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1.
Mol Med Rep ; 26(2)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35703348

RESUMO

Sepsis­induced cardiac dysfunction is one of the most common types of organ dysfunction in sepsis; its pathogenesis is highly complex and not yet fully understood. Cardiomyocytes serve a key role in the pathophysiology of cardiac function; due to the limited ability of cardiomyocytes to regenerate, their loss contributes to decreased cardiac function. The activation of inflammatory signalling pathways affects cardiomyocyte function and modes of cardiomyocyte death in sepsis. Prevention of cardiomyocyte death is an important therapeutic strategy for sepsis­induced cardiac dysfunction. Thus, understanding the signalling pathways that activate cardiomyocyte death and cross­regulation between death modes are key to finding therapeutic targets. The present review focused on advances in understanding of sepsis­induced cardiomyocyte death pathways, including apoptosis, necroptosis, mitochondria­mediated necrosis, pyroptosis, ferroptosis and autophagy. The present review summarizes the effect of inflammatory activation on cardiomyocyte death mechanisms, the diversity of regulatory mechanisms and cross­regulation between death modes and the effect on cardiac function in sepsis to provide a theoretical basis for treatment of sepsis­induced cardiac dysfunction.


Assuntos
Cardiopatias , Sepse , Apoptose , Autofagia , Cardiopatias/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Sepse/metabolismo
2.
J Am Heart Assoc ; 11(11): e025295, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35656993

RESUMO

Background cMyBP-C (Cardiac myosin binding protein-C) regulates cardiac contraction and relaxation. Previously, we demonstrated that elevated myocardial S-glutathionylation of cMyBP-C correlates with diastolic dysfunction (DD) in animal models. In this study, we tested whether circulating S-glutathionylated cMyBP-C would be a biomarker for DD. Methods and Results Humans, African Green monkeys, and mice had DD determined by echocardiography. Blood samples were acquired and analyzed for S-glutathionylated cMyBP-C by immunoprecipitation. Circulating S-glutathionylated cMyBP-C in human participants with DD (n=24) was elevated (1.46±0.13-fold, P=0.014) when compared with the non-DD controls (n=13). Similarly, circulating S-glutathionylated cMyBP-C was upregulated by 2.13±0.47-fold (P=0.047) in DD monkeys (n=6), and by 1.49 (1.22-2.06)-fold (P=0.031) in DD mice (n=5) compared with the respective non-DD controls. Circulating S-glutathionylated cMyBP-C was positively correlated with DD in humans. Conclusions Circulating S-glutathionylated cMyBP-C was elevated in humans, monkeys, and mice with DD. S-glutathionylated cMyBP-C may represent a novel biomarker for the presence of DD.


Assuntos
Proteínas de Transporte , Cardiopatias , Animais , Biomarcadores , Proteínas de Transporte/metabolismo , Chlorocebus aethiops , Diástole/fisiologia , Cardiopatias/metabolismo , Humanos , Camundongos , Contração Miocárdica , Miocárdio/metabolismo , Fosforilação
3.
Pharmacol Res ; 181: 106262, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35598715

RESUMO

Cardiac dysfunction is a vital complication of endotoxemia (ETM) with limited therapeutic options. Transient receptor potential canonical channel (TRPC)1 was involved in various heart diseases. While, the role of TRPC1 in ETM-induced cardiac dysfunction remains to be defined. In this study, we found that TRPC1 protein expression was significantly upregulated in hearts of lipopolysaccharide (LPS)-challenged mice. What's more, TRPC1 knockdown significantly alleviated LPS-induced cardiac dysfunction and injury. Further myocardial mRNA-sequencing analysis revealed that TRPC1 might participate in pathogenesis of ETM-induced cardiac dysfunction via mediating myocardial apoptosis and autophagy. Data showed that knockdown of TRPC1 significantly ameliorated LPS-induced myocardial apoptotic injury, cardiomyocytes autophagosome accumulation, and myocardial autophagic flux. Simultaneously, deletion of TRPC1 reversed LPS-induced molecular changes of apoptosis/autophagy signaling pathway in cardiomyocytes. Moreover, TRPC1 could promote LPS-triggered intracellular Ca2+ release, subsequent calpain activation and caveolin-1 degradation. Either blocking calpain by PD150606 or enhancing the amount of caveolin-1 scaffolding domain that interacts with TRPC1 by cell-permeable peptide cavtratin significantly alleviated the LPS-induced cardiac dysfunction and cardiomyocytes apoptosis/autophagy. Furthermore, cavtratin could inhibit LPS-induced calpain activation in cardiomyocytes. caveolin-1 could directly interact with calpain 2 both in vivo and in vitro. Importantly, cecal ligation and puncture-stimulated cardiac dysfunction and mortality were significantly alleviated in Trpc1-/- and cavtratin-treated mice, which further validated the contribution of TRPC1-caveolin-1 signaling axis in sepsis-induced pathological process. Overall, this study indicated that TRPC1 could promote LPS-triggered intracellular Ca2+ release, mediate caveolin-1 reduction, and in turn activates calpain to regulate myocardial apoptosis and autophagy, contributing to ETM-induced cardiac dysfunction of mice.


