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1.
Int J Mol Sci ; 20(2)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634441

RESUMO

Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1⁻7-dependent manner. Whether apelin antagonizes the over-activation of the renin⁻angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-ß) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-ß expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.


Assuntos
Angiotensina II/metabolismo , Apelina/deficiência , Disfunção Ventricular/genética , Remodelação Ventricular/genética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Biópsia , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Camundongos , Camundongos Knockout , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptidil Dipeptidase A/metabolismo
2.
Toxicol Sci ; 160(1): 74-82, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973413

RESUMO

Epidemiological studies in humans and research in vertebrates indicates that developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous and biopersistent environmental toxicant, is associated with incidence of early congenital heart disease in the embryo and later in the adult. TCDD-mediated toxicity depends on the aryl hydrocarbon receptor (AHR) but the role of the TCDD-activated AHR in cardiac function is not well-defined. To characterize the mechanisms responsible for AHR-mediated disruption of heart function, we generated several mouse strains with cardiomyocyte-specific Ahr gene knockout. Here, we report results on one of these strains in which the Ahr gene was deleted by cre recombinase regulated by the promoter of the cardiomyocyte-specific Nkx2.5 gene. We crossed mice with loxP-targeted Ahrfx/fx alleles with Nkx2.5+/cre mice bearing a "knock-in" cre recombinase gene integrated into one of the Nkx2.5 alleles. In these mice, loss of one Nkx2.5 allele is associated with disrupted cardiac development. In males, Nkx2.5 hemizygosity resulted in cardiac haploinsufficiency characterized by hypertrophy, dilated cardiomyopathy, and impaired ejection fraction. Ahr ablation protected Nkx2.5+/cre haploinsufficient males from cardiac dysfunction while inducing a significant increase in body weight. These effects were absent or largely blunted in females. Starting at 3 months of age, mice were exposed by oral gavage to 1 µg/kg/week of TCDD or control vehicle for an additional 2 months. TCDD exposure restored cardiac physiology in aging males, appearing to compensate for the heart dysfunction caused by Nkx2.5 hemizygosity. Our findings underscore the conclusion that deletion of the Ahr gene in cardiomyocytes protects males from heart dysfunction due to NKX2.5 haploinsufficiency.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Cardiomegalia/prevenção & controle , Cardiomiopatia Dilatada/prevenção & controle , Haploinsuficiência , Proteína Homeobox Nkx-2.5/deficiência , Miócitos Cardíacos/metabolismo , Receptores de Hidrocarboneto Arílico/deficiência , Disfunção Ventricular/prevenção & controle , Função Ventricular , Fatores Etários , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Modelos Animais de Doenças , Poluentes Ambientais/toxicidade , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Proteína Homeobox Nkx-2.5/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Fenótipo , Dibenzodioxinas Policloradas/toxicidade , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Fatores Sexuais , Volume Sistólico , Disfunção Ventricular/genética , Disfunção Ventricular/metabolismo , Disfunção Ventricular/fisiopatologia , Função Ventricular/efeitos dos fármacos
3.
Dis Model Mech ; 10(10): 1217-1227, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28801532

RESUMO

Hyperglycemia is an independent risk factor for diabetic cardiomyopathy in humans; however, the underlying mechanisms have not been thoroughly elucidated. Zebrafish (Danio rerio) was used in this study as a novel vertebrate model to explore the signaling pathways of human adult cardiomyopathy. Hyperglycemia was induced by alternately immersing adult zebrafish in a glucose solution or water. The hyperglycemic fish gradually exhibited some hallmarks of cardiomyopathy such as myocardial hypertrophy and apoptosis, myofibril loss, fetal gene reactivation, and severe arrhythmia. Echocardiography of the glucose-treated fish demonstrated diastolic dysfunction at an early stage and systolic dysfunction at a later stage, consistent with what is observed in diabetic patients. Enlarged hearts with decreased myocardial density, accompanied by decompensated cardiac function, indicated that apoptosis was critical in the pathological process. Significant upregulation of the expression of Nkx2.5 and its downstream targets calreticulin (Calr) and p53 was noted in the glucose-treated fish. High-glucose stimulation in vitro evoked marked apoptosis of primary cardiomyocytes, which was rescued by the p53 inhibitor pifithrin-µ. In vitro experiments were performed using compound treatment and genetically via cell infection. Genetically, knockout of Nkx2.5 induced decreased expression of Nkx2.5, Calr and p53 Upregulation of Calr resulted in increased p53 expression, whereas the level of Nkx2.5 remained unchanged. An adult zebrafish model of hyperglycemia-induced cardiomyopathy was successfully established. Hyperglycemia-induced myocardial apoptosis was mediated, at least in part, by activation of the Nkx2.5-Calr-p53 pathway in vivo, resulting in cardiac dysfunction and hyperglycemia-induced cardiomyopathy.


