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1.
Proc Natl Acad Sci U S A ; 117(31): 18822-18831, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690703

RESUMO

Muscle contraction is regulated by the movement of end-to-end-linked troponin-tropomyosin complexes over the thin filament surface, which uncovers or blocks myosin binding sites along F-actin. The N-terminal half of troponin T (TnT), TNT1, independently promotes tropomyosin-based, steric inhibition of acto-myosin associations, in vitro. Recent structural models additionally suggest TNT1 may restrain the uniform, regulatory translocation of tropomyosin. Therefore, TnT potentially contributes to striated muscle relaxation; however, the in vivo functional relevance and molecular basis of this noncanonical role remain unclear. Impaired relaxation is a hallmark of hypertrophic and restrictive cardiomyopathies (HCM and RCM). Investigating the effects of cardiomyopathy-causing mutations could help clarify TNT1's enigmatic inhibitory property. We tested the hypothesis that coupling of TNT1 with tropomyosin's end-to-end overlap region helps anchor tropomyosin to an inhibitory position on F-actin, where it deters myosin binding at rest, and that, correspondingly, cross-bridge cycling is defectively suppressed under diastolic/low Ca2+ conditions in the presence of HCM/RCM lesions. The impact of TNT1 mutations on Drosophila cardiac performance, rat myofibrillar and cardiomyocyte properties, and human TNT1's propensity to inhibit myosin-driven, F-actin-tropomyosin motility were evaluated. Our data collectively demonstrate that removing conserved, charged residues in TNT1's tropomyosin-binding domain impairs TnT's contribution to inhibitory tropomyosin positioning and relaxation. Thus, TNT1 may modulate acto-myosin activity by optimizing F-actin-tropomyosin interfacial contacts and by binding to actin, which restrict tropomyosin's movement to activating configurations. HCM/RCM mutations, therefore, highlight TNT1's essential role in contractile regulation by diminishing its tropomyosin-anchoring effects, potentially serving as the initial trigger of pathology in our animal models and humans.


Assuntos
Cardiomiopatias/metabolismo , Mutação/genética , Tropomiosina , Troponina T , Actinas/química , Actinas/metabolismo , Animais , Cálcio/metabolismo , Diástole/genética , Diástole/fisiologia , Proteínas de Drosophila , Humanos , Miócitos Cardíacos/química , Miócitos Cardíacos/metabolismo , Ligação Proteica , Ratos , Tropomiosina/química , Tropomiosina/metabolismo , Troponina T/química , Troponina T/genética , Troponina T/metabolismo
2.
Am J Physiol Heart Circ Physiol ; 319(2): H443-H455, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618511

RESUMO

Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of erythroblastic leukemia viral oncogene homolog (ERBB)4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC-specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 wk. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (ANG II), or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis, and capillary density. In general, no major differences between EC-specific Erbb4 knockout mice and control littermates were observed. However, 8 wk following TAC both myocardial hypertrophy and fibrosis were attenuated by EC-specific Erbb4 deletion, albeit these responses were normalized after 20 wk. Similarly, 4 wk after ANG II treatment, myocardial fibrosis was less pronounced compared with control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.NEW & NOTEWORTHY The role of NRG1/ERBB signaling in endothelial cells is not completely understood. Our study contributes to the understanding of spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury and shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling.


Assuntos
Comunicação Autócrina , Cardiomiopatias/metabolismo , Células Endoteliais/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Neuregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Neovascularização Fisiológica , Comunicação Parácrina , Receptor ErbB-4/deficiência , Receptor ErbB-4/genética , Transdução de Sinais
3.
Zhonghua Er Ke Za Zhi ; 58(6): 476-481, 2020 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-32521959