Assuntos
Endotoxemia , Cardiopatias , Animais , Apoptose , Autofagia , Calpaína/efeitos adversos , Calpaína/metabolismo , Caveolina 1/metabolismo , Endotoxemia/induzido quimicamente , Cardiopatias/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo
4.
Int J Mol Sci ; 23(9)2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35563444

RESUMO

Post-translational modification (PTM) is an essential mechanism for enhancing the functional diversity of proteins and adjusting their signaling networks. The reversible conjugation of ubiquitin (Ub) and ubiquitin-like proteins (Ubls) to cellular proteins is among the most prevalent PTM, which modulates various cellular and physiological processes by altering the activity, stability, localization, trafficking, or interaction networks of its target molecules. The Ub/Ubl modification is tightly regulated as a multi-step enzymatic process by enzymes specific to this family. There is growing evidence that the dysregulation of Ub/Ubl modifications is associated with various diseases, providing new targets for drug development. In this review, we summarize the recent progress in understanding the roles and therapeutic targets of the Ub and Ubl systems in the onset and progression of human diseases, including cancer, neurodegenerative disorders, and heart diseases.


Assuntos
Cardiopatias , Neoplasias , Doenças Neurodegenerativas , Ubiquitina , Ubiquitinas , Cardiopatias/metabolismo , Humanos , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Ubiquitina/metabolismo , Ubiquitinas/metabolismo
5.
DNA Cell Biol ; 41(6): 539-543, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35446147

RESUMO

The burgeoning field of immunomedicine is primed to expand beyond oncology (Aghajanian et al., 2022). Over the past several decades, many cell-based therapies have been proposed, developed, and deployed in the clinic. The recent explosion of targeted cell therapies has primarily been aimed at oncological malignancies. In parallel, cardiology researchers have been investigating the various cell types that contribute to heart diseases, especially those responsible for tissue fibrosis and myocardial dysfunction. Our laboratory proposed in 2019 to unite these two disciplines: could a targeted cell therapy be used to ameliorate cardiac fibrosis (Aghajanian et al., 2019). Although preliminary results were encouraging, the genetic engineering approach used to manufacture immune cells would result in persistent cytolytic T cell if directly translated to humans. This would pose a safety concern since activated fibroblasts are essential cells in the setting of acute injury. Therefore, we developed a novel technology to deliver modified RNA to T cells in vivo, resulting in a transient antiactivated fibroblast therapeutic (Rurik et al., 2022). Although active for only a few days, these cells were sufficient to significantly improve cardiac function in a murine model of cardiac fibrosis. These results pave the way for low-cost and scalable, and dose-able and immune therapy for fibrotic disorders.


Assuntos
Fibroblastos , Cardiopatias , Animais , Fibroblastos/metabolismo , Fibrose , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/terapia , Humanos , Sistema Imunitário , Lipossomos , Camundongos , Miocárdio/metabolismo , Nanopartículas , RNA Mensageiro/metabolismo
6.
Expert Opin Ther Targets ; 26(4): 303-317, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35426759

