scholarly journals Role of Podoplanin-Positive Cells in Cardiac Fibrosis and Angiogenesis After Ischemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Cimini ◽  
Raj Kishore
Keyword(s):  
Heart Development ◽  
Neutralizing Antibodies ◽  
Wound Repair ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Heart Function ◽  
Cardiac Injury ◽  
Mouse Heart ◽  
Alternative Mechanism

New insights into the cellular and extra-cellular composition of scar tissue after myocardial infarction (MI) have been identified. Recently, a heterogeneous podoplanin-expressing cell population has been associated with fibrogenic and inflammatory responses and lymphatic vessel growth during scar formation. Podoplanin is a mucin-like transmembrane glycoprotein that plays an important role in heart development, cell motility, tumorigenesis, and metastasis. In the adult mouse heart, podoplanin is expressed only by cardiac lymphatic endothelial cells; after MI, it is acquired with an unexpected heterogeneity by PDGFRα-, PDGFRβ-, and CD34-positive cells. Podoplanin may therefore represent a sign of activation of a cohort of progenitor cells during different phases of post-ischemic myocardial wound repair. Podoplanin binds to C-type lectin-like receptor 2 (CLEC-2) which is exclusively expressed by platelets and a variety of immune cells. CLEC-2 is upregulated in CD11bhigh cells, including monocytes and macrophages, following inflammatory stimuli. We recently published that inhibition of the interaction between podoplanin-expressing cells and podoplanin-binding cells using podoplanin-neutralizing antibodies reduces but does not fully suppress inflammation post-MI while improving heart function and scar composition after ischemic injury. These data support an emerging and alternative mechanism of interactome in the heart that, when neutralized, leads to altered inflammatory response and preservation of cardiac function and structure. The overarching objective of this review is to assimilate and discuss the available evidence on the functional role of podoplanin-positive cells on cardiac fibrosis and remodeling. A detailed characterization of cell-to-cell interactions and paracrine signals between podoplanin-expressing cells and the other type of cells that compose the heart tissue is needed to open a new line of investigation extending beyond the known function of these cells. This review attempts to discuss the role and biology of podoplanin-positive cells in the context of cardiac injury, repair, and remodeling.

scholarly journals COVID-19 cardiac injury and the use of colchicine

2021 ◽  
Vol 14 (2) ◽  
pp. e241047
Author(s):  
Vanesa Anton-Vazquez ◽  
Laura Byrne ◽  
Lisa Anderson ◽  
Lisa Hamzah
Keyword(s):  
Sinus Tachycardia ◽  
Inflammatory Responses ◽  
Troponin T ◽  
Systolic Function ◽  
Cardiac Injury ◽  
T Wave ◽  
Wave Inversion ◽  
Ventricular Extrasystoles

We report a case of cardiac injury in a 46-year-old man affected by COVID-19. The patient presented with shortness of breath and fever. ECG revealed sinus tachycardia with ventricular extrasystoles and T-wave inversion in anterior leads. Troponin T and N-terminal pro B-type natriuretic peptide were elevated. Transthoracic echocardiography showed severely reduced systolic function with an estimated left ventricle ejection fraction of 30%. A nasopharingeal swab was positive for SARS-CoV-2. On day 6, 11 days after onset of symptoms, the patient deteriorated clinically with new chest pain and type 1 respiratory failure. Treatment with colchicine 0.5 mg 8-hourly resulted in rapid clinical resolution. This case report highlights how cardiac injury can dominate the clinical picture in COVID-19 infection. The role of colchicine therapy should be further studied to determine its usefulness in reducing myocardial and possibly lung parenchymal inflammatory responses.