RESUMO

Objective: To evaluate and improve the performance of the newborn screening program for primary carnitine deficiency (PCD) based on tandem mass spectrometry and to investigate the incidence of PCD and molecular characteristics of SLC22A5 gene in Guangzhou. Methods: A total of 200 180 neonates born in Guangzhou from 2015 to 2019 were enrolled into the newborn screening program for PCD by tandem mass spectrometry at Guangzhou Newborn Screening Center. The positive results of screening for PCD was defined as free carnitine (C0) less than 10 µmol/L with decreased acylcarnitine species in dried blood spots of three to seven days after birth. Screen-positive newborns and their mothers were recalled for another blood spot sample. The diagnosis was confirmed based on decreased levels of C0 and acylcarnitine species in recalled blood spots and genetic analysis in SLC22A5 gene sequencing. The utility of using the sum of propionylcarnitine and palmitoylcarnitine (C3+C16) as a biomarker for acylcarnitine species in newborn screening was retrospectively evaluated. The levels of C0 and (C3+C16) at first screening were compared between newborns with PCD and newborns born to mothers with PCD by independent t test. The variant spectrum and known pathogenic variants carrier rate of SLC22A5 in 2 395 healthy children in Guangzhou Women and Children's Medical Center through whole exon sequencing were analyzed. Results: Among 200 180 neonates, 239 (0.12%) cases were screen-positive for PCD. A total of 37 patients including 15 newborns and 22 mothers had confirmed PCD. The incidence of PCD was 1/13 345 in newborns and 1/9 099 in mothers, respectively. The positive predictive value of this program was 15.5%. Taking cutoff values of C0<8.5 µmol/L or C0 8.5~9.9 µmol/L with (C3+C16)<2 µmol/L, the number of screen-positive cases would be reduced from 810 to 224 without additional false negative case, when compared with cutoff value C0<10 µmol/L only. Both levels of C0 and (C3+C16) at first screening were not significant difference between newborns with PCD and newborns born to mothers with PCD ((6.2±2.4) vs. (5.0±1.8) µmol/L, (1.4±0.4) vs. (1.2±0.5) µmol/L, t=3.826, 0.326; P=0.058, 0.572). Seven PCD mothers experienced moderate fatigue and dizziness in the morning. One of them presented with cardiomyopathy in pregnancy. Genetic analysis of the SLC22A5 gene showed that p.S467C, p.F17L, p.R254X were the three most common variants in newborns with PCD. In PCD mothers and healthy children, the p.S467C, p.F17L and R399W were the three most common whereas the severe variant p.R254X was rare. The population carrier rate for pathogenic variants was 1 in 65 and the estimated incidence of PCD was about 1/16 500. Conclusions: Newborn screening can detect PCD both in newborns and mothers. Adding a quantitative biomarker (C3+C16) <2 µmol/L into the newborn screening program can improve the PCD screen performance. The severe variant p.R253X was common in PCD newborns but rare in PCD mothers and healthy children, indicating that the current screening program maybe failed to detect all PCD newborns and under-estimated the incidence rate of PCD in Guangzhou.


Assuntos
Cardiomiopatias/genética , Carnitina/sangue , Carnitina/deficiência , Hiperamonemia/diagnóstico , Doenças Musculares/diagnóstico , Triagem Neonatal/métodos , Membro 5 da Família 22 de Carreadores de Soluto/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Carnitina/genética , Criança , Feminino , Predisposição Genética para Doença , Humanos , Hiperamonemia/genética , Recém-Nascido , Doenças Musculares/genética , Gravidez , Estudos Retrospectivos , Espectrometria de Massas em Tandem
4.
Ecotoxicol Environ Saf ; 197: 110605, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32311614

