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1.
Cell Biol Int ; 43(6): 695-705, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30977566

RESUMO

Cardiac hypertrophy is a common pathological change found in various cardiovascular diseases. Although it has long been recognized as an important risk factor responsible for heart failure, there is still a lack of effective treatments in clinic. Chrysophanol is a natural compound with multiple biological activities and protective roles in the cardiovascular system. However, its potential effect on cardiac hypertrophy remains unclear. In the current study, we found that chrysophanol could protect against isoproterenol (ISO)-induced cardiac hypertrophy both in vitro and in vivo. Increase of cell surface and hypertrophic marker expression induced by ISO in neonatal rat cardiomyocytes was downregulated by chrysophanol. Moreover, chrysophanol ameliorated the abnormal changes of cardiac structure and function in rats subjected to ISO injection, as shown by echocardiography and morphometry measurements. Further mechanistical investigation demonstrated that chrysophanol inhibited phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) induced by ISO. Nuclear translocation of STAT3 and transcription of downstream genes promoted by ISO treatment were also remarkably suppressed by chrysophanol. Taken together, our findings revealed that chrysophanol attenuated ISO-induced cardiac hypertrophy by inhibiting JAK2/STAT3 signaling pathway. Chrysophanol may be a potential candidate compound for the prevention and treatment of hypertrophy-related cardiomyopathy.


Assuntos
Antraquinonas/farmacologia , Cardiomegalia/tratamento farmacológico , Janus Quinase 2/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Antraquinonas/metabolismo , Cardiomegalia/enzimologia , Cardiomegalia/metabolismo , Cardiomiopatias/tratamento farmacológico , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
PLoS One ; 14(2): e0211796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30759120

RESUMO

Sirtuin 5 (SIRT5) is a member of the NAD+-dependent sirtuin family of protein deacylase that catalyzes removal of post-translational modifications, such as succinylation, malonylation, and glutarylation on lysine residues. In light of the SIRT5's roles in regulating mitochondrion function, we show here that SIRT5 deficiency leads to suppression of mitochondrial NADH oxidation and inhibition of ATP synthase activity. As a result, SIRT5 deficiency decreases mitochondrial ATP production, increases AMP/ATP ratio, and subsequently activates AMP-activated protein kinase (AMPK) in cultured cells and mouse hearts under energy stress conditions. Moreover, Sirt5 knockout attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy and cardiac dysfunction in mice, which is associated with decreased ATP level, increased AMP/ATP ratio and enhanced AMPK activation. Our study thus uncovers an important role of SIRT5 in regulating cellular energy metabolism and AMPK activation in response to energy stress.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Cardiomegalia/enzimologia , Mitocôndrias Cardíacas/enzimologia , Sirtuínas/deficiência , Proteínas Quinases Ativadas por AMP/genética , Trifosfato de Adenosina/genética , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Ativação Enzimática/genética , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Estresse Fisiológico/genética
3.
Clin Sci (Lond) ; 133(2): 225-238, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30610007

RESUMO

Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart defects (CHDs). The right ventricular hypertrophy is associated with the survival rate of patients with repaired TOF. However, very little is known concerning its genetic etiology. Based on mouse model studies, a disintergrin and metalloprotease 10/17 (ADAM10 and ADAM17) are the key enzymes for the NOTCH and ErbB pathways, which are critical pathways for heart development. Mutations in these two genes have not been previously reported in human TOF patients. In this study, we sequenced ADAM10 and ADAM17 in a Han Chinese CHD cohort comprised of 80 TOF patients, 286 other CHD patients, and 480 matched healthy controls. Three missense variants of ADAM17 were only identified in 80 TOF patients, two of which (Y42D and L659P) are novel and not found in the Exome Aggregation Consortium (ExAC) database. Point mutation knock-in (KI) and ADAM17 knock-out (KO) human embryonic stem cells (hESCs) were generated by CRISPR/Cas9 and programmed to differentiate into cardiomyocytes (CMs). Y42D or L659P KI cells or complete KO cells all developed hypertrophy with disorganized sarcomeres. RNA-seq results showed that phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt), which is downstream of epidermal growth factor receptor (EGFR) signaling, was affected in both ADAM17 KO and KI hESC-CMs. In vitro experiments showed that these two mutations are loss-of-function mutations in shedding heparin-binding EGF-like growth factor (HB-EGF) but not NOTCH signaling. Our results revealed that CM hypertrophy in TOF could be the result of mutations in ADAM17 which affects HB-EGF/ErbB signaling.