Assuntos
Glicemia/metabolismo , Calreticulina/metabolismo , Cardiomegalia/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Proteína Homeobox Nkx-2.5/metabolismo , Hiperglicemia/metabolismo , Miócitos Cardíacos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Disfunção Ventricular/metabolismo , Remodelação Ventricular , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose , Calreticulina/genética , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteína Homeobox Nkx-2.5/genética , Hiperglicemia/sangue , Hiperglicemia/genética , Miócitos Cardíacos/patologia , Transdução de Sinais , Fatores de Tempo , Proteína Supressora de Tumor p53/genética , Disfunção Ventricular/genética , Disfunção Ventricular/patologia , Disfunção Ventricular/fisiopatologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
4.
Sci Rep ; 7: 42574, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-28218306

RESUMO

Myocardial ischaemia-reperfusion (I/R) injury is a complex pathophysiological process. Current research has suggested that energy metabolism disorders, of which the abnormal consumption of fatty acids is closely related, compose the main pathological basis for myocardial I/R injury. Lipid droplets (LD) are critical regulators of lipid metabolism by LD-associated proteins. Among the lipid droplet proteins, the perilipin family members regulate lipolysis and lipogenesis through different mechanisms. Plin5, an important perilipin protein, promotes LD generation and lowers fatty acid oxidation, thus protecting the myocardium from lipotoxicity. This study investigated the protective effects of Plin5 in I/R myocardium. Our results indicated that Plin5 deficiency exacerbated the myocardial infarct area, aggravated left ventricular systolic dysfunction, reduced lipid storage, and elevated free fatty acids. Plin5-deficient myocardium exhibited severely damaged mitochondria, elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity. Furthermore, the decreased phosphorylation of PI3K/Akt in Plin5-null cardiomyocytes might contribute to I/R injury aggravation. In conclusion, Plin5, a new regulator of myocardial lipid metabolism, decreases free fatty acid peroxidation by inhibiting the lipolysis of intracellular lipid droplets, thus providing cardioprotection against I/R injury and shedding new light on therapeutic solutions for I/R diseases.


Assuntos
Gotículas Lipídicas/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , Perilipina-5/genética , Animais , Metabolismo dos Lipídeos , Lipólise , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Oxirredução , Perilipina-5/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Disfunção Ventricular/genética
5.
J Infect Dis ; 215(3): 387-395, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28003350

RESUMO

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease outcomes. We thus assessed the whole-blood transcriptome of patients with Chagas disease. Microarray analysis was performed on blood samples from 150 subjects, of whom 30 were uninfected control patients and 120 had Chagas disease (1 group had asymptomatic disease, and 2 groups had CCC with either a preserved or reduced left ventricular ejection fraction [LVEF]). Each Chagas disease group displayed distinct gene expression and functional pathway profiles. The most different expression patterns were between CCC groups with a preserved or reduced LVEF. A more stringent analysis indicated that 27 differentially expressed genes, particularly those related to natural killer (NK)/CD8+ T-cell cytotoxicity, separated the 2 groups. NK/CD8+ T-cell cytotoxicity could play a role in determining Chagas disease progression. Understanding genes associated with disease may lead to improved insight into CCC pathogenesis and the identification of prognostic factors for CCC progression.