RESUMO

Fluorosis is a worldwide public health problem, and its adverse effects on the heart have been confirmed by many studies. Abnormal myocardial contractions are often associated with impairment of cardiac function as a cause or consequence. We designed two-part experiments to search for biomarkers and clarify the underlying molecular mechanism of fluoride on myocardial contraction. First, we used Pressure-volume Loop analysis to evaluate changes in myocardial function indexes with multiple fluoride exposure levels in mice (0, 30, 70, and 150 mg/L) exposed for 4 weeks. The results showed that fluoride exposure affects the heart pump function and reduces cardiac contractility. Then, we established a rat model of fluoride exposure (0, 30, 60, and 90 mg/L) for 6 months to carry out proteomic analysis of fluoride-induced myocardial contractile injury. Hematoxylin-eosin (H&E) staining was used to determine the severity of myocardial injury, and myocardial tissue samples were submitted for isobaric tags for relative and absolute quantitation (ITRAQ) analysis. A total of 1607 proteins were successfully identified with 294 differentially expressed proteins (DEPs) in fluoride treated groups. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, 12 DEPs were confirmed to be involved in pathways related to myocardial contraction. Furthermore, we constructed a protein-protein interaction (PPI) network for these 12 core DEPs to illustrate the role and location of each DEP in the myocardial contraction pathway. The results of this study are helpful for identify a potential mechanism and biomarkers of fluoride-induced myocardial contraction function damage, moreover, which can provide a new insight into the heart toxicity of fluoride in animals at the proteomics level.


Assuntos
Cardiomiopatias/induzido quimicamente , Fluoretos/toxicidade , Contração Miocárdica/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Ontologia Genética , Masculino , Camundongos , Mapeamento de Interação de Proteínas , Proteínas/metabolismo , Proteômica/métodos , Ratos
5.
J Pharmacol Exp Ther ; 373(3): 402-415, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253261

RESUMO

Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase IIß (Top2B) activity in chronic anthracycline cardiotoxicity. Dexrazoxane was alkylated in positions that should not interfere with the metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. Because this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives [(±)-4,4'-(propane-1,2-diyl)bis(1-methylpiperazine-2,6-dione) and 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)-3-methylpiperazine-2,6-dione] were thoroughly scrutinized in vivo using a rabbit model of chronic anthracycline cardiotoxicity. In contrast to dexrazoxane, both compounds failed to protect the heart, as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and metal-chelating properties of their metabolites were comparable to those of dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects and support Top2B as a pivotal upstream druggable target for effective cardioprotection against anthracycline cardiotoxicity. SIGNIFICANCE STATEMENT: This study has revealed the previously unexpected tight structure-activity relationships of cardioprotective effects in derivatives of dexrazoxane, which is the only drug approved for the prevention of cardiomyopathy and heart failure induced by anthracycline anticancer drugs. The data presented in this study also strongly argue against the importance of metal-chelating mechanisms for the induction of this effect and support the viability of topoisomerase IIß as an upstream druggable target for effective and clinically translatable cardioprotection.


Assuntos
Antraciclinas/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , DNA Topoisomerases Tipo II/metabolismo , Dexrazoxano/farmacologia , Coração/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Linhagem Celular Tumoral , Células HL-60 , Humanos , Masculino , Modelos Animais , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Coelhos , Ratos , Ratos Wistar , Relação Estrutura-Atividade
6.
Clin Sci (Lond) ; 134(6): 609-628, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32175563

RESUMO

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-ß (TGF-ß) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.


Assuntos
Bexaroteno/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Proteínas Serina-Treonina Quinases/metabolismo , Receptores X Retinoide/agonistas , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-Dawley , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Estreptozocina
7.
Artigo em Inglês | MEDLINE | ID: mdl-32142354