RESUMO

INTRODUCTION: Abnormal calcium signaling between organelles such as the sarcoplasmic reticulum (SR), mitochondria and lysosomes is a key feature of heart diseases. Calcium serves as a secondary messenger mediating inter-organellar crosstalk, essential for maintaining the cardiomyocyte function. AREAS COVERED: This article examines the available literature related to calcium channels and transporters involved in inter-organellar calcium signaling. The SR calcium-release channels ryanodine receptor type-2 (RyR2) and inositol 1,4,5-trisphosphate receptor (IP3R), and calcium-transporter SR/ER-ATPase 2a (SERCA2a) are illuminated. The roles of mitochondrial voltage-dependent anion channels (VDAC), the mitochondria Ca2+ uniporter complex (MCUC), and the lysosomal H+/Ca2+ exchanger, two pore channels (TPC), and transient receptor potential mucolipin (TRPML) are discussed. Furthermore, recent studies showing calcium-mediated crosstalk between the SR, mitochondria, and lysosomes as well as how this crosstalk is dysregulated in cardiac diseases are placed under the spotlight. EXPERT OPINION: Enhanced SR calcium release via RyR2 and reduced SR reuptake via SERCA2a, increased VDAC and MCUC-mediated calcium uptake into mitochondria, and enhanced lysosomal calcium-release via lysosomal TPC and TRPML may all contribute to aberrant calcium homeostasis causing heart disease. While mechanisms of this crosstalk need to be studied further, interventions targeting these calcium channels or combinations thereof might represent a promising therapeutic strategy.


Assuntos
Cardiopatias , Canal de Liberação de Cálcio do Receptor de Rianodina , Cálcio/metabolismo , Sinalização do Cálcio , Cardiopatias/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo
7.
J Physiol ; 600(12): 2853-2875, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35413134

RESUMO

Sympathetic neurons densely innervate the myocardium with non-random topology and establish structured contacts (i.e. neuro-cardiac junctions, NCJ) with cardiomyocytes, allowing synaptic intercellular communication. Establishment of heart innervation is regulated by molecular mediators released by myocardial cells. The mechanisms underlying maintenance of cardiac innervation in the fully developed heart, are, however, less clear. Notably, several cardiac diseases, primarily affecting cardiomyocytes, are associated with sympathetic denervation, supporting the hypothesis that retrograde 'cardiomyocyte-to-sympathetic neuron' communication is essential for heart cellular homeostasis. We aimed to determine whether cardiomyocytes provide nerve growth factor (NGF) to sympathetic neurons, and the role of the NCJ in supporting such retrograde neurotrophic signalling. Immunofluorescence on murine and human heart slices shows that NGF and its receptor, tropomyosin-receptor-kinase-A, accumulate, respectively, in the pre- and post-junctional sides of the NCJ. Confocal immunofluorescence, scanning ion conductance microscopy and molecular analyses, in co-cultures, demonstrate that cardiomyocytes feed NGF to sympathetic neurons, and that this mechanism requires a stable intercellular contact at the NCJ. Consistently, cardiac fibroblasts, devoid of NCJ, are unable to sustain SN viability. ELISA assay and competition binding experiments suggest that this depends on the NCJ being an insulated microenvironment, characterized by high [NGF]. In further support, real-time imaging of tropomyosin-receptor-kinase-A vesicle movements demonstrate that efficiency of neurotrophic signalling parallels the maturation of such structured intercellular contacts. Altogether, our results demonstrate the mechanisms which link sympathetic neuron survival to neurotrophin release by directly innervated cardiomyocytes, conceptualizing sympathetic neurons as cardiomyocyte-driven heart drivers. KEY POINTS: CMs are the cell source of nerve growth factor (NGF), required to sustain innervating cardiac SNs; NCJ is the place of the intimate liaison, between SNs and CMs, allowing on the one hand neurons to peremptorily control CM activity, and on the other, CMs to adequately sustain the contacting, ever-changing, neuronal actuators; alterations in NCJ integrity may compromise the efficiency of 'CM-to-SN' signalling, thus representing a potentially novel mechanism of sympathetic denervation in cardiac diseases.


Assuntos
Cardiopatias , Miócitos Cardíacos , Animais , Cardiopatias/metabolismo , Humanos , Camundongos , Miócitos Cardíacos/fisiologia , Fator de Crescimento Neural/metabolismo , Neurônios/fisiologia , Receptor trkA/metabolismo , Sistema Nervoso Simpático/fisiologia , Tropomiosina/metabolismo
8.
Redox Biol ; 52: 102306, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35367810

RESUMO

Titin, as the main protein responsible for the passive stiffness of the sarcomere, plays a key role in diastolic function and is a determinant factor in the etiology of heart disease. Titin stiffness depends on unfolding and folding transitions of immunoglobulin-like (Ig) domains of the I-band, and recent studies have shown that oxidative modifications of cryptic cysteines belonging to these Ig domains modulate their mechanical properties in vitro. However, the relevance of this mode of titin mechanical modulation in vivo remains largely unknown. Here, we describe the high evolutionary conservation of titin mechanical cysteines and show that they are remarkably oxidized in murine cardiac tissue. Mass spectrometry analyses indicate a similar landscape of basal oxidation in murine and human myocardium. Monte Carlo simulations illustrate how disulfides and S-thiolations on these cysteines increase the dynamics of the protein at physiological forces, while enabling load- and isoform-dependent regulation of titin stiffness. Our results demonstrate the role of conserved cysteines in the modulation of titin mechanical properties in vivo and point to potential redox-based pathomechanisms in heart disease.