Abstract O-3: A β1-Adrenergic Receptor/β-Arrestin1-Regulatable MicroRNA, MiR-150 Protects the Mouse Heart from Ischemic Injury by Repressing Pro-apoptotic Egr2 and P2x7r

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Il-man Kim ◽  
Yaoping Tang ◽  
Yongchao Wang ◽  
Kyoung-mi Park ◽  
Qiuping Hu
Keyword(s):  
Adrenergic Receptor ◽  
Cardiac Injury ◽  
Ischemic Injury ◽  
Mouse Heart ◽  
Functional Remodeling ◽  
Β Blocker ◽  
Genetic Deletion ◽  
Circulating Levels ◽  
Cardiomyocyte Survival

MicroRNA (miR)-150 is down-regulated in patients with acute myocardial infarction (AMI), atrial fibrillation, dilated and ischemic cardiomyopathy as well as in various mouse heart failure (HF) models. Circulating miR-150 has been recently proposed as a better biomarker of HF than clinically used markers such as brain natriuretic peptide. We recently showed that β-arrestin1-biased β1-adrenergic receptor (β1AR) cardioprotective signaling activated by the β-arrestin-biased β-blocker, carvedilol (Carv) stimulates the processing of miR-150 in the heart (see figure A). However, the potential role of miR-150 in ischemic injury and HF is unknown. Here, we show that genetic deletion of miR-150 in mice causes abnormalities in cardiac structural and functional remodeling after MI. The cardioprotective roles of miR-150 during ischemic injury were attributed to repression of the pro-apoptotic genes egr2 (zinc binding transcription factor induced by ischemia) and p2x7r (pro-inflammatory ATP receptor) [see figure B]. These findings reveal a pivotal role for miR-150 as a regulator of cardiomyocyte survival during cardiac injury. In conclusion, our study will help to stratify HF patients that may respond better to β-arrestin-biased β-blockers, which is guided by circulating levels of miR-150.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Planar Cell Polarity ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Cultured Fibroblasts

AbstractBackgroundA hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early pro-inflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation.Methods and ResultsThe role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction (TAC) surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after TAC surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2-KO mice displayed a pro-inflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, TAC surgery led to the death of all mice by day 6 that was associated with myocardial hyper-inflammation and vascular leakage.ConclusionsTogether, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cultured Fibroblasts

Background A hallmark of heart failure is cardiac fibrosis, which results from the injury‐induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase–like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

scholarly journals Role of PTEN-less in cardiac injury, hypertrophy and regeneration

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Tian Liang ◽  
Feng Gao ◽  
Jinghai Chen
Keyword(s):  
Stress Responses ◽  
Cardiac Fibrosis ◽  
Cardiac Development ◽  
Heart Function ◽  
Cardiac Injury ◽  
Therapeutic Effects ◽  
Hypertrophic Growth ◽  
Dual Specificity ◽  
Cellular Factors ◽  
Physiological Homeostasis

AbstractCardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinated contractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytes undergo transition from physiological homeostasis to hypertrophic growth, proliferation, or apoptosis. During these processes, many cellular factors and signaling pathways participate. PTEN is a ubiquitous dual-specificity phosphatase and functions by dephosphorylating target proteins or lipids, such as PIP3, a second messenger in the PI3K/AKT signaling pathway. Downregulation of PTEN expression or inhibiting its biologic activity improves heart function, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosis following ischemic stress such as myocardial infarction. Inactivation of PTEN exhibits a potentially beneficial therapeutic effects against cardiac diseases. In this review, we summarize various strategies for PTEN inactivation and highlight the roles of PTEN-less in regulating cardiomyocytes during cardiac development and stress responses.

