this review, we provide updated knowledge about epicardial development and regeneration.

Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury

2006 ◽  
Vol 291 (4) ◽  
pp. L580-L587 ◽  
Author(s):  
Je Hyeong Kim ◽  
Min Hyun Suk ◽  
Dae Wui Yoon ◽  
Seung Heon Lee ◽  
Gyu Young Hur ◽  
...  
Keyword(s):  
Lung Injury ◽  
Matrix Metalloproteinase ◽  
Tidal Volume ◽  
Weight Ratio ◽  
Dry Weight ◽  
Neutrophil Infiltration ◽  
Neutrophilic Inflammation ◽  
Ventilator Induced Lung Injury ◽  
Metalloproteinase 9 ◽  
Expression And Activity

Neutrophils are considered to play a central role in ventilator-induced lung injury (VILI). However, the pulmonary consequences of neutrophil accumulation have not been fully elucidated. Matrix metalloproteinase-9 (MMP-9) had been postulated to participate in neutrophil transmigration. The purpose of this study was to investigate the role of MMP-9 in the neutrophilic inflammation of VILI. Male Sprague-Dawley rats were divided into three groups: 1) low tidal volume (LVT), 7 ml/kg of tidal volume (VT); 2) high tidal volume (HVT), 30 ml/kg of VT; and 3) HVT with MMP inhibitor (HVT+MMPI). As a MMPI, CMT-3 was administered daily from 3 days before mechanical ventilation. Degree of VILI was assessed by wet-to-dry weight ratio and acute lung injury (ALI) scores. Neutrophilic inflammation was determined from the neutrophil count in the lung tissue and myeloperoxidase (MPO) activity in the bronchoalveolar lavage fluid (BALF). MMP-9 expression and activity were examined by immunohistochemical staining and gelatinase zymography, respectively. The wet-to-dry weight ratio, ALI score, neutrophil infiltration, and MPO activity were increased significantly in the HVT group. However, in the HVT+MMPI group, pretreatment with MMPI decreased significantly the degree of VILI, as well as neutrophil infiltration and MPO activity. These changes correlated significantly with MMP-9 immunoreactivity and MMP-9 activity. Most outcomes were significantly worse in the HVT+MMPI group compared with the LVT group. In conclusion, VILI mediated by neutrophilic inflammation is closely related to MMP-9 expression and activity. The inhibition of MMP-9 protects against the development of VILI through the downregulation of neutrophil-mediated inflammation.

scholarly journals Sesame Oil Attenuates Ovalbumin-Induced Pulmonary Edema and Bronchial Neutrophilic Inflammation in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Dur-Zong Hsu ◽  
Chuan-Teng Liu ◽  
Pei-Yi Chu ◽  
Ya-Hui Li ◽  
Srinivasan Periasamy ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
Allergic Asthma ◽  
Inflammatory Diseases ◽  
Pulmonary Inflammation ◽  
Allergic Airway Inflammation ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Sesame Oil ◽  
Neutrophilic Inflammation ◽  
Nitrite Level

Background. Allergic asthma is one of the most common chronic inflammatory diseases of airways. Severe asthma may lead to hospitalization and death. Sesame oil is a natural product with anti-inflammatory property. However, the effect of sesame oil on allergic asthma has never been studied.Objective. We investigate the effect of sesame oil on pulmonary inflammation in allergic asthma model.Methods. Allergic airway inflammation was induced by sensitizing with two doses of 10 mg ovalbumin (OVA) and then challenged with 1% OVA nebulizer exposure (1 h/day) for 3 days. Sesame oil (0.25, 0.5, or 1 mL/kg/day) was given orally 30 min before each challenge. Samples were collected 24 h after the last challenge.Results. Data showed that sesame oil inhibited pulmonary edema and decreased interleukin (IL)-1βand IL-6 levels in bronchoalveolar lavage fluid in OVA-treated mice. Sesame oil also decreased pulmonary nitrite level, inducible nitric oxide synthase expression, and neutrophil infiltration induced by OVA. Further, sesame oil decreased serum IgE level in OVA-treated mice.Conclusion. Sesame oil may attenuate pulmonary edema and bronchial neutrophilic inflammation by inhibiting systemic IgE level in allergic asthma.

scholarly journals Whole-brain calcium imaging during physiological vestibular stimulation in larval zebrafish

2018 ◽  
Author(s):  
Geoffrey Migault ◽  
Thomas Panier ◽  
Raphaël Candelier ◽  
Georges Debrégeas ◽  
Volker Bormuth
Keyword(s):  
Virtual Environments ◽  
Functional Imaging ◽  
Light Sheet ◽  
Vestibular Stimulation ◽  
Brain Response ◽  
Whole Brain ◽  
Larval Zebrafish ◽  
In Vivo Functional Imaging ◽  
First Time