Assuntos
Cardiopatias , Sarcômeros , Animais , Conectina/química , Cisteína/metabolismo , Elasticidade , Cardiopatias/metabolismo , Humanos , Camundongos , Miocárdio/metabolismo , Oxirredução , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Sarcômeros/metabolismo
9.
Redox Biol ; 52: 102320, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35462320

RESUMO

The mechanism of severe hypoglycemia (SH)-induced cardiovascular disease in diabetes remains unknown. Our previous study found that SH inhibits cardiac function and lipid metabolism in diabetic mice. Conversely, in nondiabetic mice, SH does not induce cardiac dysfunction but promotes cardiac lipid metabolism. This study aims to clarify the effect of increased fatty acid metabolism on the resistance of cardiomyocytes to ß-adrenoceptor activation during hypoglycemia in diabetes. Results revealed that cardiomyocytes with enhanced lipid metabolism were more vulnerable to damage due to ß-adrenoceptor activation, which presented as decreased cell viability, disorder of mitochondrial structure, dissipation of mitochondrial membrane potential, dysfunction of mitochondrial oxidative phosphorylation, nonapoptotic damage, and accumulation of ROS and calcium from mitochondria to cytoplasm, all of which were partially reversed by mitochondrial antioxidant Mito-TEMPO. The SH-induced cardiac dysfunction, and reduction of myocardial energy metabolism in diabetic mice were rescued by Mito-TEMPO. Our findings indicate that high fatty acid metabolism crippled cardiac resistance to ß-adrenoceptor hyperactivation, with mitochondrial ROS playing a pivotal role in this process. Reducing mitochondrial ROS in diabetes could disrupt this synergistic effect and prevent poor cardiac outcomes caused by SH.


Assuntos
Diabetes Mellitus Experimental , Cardiopatias , Hipoglicemia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Ácidos Graxos/metabolismo , Cardiopatias/metabolismo , Hipoglicemia/metabolismo , Metabolismo dos Lipídeos/fisiologia , Camundongos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos/metabolismo
10.
Eur J Pharmacol ; 923: 174932, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35367419

RESUMO

Ginkgolides are terpenoids peculiar to Ginkgo biloba, which have protective properties against cardiac diseases. This study aims to explore whether ginkgolide A (GA) could improve cardiac dysfunction of MI mice, and whether it could alleviate cardiac remodeling via binding to matrix metalloproteinase-9 (MMP9) to attenuate inflammation. Cardiac remodeling in mice induced by left coronary artery ligation were used in the in vivo model, and angiotensin (Ang) II-induced cardiac fibroblasts (NRCFs) and cardiomyocytes (NRCMs) isolated from neonatal rats were used in in vitro fibrosis and hypertrophy models, respectively. Cardiac dysfunction and fibrosis in MI mice were alleviated by GA treatment. Upregulations of collagen I (Col I), collagen III (Col III) and fibronectin in NRCFs, and enhanced levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (ß-MHC) in NRCMs were inhibited by GA treatment. A total of 100 potential targets were found in 5 databases (TCMSP, BATMAN-TCM, PharmMapper, ETCM and SWISS Target). According to Protein Data Bank database GA could form hydrogen bonds between LYS65, GLU157, ASN17, ARG109, ARG106 of MMP9 protein, a target of GA. The regulatory role of GA in downregulating Col I, Col III, fibronectin in NRCFs, and enhancing levels of ANP, BNP and ß-MHC in NRCMs were reversed by MMP9 overexpression, so as the downregulation of IL-1ß, IL-6 and TNF-α in Ang II-induced NRCFs and NRCMs. GA could alleviate cardiac dysfunction and remodeling via binding to MMP9 to attenuate inflammation. Therefore, GA is a potential drug for cardiac remodeling therapy.