Abstract 277: MicroRNA-125a-5p Protects the Mouse Heart From Ischemic Injury by Repressing Pro-apoptotic Bak1 and Klf13 in Cardiomyocytes

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Bruno Moukette ◽  
Tatsuya Aonuma ◽  
Il-man Kim
Keyword(s):  
Target Genes ◽  
Cardiac Injury ◽  
Cell Types ◽  
Mouse Heart ◽  
Small Noncoding Rnas ◽  
Increased Sensitivity ◽  
Β Blocker ◽  
Apoptotic Genes

Background: Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs), which are small noncoding RNAs to downregulate target genes. MiR-125a-5p (miR-125a) is downregulated in patients with myocardial infarction (MI). We reported that miR-125a is upregulated by the β-blocker carvedilol (Carv) acting through β-arrestin1-biased β1-adrenergic receptor (β1AR; receptor found mainly in cardiomyocytes [CMs]) cardioprotective signaling (Figure A). We also showed that pro-apoptotic genes bak1 and klf13 are downregulated by Carv and are upregulated after MI. Here, we hypothesize that miR-125a in CMs favorably regulates cardiac functional and structural remodeling after MI by repressing bak1 and klf13. Methods and Results: Fractionation of cardiac cell types from heart tissues reveals that the expression of miR-125a is higher in CMs than other myocardial cells. Using cultured CM and in vivo approaches, we show that miR-125a is an ischemic stress-responsive protector against CM apoptosis. CMs lacking miR-125a exhibit an increased sensitivity to apoptosis, while CMs overexpressing miR-125a have increased phospho-AKT pro-survival signaling. Moreover, we show that miR-125a is downregulated in post-MI mouse hearts and miR-125a overexpression protects mouse hearts against MI. We also show that global genetic deletion of miR-125a in mice worsens maladaptive post-MI remodeling. Mechanistically, the cardioprotective role of miR-125a during MI is in part attributed to direct repression of the pro-apoptotic genes bak1 and klf13 in CMs (Figure B). Conclusions: These findings reveal a pivotal role for miR-125a in regulating CM survival during MI.

scholarly journals The G4 resolvase RHAU modulates mRNA translation and stability to sustain postnatal heart function and regeneration

2020 ◽  
pp. jbc.RA120.014948
Author(s):  
Mingyang Jiang ◽  
Han Hu ◽  
Ke Zhao ◽  
Ruomin Di ◽  
Xinyi Huang ◽  
...  
Keyword(s):  
Heart Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Heart Function ◽  
Mrna Translation ◽  
Mrna Levels ◽  
Protein Levels ◽  
Post Transcriptional Regulation ◽  
Heart Physiology

Post-transcriptional regulation of mRNA translation and stability is primarily achieved by RNA binding proteins (RBPs), which is of increasing importance for heart function. Furthermore, G-quadruplex (G4) and G4 resolvase activity are involved in a variety of biological processes. However, the role of G4 resolvase activity in heart function remains unknown. The present study aims to investigate the role of RHAU, an RBP with G4 resolvase activity in postnatal heart function through deletion of Rhau in the cardiomyocytes of postnatal mice. RHAU-deficient mice displayed progressive pathological remodeling leading to heart failure and mortality, and impaired neonatal heart regeneration. RHAU ablation reduced the protein levels but enhanced mRNA levels of Yap1 and Hexim1 that are important regulators for heart development and postnatal heart function. Furthermore, RHAU was found to associate with both the 5’- and 3’- UTRs of these genes to destabilize mRNA but to enhance translation. Thus, we have demonstrated the important functions of RHAU in the dual regulation of mRNA translation and stability, which is vital for heart physiology.

scholarly journals Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway

2022 ◽  
Vol 8 ◽  
Author(s):  
Zi-Qi Liao ◽  
Yi-Nong Jiang ◽  
Zhuo-Lin Su ◽  
Hai-Lian Bi ◽  
Jia-Tian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Underlying Mechanism ◽  
Protective Role ◽  
Pcr Analysis ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Akt Inhibitor

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.