AbstractDuring in vivo functional imaging, animals are head-fixed and thus deprived from vestibular inputs, which severely hampers the design of naturalistic virtual environments. To overcome this limitation, we developed a miniaturized ultra-stable light-sheet microscope that can be dynamically rotated during imaging along with a head-restrained zebrafish larva. We demonstrate that this system enables whole-brain functional imaging at single-cell resolution under controlled vestibular stimulation. We recorded for the first time the dynamic whole-brain response of a vertebrate to physiological vestibular stimulation. This development largely expands the potential of virtual-reality systems to explore complex multisensory-motor integration in 3D.

scholarly journals Acute cardiac injury is associated with adverse outcomes, including mortality in COVID-19 patients. A single-center experience

2020 ◽  
Vol 41 (11) ◽  
pp. 1204-1210
Author(s):  
Kashif Naeem ◽  
Mahmood Hachim ◽  
Ibrahim Hachim ◽  
Ayman Chkhis ◽  
Rajesh Quadros ◽  
...  
Keyword(s):  
Cardiac Injury ◽  
Adverse Outcomes ◽  
Single Center ◽  
Single Center Experience

scholarly journals Clinical characteristics of COVID-19 with cardiac injury: a systematic review and meta-analysis

2020 ◽  
Vol 148 ◽  
Author(s):  
Linwen Zeng ◽  
Shihui Wang ◽  
Jianing Cai ◽  
Shaoqing Sun ◽  
Suhuai Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chest Pain ◽  
Clinical Characteristics ◽  
Meta Analysis ◽  
Relevant Literature ◽  
Cardiac Injury ◽  
Adverse Outcomes ◽  
Systematic Analysis ◽  
Clinical Complications ◽  
Potential Risk Factors

Abstract Objectives Cardiac injury is associated with poor prognosis of 2019 novel coronavirus disease 2019 (COVID-19), but the risk factors for cardiac injury have not been fully studied. In this study, we carried out a systematic analysis of clinical characteristics in COVID-19 patients to determine potential risk factors for cardiac injury complicated COVID-19 virus infection. Methods We systematically searched relevant literature published in Pubmed, Embase, Europe PMC, CNKI and other databases. All statistical analyses were performed using STATA 16.0. Results We analysed 5726 confirmed cases from 17 studies. The results indicated that compared with non-cardiac-injured patients, patients with cardiac injury are older, with a greater proportion of male patients, with higher possibilities of existing comorbidities, with higher risks of clinical complications, need for mechanical ventilation, ICU transfer and mortality. Moreover, C-reactive protein, procalcitonin, D-dimer, NT-proBNP and blood creatinine in patients with cardiac injury are also higher while lymphocyte counts and platelet counts decreased. However, we fortuitously found that patients with cardiac injury did not present higher clinical specificity for chest distress (P = 0.304), chest pain (P = 0.334), palpitations (P = 0.793) and smoking (P = 0.234). Similarly, the risk of concomitant arrhythmia (P = 0.103) did not increase observably either. Conclusion Age, male gender and comorbidities are risk factors for cardiac injury complicated COVID-19 infection. Such patients are susceptible to complications and usually have abnormal results of laboratory tests, leading to poor outcomes. Contrary to common cardiac diseases, cardiac injury complicated COVID-19 infection did not significantly induce chest distress, chest pain, palpitations or arrhythmias. Our study indicates that early prevention should be applied to COVID-19 patients with cardiac injury to reduce adverse outcomes.

scholarly journals Fast objective coupled planar illumination microscopy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Cody J. Greer ◽  
Timothy E. Holy
Keyword(s):  
Fluorescence Microscopy ◽  
High Speed ◽  
Imaging Techniques ◽  
Light Sheet ◽  
Three Dimensions ◽  
Planar Imaging ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Larval Zebrafish ◽  
Fast Light

Abstract Among optical imaging techniques light sheet fluorescence microscopy is one of the most attractive for capturing high-speed biological dynamics unfolding in three dimensions. The technique is potentially millions of times faster than point-scanning techniques such as two-photon microscopy. However light sheet microscopes are limited by volume scanning rate and/or camera speed. We present speed-optimized Objective Coupled Planar Illumination (OCPI) microscopy, a fast light sheet technique that avoids compromising image quality or photon efficiency. Our fast scan system supports 40 Hz imaging of 700 μm-thick volumes if camera speed is sufficient. We also address the camera speed limitation by introducing Distributed Planar Imaging (DPI), a scaleable technique that parallelizes image acquisition across cameras. Finally, we demonstrate fast calcium imaging of the larval zebrafish brain and find a heartbeat-induced artifact, removable when the imaging rate exceeds 15 Hz. These advances extend the reach of fluorescence microscopy for monitoring fast processes in large volumes.

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