Assuntos
Proteína ADAM17/genética , Cardiomegalia/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Células-Tronco Embrionárias Humanas/enzimologia , Mutação com Perda de Função , Mutação de Sentido Incorreto , Miócitos Cardíacos/enzimologia , Tetralogia de Fallot/genética , Proteína ADAM17/metabolismo , Animais , Células COS , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Estudos de Casos e Controles , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Células HEK293 , Células-Tronco Embrionárias Humanas/patologia , Humanos , Lactente , Masculino , Miócitos Cardíacos/patologia , Fenótipo , Transdução de Sinais , Tetralogia de Fallot/diagnóstico , Tetralogia de Fallot/enzimologia
4.
Circ Heart Fail ; 12(1): e005622, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30621510

RESUMO

BACKGROUND: Cardiac remodeling is modulated by overnutrition or starvation. The adipokine leptin mediates energy balance between adipose tissue and brain. Leptin and its receptors are expressed in the heart. METHODS AND RESULTS: To examine the importance of endothelial leptin signaling in cardiac hypertrophy, transverse aortic constriction was used in mice with inducible endothelium-specific deletion of leptin receptors (End.LepR-KO) or littermate controls (End.LepR-WT). End.LepR-KO was associated with improved left ventricular function (fractional shortening, 28.4% versus 18.8%; P=0.0114), reduced left ventricular dilation (end-systolic inner left ventricular diameter, 3.59 versus 4.08 mm; P=0.0188) and lower heart weight (133 versus 173 mg; P<0.0001) 20 weeks after transverse aortic constriction. Histology and quantitative polymerase chain reaction analysis confirmed reduced cardiomyocyte hypertrophy. STAT3 (signal transducer and activator of transcription) activation was reduced, and Akt (protein kinase B) and mTOR (mammalian target of rapamycin) phosphorylation after transverse aortic constriction were blunted in End.LepR-KO hearts. Elevated LC3 (microtubule associated protein 1 light chain 3)-I/-II conversion ( P=0.0041) and increased (LC3II-positive) endothelial cells ( P=0.0042) in banded hearts of End.LepR-KO mice suggested improved cardiac angiogenesis because of activated autophagy. Microscopy confirmed autophagosome accumulation after genetic or small interfering RNA-mediated LepR downregulation. Enhanced sprouting angiogenesis was observed in endothelial cells ( P<0.0001) and aortic rings ( P=0.0060) from End.LepR-KO mice, and murine and human endothelial sprouting angiogenesis was reduced after mTOR inhibition using rapamycin or autophagy inhibition using 3-methyladenine. Banded End.LepR-KO mouse hearts exhibited less apoptosis ( P=0.0218), inflammation ( P=0.0251), and fibrosis ( P=0.0256). Reduced endothelial autophagy was also observed in myocardial biopsies of heart failure patients with cardiac fibrosis. CONCLUSIONS: Our findings suggest that endothelial leptin signaling contributes to cardiac fibrosis and functional deterioration by suppressing endothelial autophagy and promoting endothelial dysfunction in a chronic pressure overload model.


Assuntos
Autofagia , Cardiomegalia/enzimologia , Células Endoteliais/enzimologia , Insuficiência Cardíaca/enzimologia , Miocárdio/enzimologia , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores para Leptina/deficiência , Serina-Treonina Quinases TOR/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Fibrose , Deleção de Genes , Predisposição Genética para Doença , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos Knockout , Miocárdio/patologia , Fenótipo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Transdução de Sinais , Função Ventricular Esquerda
6.
J Mol Cell Cardiol ; 127: 134-142, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30582930