Assuntos
Cardiopatias , Infarto do Miocárdio , Angiotensina II/farmacologia , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/metabolismo , Cardiotônicos/uso terapêutico , Fibronectinas/metabolismo , Fibrose , Ginkgolídeos/farmacologia , Ginkgolídeos/uso terapêutico , Cardiopatias/metabolismo , Inflamação/metabolismo , Lactonas , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos , Ratos , Remodelação Ventricular
11.
Osteoarthritis Cartilage ; 30(5): 724-734, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35227892

RESUMO

OBJECTIVES: To investigate how ANP32A, previously linked to the antioxidant response, regulates Wnt signaling as unraveled by transcriptome analysis of Anp32a-deficient mouse articular cartilage, and its implications for osteoarthritis (OA) and diseases beyond the joint. METHODS: Anp32a knockdown chondrogenic ATDC5 cells were cultured in micromasses. Wnt target genes, differentiation markers and matrix deposition were quantified. Wnt target genes were determined in articular cartilage from Anp32a-deficient mice and primary human articular chondrocytes upon ANP32A silencing, using qPCR, luciferase assays and immunohistochemistry. Co-immunoprecipitation, immunofluorescence and chromatin-immunoprecipitation quantitative PCR probed the molecular mechanism via which ANP32A regulates Wnt signaling. Anp32a-deficient mice were subjected to the destabilization of the medial meniscus (DMM) OA model and treated with a Wnt inhibitor and an antioxidant. Severity of OA was assessed by cartilage damage and osteophyte formation. Human Protein Atlas data analysis identified additional organs where ANP32A may regulate Wnt signaling. Wnt target genes were determined in heart and hippocampus from Anp32a-deficient mice, and cardiac hypertrophy and fibrosis quantified. RESULTS: Anp32a loss triggered Wnt signaling hyper-activation in articular cartilage. Mechanistically, ANP32A inhibited target gene expression via histone acetylation masking. Wnt antagonist treatment reduced OA severity in Anp32a-deficient mice by preventing osteophyte formation but not cartilage degradation, contrasting with antioxidant treatment. Dual therapy ameliorated more OA features than individual treatments. Anp32a-deficient mice also showed Wnt hyper-activation in the heart, potentially explaining the cardiac hypertrophy phenotype found. CONCLUSIONS: ANP32A is a novel translationally relevant repressor of Wnt signaling impacting osteoarthritis and cardiac disease.


Assuntos
Cartilagem Articular , Cardiopatias , Osteoartrite , Osteófito , Animais , Antioxidantes/metabolismo , Cardiomegalia/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Cardiopatias/metabolismo , Camundongos , Osteoartrite/genética , Osteoartrite/metabolismo , Osteófito/metabolismo , Via de Sinalização Wnt/fisiologia
12.
Cell Signal ; 93: 110297, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35259455

RESUMO

Regulation of protein tyrosine phosphorylation is critical for most, if not all, fundamental cellular processes. However, we still do not fully understand the complex and tissue-specific roles of protein tyrosine phosphatases in the normal heart or in cardiac pathology. This review compares and contrasts the various roles of protein tyrosine phosphatases known to date in the context of cardiac disease and development. In particular, it will be considered how specific protein tyrosine phosphatases control cardiac hypertrophy and cardiomyocyte contractility, how protein tyrosine phosphatases contribute to or ameliorate injury induced by ischaemia / reperfusion or hypoxia / reoxygenation, and how protein tyrosine phosphatases are involved in normal heart development and congenital heart disease. This review delves into the newest developments and current challenges in the field, and highlights knowledge gaps and emerging opportunities for future research.


Assuntos
Cardiopatias , Proteínas Tirosina Fosfatases , Cardiopatias/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Fosforilação , Proteínas Tirosina Fosfatases/metabolismo
13.
Basic Res Cardiol ; 117(1): 13, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35260914

RESUMO

Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20+ B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients.