RESUMO

Sepsis-induced cardiomyopathy (SIC) is associated with increased patient mortality. At present, there are no specific therapies for SIC. Previous studies have reported increased reactive oxygen species (ROS) and mitochondrial dysfunction during SIC. However, a unifying mechanism remains to be defined. We hypothesized that PKCδ is required for abnormal calcium handling and cardiac mitochondrial dysfunction during sepsis and that genetic deletion of PKCδ would be protective. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) surgery decreased the ejection fraction of wild-type (WT) mice but not PKCδ knockout (KO) mice. Similarly, WT cardiomyocytes exposed to lipopolysaccharide (LPS) demonstrated decreases in contractility and calcium transient amplitude that were not observed in PKCδ KO cardiomyocytes. LPS treatment decreased sarcoplasmic reticulum calcium stores in WT cardiomyocytes, which correlated with increased ryanodine receptor-2 oxidation in WT hearts but not PKCδ KO hearts after sepsis. LPS exposure increased mitochondrial ROS and decreased mitochondrial inner membrane potential in WT cardiomyocytes. This corresponded to morphologic changes consistent with mitochondrial dysfunction such as decreased overall size and cristae disorganization. Increased cellular ROS and changes in mitochondrial morphology were not observed in PKCδ KO cardiomyocytes. These data show that PKCδ is required in the pathophysiology of SIC by generating ROS and promoting mitochondrial dysfunction. Thus, PKCδ is a potential target for cardiac protection during sepsis.NEW & NOTEWORTHY Sepsis is often complicated by cardiac dysfunction, which is associated with a high mortality rate. Our work shows that the protein PKCδ is required for decreased cardiac contractility during sepsis. Mice with deletion of PKCδ are protected from cardiac dysfunction after sepsis. PKCδ causes mitochondrial dysfunction in cardiac myocytes, and reducing mitochondrial oxidative stress improves contractility in wild-type cardiomyocytes. Thus, PKCδ is a potential target for cardiac protection during sepsis.


Assuntos
Cardiomiopatias/genética , Mitocôndrias Cardíacas/metabolismo , Proteína Quinase C-delta/genética , Sepse/complicações , Animais , Sinalização do Cálcio , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Células Cultivadas , Feminino , Deleção de Genes , Lipopolissacarídeos/toxicidade , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Estresse Oxidativo , Proteína Quinase C-delta/metabolismo
8.
Am J Hum Genet ; 106(2): 272-279, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004445

RESUMO

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Colesterol/metabolismo , Duplicação Gênica , Recombinação Homóloga , Proteínas de Membrana/genética , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/genética , ATPases Associadas a Diversas Atividades Celulares/química , Sequência de Aminoácidos , Encefalopatias/etiologia , Encefalopatias/metabolismo , Encefalopatias/patologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Opacidade da Córnea/etiologia , Opacidade da Córnea/metabolismo , Opacidade da Córnea/patologia , Variações do Número de Cópias de DNA , Feminino , Rearranjo Gênico , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/química , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Hipotonia Muscular/etiologia , Hipotonia Muscular/metabolismo , Hipotonia Muscular/patologia , Mutação , Conformação Proteica , Convulsões/etiologia , Convulsões/metabolismo , Convulsões/patologia , Homologia de Sequência
9.
Oxid Med Cell Longev ; 2020: 4105382, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064023

RESUMO

Harmful, stressful conditions or events in the cardiovascular system result in cellular damage, inflammation, and fibrosis. Currently, there is no targeted therapy for myocardial fibrosis, which is highly associated with a large number of cardiovascular diseases and can lead to fatal heart failure. Hydrogen sulfide (H2S) is an endogenous gasotransmitter similar to nitric oxide and carbon monoxide. H2S is involved in the suppression of oxidative stress, inflammation, and cellular death in the cardiovascular system. The level of H2S in the body can be boosted by stimulating its synthesis or supplying it exogenously with a simple H2S donor with a rapid- or slow-releasing mode, an organosulfur compound, or a hybrid with known drugs (e.g., aspirin). Hypertension, myocardial infarction, and inflammation are exaggerated when H2S is reduced. In addition, the exogenous delivery of H2S mitigates myocardial fibrosis caused by various pathological conditions, such as a myocardial infarct, hypertension, diabetes, or excessive ß-adrenergic stimulation, via its involvement in a variety of signaling pathways. Numerous experimental findings suggest that H2S may work as a potential alternative for the management of myocardial fibrosis. In this review, the antifibrosis role of H2S is briefly addressed in order to gain insight into the development of novel strategies for the treatment of myocardial fibrosis.