RESUMO

The Raf/MAPK/ERK kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is activated in cardiac hypertrophy after a myocardial infarction. Although heat-shock protein 90 (Hsp90) may regulate the Raf/Mek/Erk signal pathway, the role of Hsp90 in pathophysiological cardiac hypertrophy remains unclear. In this study, we examined the role of Hsp90 in this pathway in cardiac hypertrophy under in vivo and in vitro experimental conditions. Cultured rat cardiomyocytes were treated with the Hsp90 inhibitor 17-(allylamino)-17-dimethoxy-geldanamycin (17-AAG) and proteasome inhibitor MG-132, and then incubated with endothelin-1 (ET) to induce hypertrophy of the cells. The ET-induced increase in the cell size was attenuated by 17-AAG pretreatment. Immunoblot analysis revealed that the c-Raf content of ET-treated cardiomyocytes was decreased in the presence of 17-AAG. An increase in phosphorylation levels of Erk1/2 and GATA4 in ET-treated cardiomyocytes was also attenuated by the 17-AAG pretreatment. Myocardial infarction was produced by ligation of the left ventricular coronary artery in rats, and then 17-AAG was intraperitoneally administered to the animals starting from the 2ndweek after coronary artery ligation (CAL). CAL-induced increases in the heart weight and cross-sectional area were attenuated by 17-AAG treatment. CAL rats showed signs of chronic heart failure with cardiac hypertrophy, whereas cardiac function in CAL rats treated with 17-AAG was not reduced. Treatment of CAL rats with 17-AAG caused a decrease in the c-Raf content and Erk1/2 and GATA4 phosphorylation levels. These findings suggest that Hsp90 is involved in the activation of the Raf/Mek/Erk pathway via stabilization of c-Raf in cardiomyocytes, resulting in the development of cardiac hypertrophy following myocardial infarction.


Assuntos
Cardiomegalia/enzimologia , Cardiomegalia/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Ventrículos do Coração/enzimologia , Ventrículos do Coração/patologia , Sistema de Sinalização das MAP Quinases , Animais , Cardiomegalia/complicações , Cardiomegalia/fisiopatologia , Regulação para Baixo , Endotelina-1 , Feminino , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos
7.
Arq Bras Cardiol ; 112(2): 173-178, 2019 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30570065

RESUMO

BACKGROUND: Trimetazidine (TMZ) is an anti-ischemic drug. In spite of its protective effects on cardiovascular system, there is no scientific study on the usefulness of TMZ treatment for prolonged QT interval and cardiac hypertrophy induced by diabetes. OBJECTIVES: To evaluate the effects of TMZ on QT interval prolongation and cardiac hypertrophy in the diabetic rats. METHODS: Twenty-four male Sprague-Dawley rats (200-250 g) were randomly assigned into three groups (n = 8) by simple random sampling method. Control (C), diabetic (D), and diabetic administrated with TMZ at 10 mg/kg (T10). TMZ was administrated for 8 weeks. The echocardiogram was recorded before isolating the hearts and transfer to a Langendorff apparatus. Hemodynamic parameters, QT and corrected QT interval (QTc) intervals, heart rate and antioxidant enzymes were measured. The hypertrophy index was calculated. The results were evaluated by one-way ANOVA and paired t-test using SPSS (version 16) and p < 0.05 was regarded as significant. RESULTS: The diabetic rats significantly indicated increased hypertrophy, QT and QTc intervals and decreased Left ventricular systolic pressure (LVSP), Left ventricular developed pressure (LVDP), rate pressure product (RPP), Max dp/dt, and min dp/dt (±dp/dt max), heart rate, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase in the heart. Treatment with TMZ in the diabetic animals was significantly improved these parameters in comparison to the untreated diabetic group. CONCLUSIONS: TMZ improves QTc interval prolongation and cardiac hypertrophy in diabetes.


Assuntos
Cardiomegalia/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Síndrome do QT Longo/tratamento farmacológico , Substâncias Protetoras/farmacologia , Trimetazidina/farmacologia , Animais , Cardiomegalia/enzimologia , Cardiomegalia/etiologia , Cardiomegalia/fisiopatologia , Catalase/análise , Complicações do Diabetes/enzimologia , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Ecocardiografia , Glutationa Peroxidase/análise , Hemodinâmica/efeitos dos fármacos , Síndrome do QT Longo/enzimologia , Síndrome do QT Longo/fisiopatologia , Masculino , Distribuição Aleatória , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Superóxido Dismutase/análise , Fatores de Tempo
8.
Nat Commun ; 9(1): 5230, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30531796

RESUMO

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.