Assuntos
Cardiopatias , Insuficiência Cardíaca , Células-Tronco Pluripotentes Induzidas , Linfoma de Células B , Neoplasias , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Doxorrubicina/metabolismo , Doxorrubicina/toxicidade , Cardiopatias/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Miócitos Cardíacos/metabolismo , Neoplasias/metabolismo
14.
Pharmacol Res ; 178: 106186, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35306141

RESUMO

Doxorubicin (DOX) is a widely used and effective antineoplastic drug; however, its clinical application is limited by cardiotoxicity. A safe and effective strategy to prevent from doxorubicin-induced cardiotoxicity (DIC) is still beyond reach. Elabela (ELA), a new APJ ligand, has exerted cardioprotective effect against multiple cardiovascular diseases. Here, we asked whether ELA alleviates DIC. Mice were injected with DOX to established acute DIC. In vivo studies were assessed with echocardiography, serum cTnT and CK-MB, HW/BW ratio and WGA staining. Cell death and atrophy were measured by AM/PI staining and phalloidin staining respectively in vitro. Autophagic flux was monitored with Transmission electron microscopy in vivo, as well as LysoSensor and mRFP-GFP-LC3 puncta in vitro. Our results showed that ELA improved cardiac dysfunction in DIC mice. ELA administration also attenuated cell death and atrophy in DOX-challenged neonatal rat cardiomyocytes (NRCs). Additionally, we found that ELA restored DOX-induced autophagic flux blockage, which was evidenced by the reverse of p62 and LC3II, improvement of lysosome function and accelerated degradation of accumulated autolysosomes. Chloroquine, a classical autophagic flux inhibitor, blunted the improvement of ELA on cardiac dysfunction. At last, we revealed that ELA reversed DOX-induced downregulation of transcription factor EB (TFEB), and silencing TFEB by siRNA abrogated the effects of ELA on autophagic flux as well as cell death and atrophy in NRCs. In conclusion, this study indicated that ELA ameliorated DIC through enhancing autophagic flux via activating TFEB. ELA may become a potential target against DIC.


Assuntos
Cardiotoxicidade , Cardiopatias , Animais , Atrofia/metabolismo , Atrofia/patologia , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Doxorrubicina/farmacologia , Cardiopatias/metabolismo , Camundongos , Miócitos Cardíacos , Ratos
15.
Cells ; 11(6)2022 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-35326441

RESUMO

Tumor-derived cachectic factors such as proinflammatory cytokines and neuromodulators not only affect skeletal muscle but also affect other organs, including the heart, in the form of cardiac muscle atrophy, fibrosis, and eventual cardiac dysfunction, resulting in poor quality of life and reduced survival. This article reviews the holistic approaches of existing diagnostic, pathophysiological, and multimodal therapeutic interventions targeting the molecular mechanisms that are responsible for cancer-induced cardiac cachexia. The major drivers of cardiac muscle wasting in cancer patients are autophagy activation by the cytokine-NFkB, TGF ß-SMAD3, and angiotensin II-SOCE-STIM-Ca2+ pathways. A lack of diagnostic markers and standard treatment protocols hinder the early diagnosis of cardiac dysfunction and the initiation of preventive measures. However, some novel therapeutic strategies, including the use of Withaferin A, have shown promising results in experimental models, but Withaferin A's effectiveness in human remains to be verified. The combined efforts of cardiologists and oncologists would help to identify cost effective and feasible solutions to restore cardiac function and to increase the survival potential of cancer patients.


Assuntos
Cardiopatias , Neoplasias , Caquexia/etiologia , Caquexia/metabolismo , Citocinas , Cardiopatias/metabolismo , Humanos , Atrofia Muscular/metabolismo , Neoplasias/complicações , Neoplasias/metabolismo , Qualidade de Vida
16.
Bioengineered ; 13(3): 7471-7484, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35293279

RESUMO

Doxorubicin (DOX) has limited antitumor applications owing to its association with life-threatening cardiac injury. Oxidative damage and cardiac apoptosis are crucial in DOX-induced cardiac injury. Bone morphogenetic protein 10 (BMP10) is predominantly distributed in the heart and acts as a cardioprotective factor that preserves cardiac function. However, the role of BMP10 in DOX-induced cardiac injury has not yet been explored. The current study aimed to examine the function and mechanism of action of BMP10 in DOX-induced cardiac injury. An adeno-associated viral system was used for the overexpression or silencing of cardiac-specific BMP10, and subsequently, a single dose of DOX was intraperitoneally injected to induce cardiac injury. Results showed that DOX exposure decreased BMP10 expression in the heart. Cardiac-specific overexpression of BMP10 alleviated the oxidative stress and apoptosis and improved cardiac function. Conversely, cardiac-specific silencing of BMP10 aggravated the redox disorder and apoptosis and worsened the cardiac dysfunction caused by DOX. Exogenous BMP10 supplementation amelioratesd the DOX-induced cardiac contractile dysfunction. Mechanistically, we found that phosphorylation of signal transducer and activator of transcription 3 (STAT3) is reduced in DOX-induced cardiotoxicity, and, BMP10 activated impaired STAT3 via a non-canonical pathway. BMP10 lost its cardioprotective function in cardiomyocyte-specific STAT3 knockout (STAT3-cKO) mice. Based on our findings, we suggested that BMP10 is a potential therapeutic agent against DOX-induced cardiac injury and that the cardioprotective effects of BMP10 are dependent on the activation of STAT3.