Assuntos
Cardiomiopatias/metabolismo , Diabetes Mellitus/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hipertensão/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/genética , Diabetes Mellitus/enzimologia , Diabetes Mellitus/genética , Fibrose , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/genética , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Espécies Reativas de Oxigênio/metabolismo
10.
Lab Invest ; 100(6): 887-899, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32060408

RESUMO

Genetic cardiomyopathy is a group of intractable cardiovascular disorders involving heterogeneous genetic contribution. This heterogeneity has hindered the development of life-saving therapies for this serious disease. Genetic mutations in dystrophin and its associated glycoproteins cause cardiomuscular dysfunction. Large animal models incorporating these genetic defects are crucial for developing effective medical treatments, such as tissue regeneration and gene therapy. In the present study, we knocked out the δ-sarcoglycan (δ-SG) gene (SGCD) in domestic pig by using a combination of efficient de novo gene editing and somatic cell nuclear transfer. Loss of δ-SG expression in the SGCD knockout pigs caused a concomitant reduction in the levels of α-, ß-, and γ-SG in the cardiac and skeletal sarcolemma, resulting in systolic dysfunction, myocardial tissue degeneration, and sudden death. These animals exhibited symptoms resembling human genetic cardiomyopathy and are thus promising for use in preclinical studies of next-generation therapies.


Assuntos
Cardiomiopatias , Sarcoglicanas , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Feminino , Mutação da Fase de Leitura/genética , Técnicas de Inativação de Genes , Masculino , Miocárdio/química , Miocárdio/metabolismo , Miocárdio/patologia , Sarcoglicanas/deficiência , Sarcoglicanas/genética , Suínos
11.
BMC Cardiovasc Disord ; 20(1): 74, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046637

RESUMO

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown. METHODS: A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. RESULTS: The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of ß-catenin, when compared with WT. CONCLUSION: We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/ß-catenin signaling pathway.


Assuntos
Arritmias Cardíacas/genética , Cardiomiopatias/genética , Análise Mutacional de DNA , Desmoplaquinas/genética , Mutação da Fase de Leitura , Sequenciamento de Nucleotídeos em Larga Escala , Adolescente , Adulto , Idoso de 80 Anos ou mais , Arritmias Cardíacas/diagnóstico por imagem , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Morte Súbita Cardíaca/etiologia , Desmoplaquinas/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Função Ventricular Direita/genética , Adulto Jovem , beta Catenina/metabolismo , gama Catenina/metabolismo
12.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G531-G541, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961720

RESUMO

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TGneg) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TGneg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TGneg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TGneg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TGneg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis.NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Caveolina 3/metabolismo , Cirrose Hepática Biliar/metabolismo , Miocárdio/metabolismo , Potenciais de Ação , Animais , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Cardiomiopatias/prevenção & controle , Caveolina 3/genética , Modelos Animais de Doenças , Frequência Cardíaca , Preparação de Coração Isolado , Cirrose Hepática Biliar/induzido quimicamente , Cirrose Hepática Biliar/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Contração Miocárdica , Miocárdio/patologia , Piridinas , Transdução de Sinais , Fatores de Tempo , Regulação para Cima
14.
Curr Cardiol Rep ; 22(1): 1, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932992

RESUMO

PURPOSE OF REVIEW: Cardiac regeneration has received much attention as a possible means to treat various forms of cardiac injury. This review will explore the field of cardiac regeneration by highlighting the existing animal models, describing the involved molecular pathways, and discussing attempts to harness cardiac regeneration to treat cardiomyopathies. RECENT FINDINGS: Light chain cardiac amyloidosis is a degenerative disease characterized by progressive heart failure due to amyloid fibril deposition and light chain-mediated cardiotoxicity. Recent findings in a zebrafish model of light chain amyloidosis suggest that cardiac regenerative confers a protective effect against this disease. Cardiac regeneration remains an intriguing potential tool for treating cardiovascular disease. Degenerative diseases, such as light chain cardiac amyloidosis, may be particularly suited for therapeutic interventions that target cardiac regeneration. Further studies are needed to translate preclinical findings for cardiac regeneration into effective therapies.