Assuntos
Cardiomegalia/genética , Regulação da Expressão Gênica/genética , Histona Desmetilases/genética , Miocárdio/metabolismo , Aminopiridinas/farmacologia , Animais , Animais Recém-Nascidos , Cardiomegalia/enzimologia , Células Cultivadas , Fibrose/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Humanos , Hidrazonas/farmacologia , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/enzimologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ratos Sprague-Dawley
9.
Sci Rep ; 8(1): 13100, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166619

RESUMO

Previous studies have shown that the activity and expression of Na+/K+-ATPase (NKA) are down-regulated in the failing hearts, and that an antibody against the DR-region of NKA (DR-Ab) can stimulate its activity. The present study was designed to investigate the beneficial effects of this antibody against cardiac injury and the underlying mechanisms. We found that DR-Ab improved cardiac function, alleviated cardiac hypertrophy and reduced oxidative stress in isoproterenol-treated mice. In AC16 human cardiomyocytes, DR-Ab increased cell viability and attenuated apoptosis under oxidative stress. Corresponding to the observation of reduced NKA activity, NKA abundance on plasma membrane was lowered during oxidative stress. Suppressed activity of protein phosphatase 2 A (PP2A) was responsible for the loss of membrane NKA due to the increased phosphorylation of key serine residues that trigger endocytosis. Incubation with DR-Ab restored PP2A activity and stabilized NKA expression on the plasma membrane. Inhibitors of PP2A abolished the protective effect of DR-Ab against oxidative stress. In summary, our data indicate that loss of membrane NKA may contribute to cardiac pathologies in heart failure. DR-Ab, by stabilizing membrane NKA, protects cardiomyocytes against oxidative injury and improves cardiac function in the failing hearts, suggesting a novel approach to treat heart failure.


Assuntos
Cardiomegalia/enzimologia , Miocárdio/enzimologia , Miócitos Cardíacos/enzimologia , Estresse Oxidativo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Linhagem Celular , Humanos , Masculino , Miocárdio/patologia , Miócitos Cardíacos/patologia , Oxirredução , Ratos , Ratos Sprague-Dawley , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores
10.
BMC Med Genet ; 19(1): 172, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30223778

RESUMO

BACKGROUND: PNPLA2 gene mutations cause neutral lipid storage disease with myopathy (NLSD-M) or cardiomyopathies. The clinical phenotype, blood test results, imaging examination and gene analysis can be used to improve the understanding of NLSD-M, reduce the misdiagnosis rate and prevent physical disability and even premature death. CASE PRESENTATION: We report a Chinese child with NLSD-M presenting with marked asymmetric skeletal myopathy and hypertrophic cardiomyopathy. Blood biochemical tests revealed increased creatine kinase levels, and echocardiography revealed a diffuse and thick left ventricular wall. Gene analysis revealed a homozygous mutation c.155C > G (p.Thr52Arg) in PNPLA2. CONCLUSIONS: An understanding of the characteristic features is essential for the early diagnosis of NLSD-M. Our data expand the allelic spectrum of PNPLA2 mutations, providing further evidence for genetic and clinical NLSD-M heterogeneity in younger individuals.


Assuntos
Cardiomegalia/genética , Cardiomiopatias/genética , Lipase/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Musculares/genética , Sequência de Bases , Cardiomegalia/diagnóstico , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/enzimologia , Cardiomiopatias/patologia , Criança , Creatina Quinase/sangue , Creatina Quinase/genética , Análise Mutacional de DNA , Diagnóstico Precoce , Expressão Gênica , Ventrículos do Coração/enzimologia , Ventrículos do Coração/patologia , Humanos , Lipase/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Doenças Musculares/diagnóstico , Doenças Musculares/enzimologia , Doenças Musculares/patologia , Mutação
11.
J Cell Mol Med ; 22(12): 5964-5977, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30256522

RESUMO

We previously reported that gentisic acid (2,5-dihydroxybenzoic acid) is the third most abundant phenolic component of Dendropanax morbifera branch extracts. Here, we investigated its effects on cardiac hypertrophy and fibrosis in a mouse model of pressure overload and compared them to those of the beta blocker bisoprolol and calcium channel blocker diltiazem. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC). Beginning 2 weeks after this procedure, the mice were given daily intraperitoneal injections of gentisic acid (100 mg/kg/d), bisoprolol (5 mg/kg/d) or diltiazem (10 mg/kg/d) for 3 weeks. Cardiac hypertrophy was evaluated by the heart weight-to-body weight ratio, the cardiomyocyte cross-sectional area after haematoxylin and eosin staining, and echocardiography. Markers of cardiac hypertrophy and fibrosis were tested by reverse transcription-quantitative real-time polymerase chain reaction, western blotting and Masson's trichrome staining. The suppressive effects of gentisic acid treatment on TAC-induced cardiac hypertrophy and fibrosis were comparable to those of bisoprolol administration. Cardiac hypertrophy was reversed and left ventricular septum and posterior wall thickness were restored by gentisic acid, bisoprolol and diltiazem treatment. Cardiac hypertrophic marker gene expression and atrial and brain natriuretic peptide levels were decreased by gentisic acid and bisoprolol, as were cardiac (interstitial and perivascular) fibrosis and fibrosis-related gene expression. Cardiac hypertrophy-associated upregulation of the transcription factors GATA4 and Sp1 and activation of extracellular signal-regulated kinase 1/2 were also negated by these drugs. These results suggest that gentisic acid could serve as a therapeutic agent for cardiac hypertrophy and fibrosis.


Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/enzimologia , Gentisatos/uso terapêutico , Sistema de Sinalização das MAP Quinases , Miocárdio/patologia , Pressão , Animais , Aorta/patologia , Cardiomegalia/genética , Cardiomegalia/patologia , Constrição Patológica , Eletrocardiografia , Fibrose , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Gentisatos/farmacologia , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo
12.
Proc Natl Acad Sci U S A ; 115(35): E8143-E8152, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30104387

RESUMO

Mutations in ß-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human ß-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.


Assuntos
Benzilaminas/química , Uracila/análogos & derivados , Miosinas Ventriculares/química , Animais , Benzilaminas/farmacologia , Cardiomegalia/enzimologia , Cardiomegalia/genética , Humanos , Músculo Esquelético/enzimologia , Mutação , Suínos , Porco Miniatura , Uracila/química , Uracila/farmacologia , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismo
13.
Am J Physiol Heart Circ Physiol ; 315(5): H1236-H1249, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30095997

RESUMO

Doxorubicin (Doxo) is an effective agent commonly used in cancer therapeutics. Unfortunately, Doxo treatment can stimulate cardiomyopathy and subsequent heart failure, limiting the use of this drug. The role of phosphatase and tensin homolog (PTEN) in apoptosis has been documented in Doxo-induced cardiomyopathy (DIC) and heart failure models. However, whether direct inhibition of PTEN attenuates apoptosis, cardiac remodeling, and inflammatory M1 macrophages in the DIC model remains elusive. Therefore, the present study was designed to understand the effects of VO-OHpic (VO), a potent inhibitor of PTEN, in reducing apoptosis and cardiac remodeling. At day 56, echocardiography was performed, which showed that VO treatment significantly ( P < 0.05) improved heart function. Immunohistochemistry, TUNEL, and histological staining were used to determine apoptosis, proinflammatory M1 macrophages, anti-inflammatory M2 macrophages, and cardiac remodeling. Our data show a significant increase in apoptosis, hypertrophy, fibrosis, and proinflammatory M1 macrophages with Doxo treatment, whereas VO treatment significantly reduced apoptosis, adverse cardiac remodeling, and proinflammatory M1 macrophages significantly ( P < 0.05) compared with the Doxo-treated group. Western blot analysis confirmed the reduction of phosphorylated PTEN and increase in phosphorylated AKT protein expression in the Doxo + VO-treated group. Moreover, VO administration increased anti-inflammatory M2 macrophages. Collectively, our data suggest that VO treatment attenuates apoptosis and adverse cardiac remodeling, a process that is mediated through the PTEN/AKT pathway, resulting in improved heart function in DIC. NEW & NOTEWORTHY Doxorubicin-induced cardiomyopathy (DIC) is still a major issue in patients with cancer. These novel findings on the phosphatase and tensin homolog inhibitor VO-OHpic in DIC is the first report, as per the best of our knowledge, that VO-OHpic significantly decreases apoptosis, fibrosis, hypertrophy, adverse cardiac remodeling, and proinflammatory M1 macrophages and increases anti-inflammatory M2 macrophages along with significantly improved cardiac function. VO-OHpic could be a future therapeutic agent for patients with DIC.