Assuntos
Cardiomiopatia Chagásica/genética , Disfunção Ventricular/genética , Linfócitos T CD8-Positivos/imunologia , Cardiomiopatia Chagásica/sangue , Cardiomiopatia Chagásica/fisiopatologia , Citotoxicidade Imunológica/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Células Matadoras Naturais/imunologia , Análise em Microsséries , Pessoa de Meia-Idade , Miocárdio/patologia , Reação em Cadeia da Polimerase em Tempo Real , Disfunção Ventricular/sangue , Disfunção Ventricular/parasitologia
6.
J Mol Cell Cardiol ; 100: 64-71, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27693463

RESUMO

RATIONALE: Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart. OBJECTIVE: To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart. METHODS AND RESULTS: We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20mg/kg/day for 5days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer+ mice (iKO). After 4weeks of AngII (1.1mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E' and E'/A' ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a~50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities. CONCLUSION: These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction.


Assuntos
Angiotensina II/administração & dosagem , Ácidos Graxos/metabolismo , Miocárdio/metabolismo , Oxirredução/efeitos dos fármacos , Disfunção Ventricular/metabolismo , Acetil-CoA Carboxilase/deficiência , Animais , Cardiomegalia/diagnóstico , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Diástole/efeitos dos fármacos , Modelos Animais de Doenças , Ecocardiografia , Metabolismo Energético/genética , Fibrose , Deleção de Genes , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Miocárdio/patologia , Miocárdio/ultraestrutura , Biogênese de Organelas , Estresse Oxidativo/genética , Disfunção Ventricular/tratamento farmacológico , Disfunção Ventricular/genética
8.
J Mol Cell Cardiol ; 100: 109-117, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27746126

RESUMO

Matrix metalloproteinase-9 (MMP-9) is robustly elevated in the first week post-myocardial infarction (MI). Targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-MI by reducing macrophage infiltration and collagen accumulation through increased apoptosis and reduced inflammation. In this study, we used a translational experimental design to determine whether selective MMP-9 inhibition early post-MI would be an effective therapeutic strategy in mice. We enrolled male C57BL/6J mice (3-6months old, n=116) for this study. Mice were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03µg/day) treatment was initiated at 3h post-MI and the mice were sacrificed at day (D) 1 or 7 post-MI. MMP-9i reduced MMP-9 activity by 31±1% at D1 post-MI (p<0.05 vs saline) and did not affect survival or infarct area. Surprisingly, MMP-9i treatment increased infarct wall thinning and worsened cardiac function at D7 post-MI. While MMP-9i enhanced neutrophil infiltration at D1 and macrophage infiltration at D7 post-MI, CD36 levels were lower in MMP-9i compared to saline, signifying reduced phagocytic potential per macrophage. Escalation and prolongation of the inflammatory response at D7 post-MI in the MMP-9i group was evident by increased expression of 18 pro-inflammatory cytokines (all p<0.05). MMP-9i reduced cleaved caspase 3 levels at D7 post-MI, consistent with reduced apoptosis and defective inflammation resolution. Because MMP-9i effects on inflammatory cells were significantly different from previously observed MMP-9 null mechanisms, we evaluated pre-MI (baseline) systemic differences between C57BL/6J and MMP-9 null plasma. By mass spectrometry, 34 plasma proteins were significantly different between groups, revealing a previously unappreciated altered baseline environment pre-MI when MMP-9 was deleted. In conclusion, early MMP-9 inhibition delayed inflammation resolution and exacerbated cardiac dysfunction, highlighting the importance of using translational approaches in mice.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Disfunção Ventricular/metabolismo , Animais , Apoptose , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Matriz Extracelular/metabolismo , Expressão Gênica , Imuno-Histoquímica , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Camundongos , Mortalidade , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infiltração de Neutrófilos , Interferência de RNA , Disfunção Ventricular/genética , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
9.
J Mol Cell Cardiol ; 99: 100-112, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27539860