Assuntos
Cardiopatias , Fator de Transcrição STAT3 , Animais , Apoptose , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/farmacologia , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Cardiopatias/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
17.
Cell Cycle ; 21(9): 961-971, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35230891

RESUMO

Sepsis-induced myocardial dysfunction is a common complication in septic patients. To date, a limited number of biomarkers that could predict cardiomyocyte apoptosis have been explored. In this study, we successfully established a cecal ligation and puncture (CLP)-induced septic model, and it was found that miR-501-5p expression was down-regulated in peripheral blood samples of septic patients with cardiac dysfunction, lipopolysaccharide (LPS)-induced cardiomyocytes, and the myocardium and peripheral blood in the septic model. Moreover, it was revealed that miR-501-5p overexpression could increase left ventricular diastolic pressure (LVDP), fractional shortening (FS), ejection fraction (EF), and maximum rate of the rise of left ventricular pressure (+dp/dt) in vivo, while it decreased the levels of myocardial injury-related indicators. In addition, LPS induction accelerated apoptosis and elevated the inflammation in HL-1 and HCM cells, which could be reversed by miR-501-5p overexpression. Mechanistically, we considered nuclear receptor subfamily 4 group A member 3 (NR4A3) as the target of miR-501-5p, and it was found that miR-501-5p prevented the binding between NR4A3 and Bcl-2. It was found that miR-501-5p exerted an inhibitory effect on cardiomyocyte apoptosis and inflammation in a NR4A3-dependent manner. Overall, our results may provide evidence for consideration of miR-501-5p in the therapy of sepsis.


Assuntos
Proteínas de Ligação a DNA , Cardiopatias , MicroRNAs , Proteínas Proto-Oncogênicas c-bcl-2 , Receptores de Esteroides , Receptores dos Hormônios Tireóideos , Sepse , Apoptose/genética , Proteínas de Ligação a DNA/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Sepse/complicações , Sepse/genética
18.
Bioengineered ; 13(1): 1049-1061, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35112970

RESUMO

As a leading complication of sepsis, sepsis-induced cardiac dysfunction (SICD) contributed to the high mortality of patients with sepsis. Long non-coding RNA (LncRNA) LINC00472 has been reported to be in sepsis-induced disease. Nonetheless, its biological function and underlying molecular in SICD remain largely unknown. In this study, in vivo and in vitro SICD models were established via LPS treatment. H&E staining was employed for the evaluation of myocardial injury. ELISA assay was performed to detect cardiac Troponin I (cTnI), creatine kinase-MB (CK-MB), interleukin (IL)-1ß, and tumor necrosis factor-α (TNF-α) levels. Cardiomyocyte viability and apoptosis were assessed via CCK-8 and flow cytometry assays. The transcriptional regulation of YY1 on LINC00472 was demonstrated via ChIP assay. Besides, the interaction between YY1 and LINC00472, as well as the association between miR-335-3p and LINC00472 or MAOA were verified via luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Herein, highly expressed LINC00472 was observed in both in vivo and in vitro SICD models. LINC00472 knockdown substantially attenuated LPS-induced inhibition on cardiomyocyte viability and reversed cardiomyocyte apoptosis and inflammatory response mediated by LPS treatment. YY1 induced LINC00472 upregulation, thereby promoting cardiomyocyte dysfunction induced by LPS. In addition, MAOA upregulation or miR-335-3p inhibition could partly reverse the suppressive effect on LPS-induced cardiomyocyte dysfunction mediated by LINC00472 knockdown. Based on our results, it seemed that YY1-activated LINC00472 might contribute to SICD progression via the miR-335-3p/MAOA pathway.