Abstract 305: E2F1 Suppresses Cardiac Fibrosis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Dauren Biyashev ◽  
Chan Boriboun ◽  
Gangjian Qin
Keyword(s):  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Mouse Heart ◽  
Wild Type ◽  
Alpha Smooth Muscle Actin ◽  
Embryonic Fibroblasts ◽  
Smad 3 ◽  
Regulation Of Cell Cycle

E2F1 transcription factor is best known for regulation of cell cycle; its role in the cardiovascular system is not well understood. In a transcriptome analysis, we detected a significantly elevated level in the expression of collagen I and alpha-smooth muscle actin in the E2F1-null (E2F1-/-) mouse embryonic fibroblasts (MEFs) as compared to wild-type (WT) MEFs. Levels of Smad 2 and Smad 3 were also significantly higher in E2F1-/- MEFs. In addition, treatment with TGF-beta (10 ng/ml) induced a greater degree of Smad 2 and Smad 3 phosphorylation in E2F1-/- MEFs than in WT MEFs. Interestingly, these in vitro observations were corroborated with our results obtained from mouse heart samples: the basal levels of both total and phosphorylated Smad 2 were significantly higher in the E2F1-/- heart than in the WT heart (n=3). To understand the significance of these findings in the pathogenesis of cardiac fibrosis, we administered Angiotensin II (3 mg/kg/day) to animals for 7 or 14 days with a subcutaneous osmotic minipump. The total area of cardiac fibrosis was significantly greater in the E2F1-/- mice than in WT littermates (E2F1-/- vs. WT: 17+/-3.8% vs. 6+/-2.6%, p<0.05). Thus, we disclose a novel role of E2F1 in the control of Smad signaling that may limit the development of fibrosis in the stressed heart.

scholarly journals Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Hong Wei ◽  
Xiao Guo ◽  
Chun-Shui Pan ◽  
Huan Li ◽  
Yuan-Chen Cui ◽  
...  
Keyword(s):  
Survival Rate ◽  
Energy Metabolism ◽  
Quantitative Proteomics ◽  
Heart Function ◽  
Cardiac Injury ◽  
Cardioprotective Effect ◽  
Phase Iii ◽  
Morphological Observation ◽  
Glycolipid Metabolism

BackgroundT89, a traditional Chinese medicine, has passed phase II, and is undergoing phase III clinical trials for treatment of ischemic cardiovascular disease by the US FDA. However, the role of T89 on isoproterenol (ISO)-induced cardiac injury is unknown. The present study aimed to explore the effect and underlying mechanism of T89 on ISO-induced cardiac injury.MethodsMale Sprague-Dawley rats received subcutaneous injection of ISO saline solution at 24 h intervals for the first 3 days and then at 48 h intervals for the next 12 days. T89 at dose of 111.6 and 167.4 mg/kg was administrated by gavage for 15 consecutive days. Rat survival rate, cardiac function evaluation, morphological observation, quantitative proteomics, and Western blotting analysis were performed.ResultsT89 obviously improved ISO-induced low survival rate, attenuated ISO-evoked cardiac injury, as evidenced by myocardial blood flow, heart function, and morphology. Quantitative proteomics revealed that the cardioprotective effect of T89 relied on the regulation of metabolic pathways, including glycolipid metabolism and energy metabolism. T89 inhibited the enhancement of glycolysis, promoted fatty acid oxidation, and restored mitochondrial oxidative phosphorylation by regulating Eno1, Mcee, Bdh1, Ces1c, Apoc2, Decr1, Acaa2, Cbr4, ND2, Cox 6a, Cox17, ATP5g, and ATP5j, thus alleviated oxidative stress and energy metabolism disorder and ameliorated cardiac injury after ISO. The present study also verified that T89 significantly restrained ISO-induced increase of HSP70/HSP40 and suppressed the phosphorylation of ERK, further restored the expression of CX43, confirming the protective role of T89 in cardiac hypertrophy. Proteomics data are available via ProteomeXchange with identifier PXD024641.ConclusionT89 reduced mortality and improves outcome in the model of ISO-induced cardiac injury and the cardioprotective role of T89 is correlated with the regulation of glycolipid metabolism, recovery of mitochondrial function, and improvement of myocardial energy.

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