Assuntos
Amiloidose/diagnóstico , Cardiomiopatias/metabolismo , Cardiotoxicidade/fisiopatologia , Insuficiência Cardíaca/etiologia , Cadeias Leves de Imunoglobulina/metabolismo , Miocárdio/patologia , Regeneração , Amiloidose/complicações , Animais , Cardiomiopatias/complicações , Cardiomiopatias/terapia , Insuficiência Cardíaca/diagnóstico , Humanos , Peixe-Zebra
15.
Artigo em Inglês | MEDLINE | ID: mdl-31977249

RESUMO

Tandem pore domain acid-sensitive K+ (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction using both human tissue and mouse models of genetic TASK channel loss of function. Compared with normal human cardiac tissue, TASK-1 gene expression is reduced in association with either cardiac hypertrophy alone or combined cardiac hypertrophy and heart failure. In a pressure overload cardiomyopathy model, TASK-1 global knockout (TASK-1 KO) mice have both reduced cardiac hypertrophy and preserved cardiac function compared with wild-type mice. In contrast to the TASK-1 KO mouse pressure overload response, TASK-3 global knockout (TASK-3 KO) mice develop cardiac hypertrophy and a delayed onset of cardiac dysfunction compared with wild-type mice. The cardioprotective effects observed in TASK-1 KO mice are associated with pressure overload-induced augmentation of AKT phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression, with consequent augmentation of cardiac energetics and fatty acid oxidation. The protective effects of TASK-1 loss of function are associated with an enhancement of physiologic hypertrophic signaling and preserved metabolic functions. These findings may provide a rationale for TASK-1 channel inhibition in the treatment of cardiac dysfunction.NEW & NOTEWORTHY The role of tandem pore domain acid-sensitive K+ (TASK) channels in cardiac function is not well understood. This study demonstrates that TASK channel gene expression is associated with the onset of human cardiac hypertrophy and heart failure. TASK-1 and TASK-3 strongly affect the development of pressure overload cardiomyopathies in genetic models of TASK-1 and TASK-3 loss of function. The effects of TASK-1 loss of function were associated with enhanced AKT phosphorylation and expression of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury.


Assuntos
Cardiomegalia/metabolismo , Cardiomiopatias/metabolismo , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Cardiomegalia/genética , Cardiomiopatias/genética , Humanos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , Canais de Potássio/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
16.
Circulation ; 141(9): 751-767, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-31948273

RESUMO

BACKGROUND: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis. METHODS: Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin II-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat model. To investigate the mechanism underlying the antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing. RESULTS: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. Using multiple in vitro fibrosis assays and stringent selection algorithms, we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds. CONCLUSIONS: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Bufanolídeos/farmacologia , Cardiomiopatias/prevenção & controle , Fármacos Cardiovasculares/farmacologia , Fibroblastos/efeitos dos fármacos , Fenantridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diástole , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Ensaios de Triagem em Larga Escala , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Endogâmicos Dahl , Selenoproteína P/genética , Selenoproteína P/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
17.
DNA Cell Biol ; 39(1): 105-117, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794266