Assuntos
Anti-Inflamatórios/farmacologia , Cardiomiopatias/prevenção & controle , Doxorrubicina , Inibidores Enzimáticos/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Compostos Organometálicos/farmacologia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Cardiomegalia/enzimologia , Cardiomegalia/fisiopatologia , Cardiomegalia/prevenção & controle , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/enzimologia , Cardiomiopatias/fisiopatologia , Cardiotoxicidade , Modelos Animais de Doenças , Fibrose , Ventrículos do Coração/enzimologia , Ventrículos do Coração/fisiopatologia , Macrófagos/enzimologia , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Basic Res Cardiol ; 113(4): 31, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934662

RESUMO

The underlying cause of cardiac hypertrophy, fibrosis, and heart failure has been investigated in great detail using different mouse models. These studies indicated that cGMP and cGMP-dependent protein kinase type I (cGKI) may ameliorate these negative phenotypes in the adult heart. Recently, evidence has been published that cardiac mitochondrial BKCa channels are a target for cGKI and that activation of mitoBKCa channels may cause some of the positive effects of conditioning in ischemia/reperfusion injury. It will be pointed out that most studies could not present convincing evidence that it is the cGMP level and the activity cGKI in specific cardiac cells that reduces hypertrophy or heart failure. However, anti-fibrotic compounds stimulating nitric oxide-sensitive guanylyl cyclase may be an upcoming therapy for abnormal cardiac remodeling.


Assuntos
Cardiomegalia/enzimologia , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , GMP Cíclico/metabolismo , Insuficiência Cardíaca/enzimologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Miocárdio/enzimologia , Remodelação Ventricular , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Fibrose , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Sistemas do Segundo Mensageiro , Remodelação Ventricular/efeitos dos fármacos
15.
Int J Cardiol ; 270: 204-213, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29857938

RESUMO

BACKGROUND: Chronic pressure overload and a variety of mediators induce concentric cardiac hypertrophy. When prolonged, cardiac hypertrophy culminates in decreased myocardial function and heart failure. Activation of the extracellular signal-regulated kinase (ERK) is consistently observed in animal models of hypertrophy and in human patients, but its role in the process is controversial. METHODS: We generated transgenic mouse lines with cardiomyocyte restricted overexpression of intrinsically active ERK1, which similar to the observations in hypertrophy is phosphorylated on both the TEY and the Thr207 motifs and is overexpressed at pathophysiological levels. RESULTS: The activated ERK1 transgenic mice developed a modest adaptive hypertrophy with increased contractile function and without fibrosis. Following induction of pressure-overload, where multiple pathways are stimulated, this activation did not further increase the degree of hypertrophy but protected the heart through a decrease in the degree of fibrosis and maintenance of ventricular contractile function. CONCLUSIONS: The ERK pathway acts to promote a compensated hypertrophic response, with enhanced contractile function and reduced fibrosis. The activation of this pathway may be a therapeutic strategy to preserve contractile function when the pressure overload cannot be easily alleviated. The inhibition of this pathway, which is increasingly being used for cancer therapy on the other hand, should be used with caution in the presence of pressure-overload.


Assuntos
Pressão Sanguínea/fisiologia , Cardiomegalia/enzimologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteína Quinase 3 Ativada por Mitógeno/biossíntese , Miócitos Cardíacos/enzimologia , Animais , Animais Recém-Nascidos , Cardiomegalia/patologia , Células Cultivadas , Ativação Enzimática/fisiologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Contração Miocárdica/fisiologia , Miócitos Cardíacos/patologia , Ratos , Ratos Wistar
16.
Free Radic Biol Med ; 121: 215-230, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29733904

RESUMO

RATIONALE: Complement C1q tumor necrosis factor related proteins (C1QTNFs) have been reported to have diverse biological influence on the cardiovascular system. C1QTNF1 is a member of the CTRP superfamily. C1QTNF1 is expressed in the myocardium; however, its function in myocytes has not yet been investigated. OBJECTIVE: To systematically investigate the roles of C1QTNF1 in angiotensin II (Ang II)-induced cardiac hypertrophy. METHODS AND RESULTS: C1QTNF1 knock-out mice were used with the aim of determining the role of C1QTNF1 in cardiac hypertrophy in the adult heart. Data from experiments showed that C1QTNF1 was up-regulated during cardiac hypertrophic processes, which were triggered by increased reactive oxygen species. C1QTNF1 deficiency accelerated cardiac hypertrophy, fibrosis, inflammation responses, and oxidative stress with deteriorating cardiac dysfunction in the Ang II-induced cardiac hypertrophy mouse model. We identified C1QTNF1 as a negative regulator of cardiomyocyte hypertrophy in Ang II-stimulated neonatal rat cardiomyocytes using the recombinant human globular domain of C1QTNF1 and C1QTNF1 siRNA. Injection of the recombinant human globular domain of C1QTNF1 also suppressed the Ang II-induced cardiac hypertrophic response in vivo. The anti-hypertrophic effects of C1QTNF1 rely on AMPKa activation, which inhibits mTOR P70S6K phosphorylation. An AMPKa inhibitor abrogated the anti-hypertrophic effects of the recombinant human globular domain of C1QTNF1 both in vivo and vitro. Moreover, C1QTNF1-mediated AMPKa activation was triggered by the inhibition of PDE1-4, which subsequently activated the cAMP/PKA/LKB1 pathway. CONCLUSION: Our results demonstrated that C1QTNF1 improves cardiac function and inhibits cardiac hypertrophy and fibrosis by increasing and activating AMPKa, suggesting that C1QTNF1 could be a therapeutic target for cardiac hypertrophy and heart failure.