Assuntos
Cardiopatias , MicroRNAs , RNA Longo não Codificante , Sepse , Fator de Transcrição YY1 , Animais , Modelos Animais de Doenças , Cardiopatias/etiologia , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Sepse/complicações , Sepse/genética , Sepse/metabolismo , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo
19.
Molecules ; 27(3)2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35164412

RESUMO

HSPB5 or alpha B-crystallin (CRYAB), originally identified as lens protein, is one of the most widespread and represented of the human small heat shock proteins (sHSPs). It is greatly expressed in tissue with high rates of oxidative metabolism, such as skeletal and cardiac muscles, where HSPB5 dysfunction is associated with a plethora of human diseases. Since HSPB5 has a major role in protecting muscle tissues from the alterations of protein stability (i.e., microfilaments, microtubules, and intermediate filament components), it is not surprising that this sHSP is specifically modulated by exercise. Considering the robust content and the protective function of HSPB5 in striated muscle tissues, as well as its specific response to muscle contraction, it is then realistic to predict a specific role for exercise-induced modulation of HSPB5 in the prevention of muscle diseases caused by protein misfolding. After offering an overview of the current knowledge on HSPB5 structure and function in muscle, this review aims to introduce the reader to the capacity that different exercise modalities have to induce and/or activate HSPB5 to levels sufficient to confer protection, with the potential to prevent or delay skeletal and cardiac muscle disorders.


Assuntos
Exercício Físico , Cardiopatias/metabolismo , Doenças Musculares/metabolismo , Cadeia B de alfa-Cristalina/metabolismo , Animais , Cardiopatias/patologia , Cardiopatias/prevenção & controle , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/patologia , Doenças Musculares/prevenção & controle , Miocárdio/metabolismo , Miocárdio/patologia , Fatores de Proteção
20.
Theranostics ; 12(3): 1267-1285, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154486

RESUMO

Background: The continued success of oncological therapeutics is dependent on the mitigation of treatment-related adverse events, particularly cardiovascular toxicities. As such, there is an important need to understand the basic mechanisms of drug toxicities in the process of antitumor therapy. Our aim in this study was to elucidate the underlying mechanisms of sorafenib (sor)-induced cardiomyocyte damage. Methods: Primary mouse cardiomyocytes were prepared and treated with sor and various other treatments. Cardiomyocyte necroptosis was detected by flow cytometry, western blotting, and CCK8 assays. Mitochondrial Ca2+ uptake was detected by the Rhod-2 probe using confocal imaging. Morphological changes in mitochondria and mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) were imaged using transmission electron microscopy (TEM) and confocal microscopy. Cardiac perfusion was performed to detect cardiac specific role of MFN2 overexpression in vivo. Results: We reported that mitochondrial Ca2+ overload, the subsequent increase in calmodulin-dependent protein kinase II delta (CaMKIIδ) and RIP3/MLKL cascade activation, contributed to sor-induced cardiac necroptosis. Excess MAM formation and close ER-mitochondria contact were key pathogenesis of sor-induced Ca2+ overload. Sor mediated MFN2 downregulation in a concentration-dependent manner. Furthermore, we found that reduced mitofusin-2 (MFN2) level augmented sor-mediated elevated MAM biogenesis and increased mitochondria-MAM tethering in cardiomyocytes. Sor-induced Mammalian Target of Rapamycin (mTOR) inactivation, followed by the activation and nuclear translocation of Transcription Factor EB (TFEB), contributed to mitophagy and MFN2 degradation. In an in vivo model, mice subjected to sor administration developed cardiac dysfunction, autophagy activation and necroptosis; our investigation found that global and cardiac-specific overexpression of MFN2 repressed cardiac dysfunction, and sor-induced cardiomyocyte necroptosis via repressing the MAM-CaMKIIδ-RIP3/MLKL pathway. Conclusion: Sorafenib mediated cardiomyocyte necroptosis through the MFN2-MAM-Ca2+-CaMKIIδ pathway in vitro and in vivo. The overexpression of MFN2 could rescue sor-induced cardiomyocyte necroptosis without disturbing the anti-tumor effects.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , GTP Fosfo-Hidrolases , Cardiopatias , Miócitos Cardíacos , Proteínas Repressoras , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , GTP Fosfo-Hidrolases/biossíntese , GTP Fosfo-Hidrolases/metabolismo , Cardiopatias/metabolismo , Camundongos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Necroptose , Proteínas Repressoras/metabolismo , Sorafenibe
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