RESUMO

Septic cardiomyopathy (SC) is a rare and harmful cardiovascular disease with decreased left ventricular (LV) output and multiple organ failure, which poses a serious threat to human life. Despite the advances in SC, its diagnostic basis and treatment methods are limited, and the specific diagnostic biomarkers and its candidate regulatory targets have not yet been fully established. In this study, the GSE79962 gene expression profile was retrieved, with 20 patients with SC and 11 healthy donors as control. Weighted gene coexpression network analysis (WGCNA) was employed to investigate gene modules that were strongly correlated with clinical phenotypes. Blue module was found to be most significantly related to SC. Moreover, Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the coexpression genes in blue module and showed that it was associated with metabolic pathways, oxidative phosphorylation, and cardiac muscle contraction. Furthermore, a total of 10 hub genes NDUFB5, TIMMDC1, VDAC3, COQ10A, MRPL16 (mitochondrial ribosomal protein L16), C3orf43, TMEM182, DLAT, NDUFA8, and PDHB (pyruvate dehydrogenase E1 beta subunit) in the blue module were identified at transcriptional level and further validated at translational level in myocardium of an lipopolysaccharide-induced septic cardiac dysfunction mouse model. Overall, the results of quantitative real-time polymerase chain reaction were consistent with most of the microarray analysis results. Intriguingly, we observed that the highest change was NDUFB5, TIMMDC1, and VDAC3. These identified and validated genes provided references that would advance the understanding of molecular mechanisms of SC. Taken together, using WGCNA, the hub genes NDUFB5, TIMMDC1, and VDAC3 might serve as potential biomarkers for diagnosis and/or therapeutic targets for precise treatment of SC in the future.


Assuntos
Cardiomiopatias/genética , Complexo I de Transporte de Elétrons/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Transporte da Membrana Mitocondrial/genética , Sepse/genética , Canais de Ânion Dependentes de Voltagem/genética , Idoso , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Biologia Computacional/métodos , Progressão da Doença , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Ontologia Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Sepse/metabolismo , Sepse/patologia , Canais de Ânion Dependentes de Voltagem/metabolismo
18.
Biomed Res Int ; 2019: 4352905, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828104

RESUMO

Keshan disease (KD) is an endemic cardiomyopathy, which mainly occurs in China. Selenium deficiency is believed to play an important role in the pathogenesis of KD, but the molecular mechanism of selenium-induced damage remains unclear. To identify the key genes involved in selenium-induced damage, we compared the expression profiles of selenium-related genes between patients with KD and normal controls. Total RNA was isolated, amplified, labeled, and hybridized to Agilent human 4 × 44 K whole genome microarrays. Selenium-related genes were screened using the Comparative Toxicogenomics Database. The microarray data were subjected to single-gene and gene ontology (GO) expression analysis using R Studio and Gene Set Enrichment Analysis (GSEA) software. Quantitative real-time PCR was conducted to validate the microarray results. We identified 16 upregulated and 11 downregulated selenium-related genes in patients. These genes are involved in apoptosis, metabolism, transcription regulation, ion transport, and growth and development. Of the significantly enriched GO categories in KD patients, we identified four apoptosis-related, two metabolism-related, four growth and development-related, and four ion transport-related GOs. Based on our results, we suggest that selenium might contribute to the development of KD through dysfunction of selenium-related genes involved in apoptosis, metabolism, ion transport, and growth and development in the myocardium.


Assuntos
Cardiomiopatias/genética , Infecções por Enterovirus/genética , Leucócitos Mononucleares/metabolismo , Selênio/metabolismo , Transcriptoma/genética , Adulto , Apoptose/genética , Cardiomiopatias/metabolismo , Estudos de Casos e Controles , Regulação para Baixo/genética , Infecções por Enterovirus/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima/genética
19.
Oxid Med Cell Longev ; 2019: 4025496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871548