Assuntos
Adipocinas/fisiologia , Angiotensina II/toxicidade , Cardiomegalia/prevenção & controle , Modelos Animais de Doenças , Fibrose/prevenção & controle , Proteínas Quinases/metabolismo , Vasoconstritores/toxicidade , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Células Cultivadas , Fibrose/induzido quimicamente , Fibrose/enzimologia , Fibrose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
17.
Cardiovasc Pathol ; 35: 29-36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29747050

RESUMO

BACKGROUND: Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been demonstrated as central mediators in cardiac hypertrophy responses. LncRNA cardiac hypertrophy related factor (CHRF) has been reported to be implicated in cardiac hypertrophy. However, the underlying mechanisms of CHRF have not been thoroughly elucidated. METHODS: Expressions of CHRF and microRNA-93 (miR-93) in heart tissues and cardiomyocytes were detected by RT-qPCR assay. Cell surface area, protein/DNA ratio, atrial natriuretic peptide (ANP) and ß-myosin heavy chain (ß-MHC) levels were examined as the indicators of cardiac hypertrophy responses. Luciferase reporter assay was used to validate the direct binding between miR-93 and CHRF or Akt3 3'UTR. RIP assay was performed to demonstrate the potential interaction between CHRF and miR-93. Akt3 protein level was determined by western blot assay. RESULTS: CHRF expression was up-regulated and miR-93 expression was down-regulated in mice and cellular models of cardiac hypertrophy. CHRF knockdown attenuated isoproterenol (Iso)-induced hypertrophy responses through up-regulating miR-93 expression in cardiomyocytes. Moreover, CHRF acted as a competing endogenous RNA of miR-93 to sequester miR-93 from Akt3, resulting in the increase of Akt3 expression. Furthermore, miR-93 suppressed cardiac hypertrophy responses by targeting Akt3 in Iso-stimulated cardiomyocytes. CONCLUSIONS: CHRF induced cardiac hypertrophy by regulating miR-93/Akt3 axis in Iso-stimulated cardiomyocytes, deepening our understanding of the molecular mechanisms of lncRNAs in cardiac hypertrophy and providing a potential therapy target for cardiac hypertrophy.


Assuntos
Cardiomegalia/enzimologia , MicroRNAs/metabolismo , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Regiões 3' não Traduzidas , Agonistas Adrenérgicos beta/toxicidade , Animais , Sítios de Ligação , Cardiomegalia/genética , Cardiomegalia/patologia , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Isoproterenol/toxicidade , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Proteínas Proto-Oncogênicas c-akt/genética , RNA Longo não Codificante/genética , Transdução de Sinais
18.
J Mol Cell Cardiol ; 118: 183-192, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29627295

RESUMO

Pathological cardiac hypertrophy is associated with the accumulation of lipid peroxidation-derived aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and acrolein in the heart. These aldehydes are metabolized via several pathways, of which aldose reductase (AR) represents a broad-specificity route for their elimination. We tested the hypothesis that by preventing aldehyde removal, AR deficiency accentuates the pathological effects of transverse aortic constriction (TAC). We found that the levels of AR in the heart were increased in mice subjected to TAC for 2 weeks. In comparison with wild-type (WT), AR-null mice showed lower ejection fraction, which was exacerbated 2 weeks after TAC. Levels of atrial natriuretic peptide and myosin heavy chain were higher in AR-null than in WT TAC hearts. Deficiency of AR decreased urinary levels of the acrolein metabolite, 3-hydroxypropylmercapturic acid. Deletion of AR did not affect the levels of the other aldehyde-metabolizing enzyme - aldehyde dehydrogenase 2 in the heart, or its urinary product - (N-Acetyl-S-(2-carboxyethyl)-l-cystiene). AR-null hearts subjected to TAC showed increased accumulation of HNE- and acrolein-modified proteins, as well as increased AMPK phosphorylation and autophagy. Superfusion with HNE led to a greater increase in p62, LC3II formation, and GFP-LC3-II punctae formation in AR-null than WT cardiac myocytes. Pharmacological inactivation of JNK decreased HNE-induced autophagy in AR-null cardiac myocytes. Collectively, these results suggest that during hypertrophy the accumulation of lipid peroxidation derived aldehydes promotes pathological remodeling via excessive autophagy, and that metabolic detoxification of these aldehydes by AR may be essential for maintaining cardiac function during early stages of pressure overload.


Assuntos
Aldeído Redutase/deficiência , Autofagia , Coração/fisiopatologia , Pressão , Aldeído Redutase/metabolismo , Aldeídos/metabolismo , Animais , Aorta/patologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Constrição Patológica , Deleção de Genes , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Contração Miocárdica , Miocárdio/enzimologia , Proteína Sequestossoma-1/metabolismo
19.
Cardiovasc Toxicol ; 18(4): 365-373, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29396798

RESUMO

Cytochrome c oxidase (CCO) is a copper-dependent enzyme of mitochondrial respiratory chain. In pressure overload-induced cardiac hypertrophy, copper level and CCO activity are both depressed, along with disturbance in mitochondrial fusion and fission dynamics. Copper repletion leads to recovery of CCO activity and normalized mitochondrial dynamics. The present study was undertaken to define the link between CCO activity and mitochondrial dynamic changes. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine to induce cell hypertrophy. Hypertrophic cardiomyocytes were then treated with copper to reverse hypertrophy. In the hypertrophic cardiomyocytes, CCO activity was depressed and mitochondrial fusion was suppressed. Upon copper repletion, CCO activity was recovered and mitochondrial fusion was reestablished. Depression of CCO activity by siRNA targeting CCO assembly homolog 17 (COX17), a copper chaperone for CCO, led to fragmentation of mitochondria, which was not recoverable by copper supplementation. This study thus demonstrates that copper-dependent CCO is critical for mitochondrial fusion in the regression of cardiomyocyte hypertrophy.


Assuntos
Cardiomegalia/tratamento farmacológico , Sulfato de Cobre/farmacologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fenilefrina/toxicidade , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Células Cultivadas , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Cultura Primária de Células , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
J Mol Cell Cardiol ; 117: 49-61, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29452156

RESUMO

PRKAG2 cardiac syndrome is a distinct form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and progressive cardiac conduction disorder. However, it remains unclear how mutations in the PRKAG2 gene give rise to such a complicated disease. To investigate the underlying molecular mechanisms, we generated disease-specific hiPSC-derived cardiomyocytes from two brothers both carrying a heterozygous missense mutation c.905G>A (R302Q) in the PRKAG2 gene and further corrected the R302Q mutation with CRISPR-Cas9 mediated genome editing. Disease-specific hiPSC-cardiomyocytes recapitulated many phenotypes of PRKAG2 cardiac syndrome including cellular enlargement, electrophysiological irregularities and glycogen storage. In addition, we found that the PRKAG2-R302Q mutation led to increased AMPK activities, resulting in extensive glycogen deposition and cardiomyocyte hypertrophy. Finally we confirmed that disrupted phenotypes of PRKAG2 cardiac syndrome caused by the specific PRKAG2-R302Q mutation can be alleviated by small molecules inhibiting AMPK activity and be rescued with CRISPR-Cas9 mediated genome correction. Our results showed that disease-specific hiPSC-CMs and genetically-corrected hiPSC-cardiomyocytes would be a very useful platform for understanding the pathogenesis of, and testing autologous cell-based therapies for, PRKAG2 cardiac syndrome.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cardiopatias/enzimologia , Cardiopatias/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/genética , Adulto , Sequência de Bases , Cálcio/metabolismo , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Diferenciação Celular , Fenômenos Eletrofisiológicos , Glicogênio/metabolismo , Cardiopatias/fisiopatologia , Humanos , Masculino , Mitocôndrias/metabolismo , Mutação/genética , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/ultraestrutura , Oxirredução , Fenótipo , Reprodutibilidade dos Testes , Síndrome
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