RESUMO

Fibroblast proliferation and migration are central in atrial fibrillation (AF) promoting structure remodeling, which is strongly associated with aging and hypertension. Transient receptor potential canonical-3 channel (TRPC3) is a key mediator of cardiac fibrosis and the pathogenesis of AF. Here, we have observed the increased TRPC3 expression that induced atrial fibrosis which possibly is either mediated by the aging process or related to hypertensive progression. In this study, we measured the pathological structure remodeling by H&E staining, Masson staining, and transmission electron microscope (TEM). The protein expression levels of fibrotic biomarkers and TRPC3 were measured by Western blotting with atrial tissues from normotensive Wistar Kyoto rats (WKY 4m-o (4 months old)), old WKY (WKY 24m-o (24 months old)), spontaneously hypertensive rat (SHR 4m-o (4 months old)), and old SHR (SHR 24m-o (24 months old)). To illuminate the molecular mechanism of TRPC3 in atrial fibrosis of aging rats and SHR, we detected the inhibited role of TRPC3 selective blocker ethyl-1-(4-(2,3,3-trichloroacrylamide) phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate,pyrazole-3 (Pyr3) on angiotensin II (Ang II) induced fibrosis in neonatal rat atrial fibroblasts. The pathological examination showed that the extracellular matrix (ECM) and collagen fibrils were markedly increased in atrial tissues from aged and hypertensive rats. The protein expressions of fibrotic biomarkers (collagen I, collagen III, and transforming growth factor-ß1 (TGF-ß1)) were significantly upregulated in atrial tissues from the WKY 24m-o group, SHR 4m-o group, and SHR 24m-o group compared with the WKY 4m-o group. Meanwhile, the expression level of TRPC3 was significantly upregulated in WKY 24m-o and SHR 4m-o atrial tissues compared to WKY 4m-o rats. In isolated and cultured neonatal rat atrial fibroblasts, Ang II induced the atrial fibroblast migration and proliferation and upregulated the expression levels of TRPC3 and fibrotic biomarkers. TRPC3 selected blocker Pyr3 attenuated the migration and proliferation in neonatal rat atrial fibroblasts. Furthermore, Pyr3 significantly alleviated Ang II-induced upregulation of TRPC3, collagen I, collagen III, and TGF-ß1 through the molecular mechanism of the TGF-ß/Smad2/3 signaling pathway. Similarly, knocking down TRPC3 using short hairpin RNA (shTRPC3) also attenuated Ang II-induced upregulation of TGF-ß1. Pyr3 preconditioning decreased Ang II-induced intracellular Ca2+ transient amplitude elevation. Furthermore, AT1 receptor was involved in Ang II-induced TRPC3 upregulation. Hence, upregulation of TRPC3 in aging and hypertension is involved in an atrial fibrosis process. Inhibition of TRPC3 contributes to reverse Ang II-induced fibrosis. TRPC3 may be a potential therapeutic target for preventing fibrosis in aging and hypertension.


Assuntos
Cardiomiopatias/metabolismo , Fibrose/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Cardiomiopatias/patologia , Hipertensão/metabolismo , Hipertensão/patologia , Técnicas In Vitro , Masculino , Microscopia Eletrônica de Transmissão , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Proteína Smad2/genética , Proteína Smad3/genética , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismo , Fator de Crescimento Transformador beta1/genética
20.
Exp Mol Med ; 51(12): 1-13, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857574

RESUMO

Beyond their role as a cellular powerhouse, mitochondria are emerging as integral players in molecular signaling and cell fate determination through reactive oxygen species (ROS). While ROS production has historically been portrayed as an unregulated process driving oxidative stress and disease pathology, contemporary studies reveal that ROS also facilitate normal physiology. Mitochondria are especially abundant in cardiac tissue; hence, mitochondrial dysregulation and ROS production are thought to contribute significantly to cardiac pathology. Moreover, there is growing appreciation that medical therapies designed to mediate mitochondrial ROS production can be important strategies to ameliorate cardiac disease. In this review, we highlight evidence from animal models that illustrates the strong connections between mitochondrial ROS and cardiac disease, discuss advancements in the development of mitochondria-targeted antioxidant therapies, and identify challenges faced in bringing such therapies into the clinic.


Assuntos
Cardiopatias/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Estresse Oxidativo/fisiologia , Animais , Cardiomiopatias/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
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