RESUMO

Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARα signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RARαKO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RARαKO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RARαKO mouse hearts, which were rescued by overexpression of RARα in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase II δ (CaMKII δ) was observed in RARαKO mouse hearts. Ca2+ reuptake and cardiomyocyte relaxation were delayed by RARα deletion. Overexpression of RARα or inhibition of ROS generation or NOX activation prevented RARα deletion-induced decrease in SERCA2a expression/activation and delayed Ca2+ reuptake. Moreover, the gene and protein expression of RARα was significantly decreased in aged or metabolic stressed mouse hearts. RARα deletion accelerated the development of diastolic dysfunction in streptozotocin (STZ)-induced type 1 diabetic mice or in high fat diet fed mice. In conclusion, myocardial RARα deletion promoted diastolic dysfunction, with a relative preserved LVEF. Increased oxidative stress have an important role in the decreased expression/activation of SERCA2a and Ca2+ mishandling in RARαKO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RARα signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction.


Assuntos
Cálcio/metabolismo , Diástole , Miocárdio/metabolismo , Estresse Oxidativo , Receptor alfa de Ácido Retinoico/deficiência , Disfunção Ventricular/genética , Disfunção Ventricular/metabolismo , Disfunção Ventricular/fisiopatologia , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática , Fibrose , Deleção de Genes , Expressão Gênica , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Disfunção Ventricular/diagnóstico por imagem
10.
PLoS One ; 11(7): e0160168, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27472518

RESUMO

BACKGROUND: Intercalated disks are unique structures in cardiac tissue, in which adherens junctions, desmosomes, and GAP junctions co-localize, thereby facilitating cardiac muscle contraction and function. Protocadherins are involved in these junctions; however, their role in heart physiology is poorly understood. We aimed to analyze the transcriptomic profile of adhesion molecules in patients with ischemic cardiomyopathy (ICM) and relate the changes uncovered with the hemodynamic alterations and functional depression observed in these patients. METHODS AND RESULTS: Twenty-three left ventricular tissue samples from patients diagnosed with ICM (n = 13) undergoing heart transplantation and control donors (CNT, n = 10) were analyzed using RNA sequencing. Forty-two cell adhesion genes involved in cellular junctions were differentially expressed in ICM myocardium. Notably, the levels of protocadherin PCDHGA3 were related with the stroke volume (r = -0.826, P = 0.003), ejection fraction (r = -0.793, P = 0.004) and left ventricular end systolic and diastolic diameters (r = 0.867, P = 0.001; r = 0.781, P = 0.005, respectively). CONCLUSIONS: Our results support the importance of intercalated disks molecular alterations, closely involved in the contractile function, highlighting its crucial significance and showing gene expression changes not previously described. Specifically, altered PCDHGA3 gene expression was strongly associated with reduced stroke volume and ventricular dysfunction in ICM, suggesting a relevant role in hemodynamic perturbations and cardiac performance for this unexplored protocadherin.


Assuntos
Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Isquemia Miocárdica/metabolismo , Volume Sistólico/genética , Disfunção Ventricular/genética , Western Blotting , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA , Transcriptoma
11.
Am J Physiol Heart Circ Physiol ; 310(11): H1671-82, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27059079

RESUMO

Hypertension (HTN) is a major risk factor for heart failure. We investigated the influence of HTN on cardiac contraction and relaxation in transgenic renin overexpressing rats (carrying mouse Ren-2 renin gene, mRen2, n = 6). Blood pressure (BP) was measured. Cardiac contractility was characterized by echocardiography, cellular force measurements, and biochemical assays were applied to reveal molecular mechanisms. Sprague-Dawley (SD) rats (n = 6) were used as controls. Transgenic rats had higher circulating renin activity and lower cardiac angiotensin-converting enzyme two levels. Systolic BP was elevated in mRen2 rats (235.11 ± 5.32 vs. 127.03 ± 7.56 mmHg in SD, P < 0.05), resulting in increased left ventricular (LV) weight/body weight ratio (4.05 ± 0.09 vs. 2.77 ± 0.08 mg/g in SD, P < 0.05). Transgenic renin expression had no effect on the systolic parameters, such as LV ejection fraction, cardiomyocyte Ca(2+)-activated force, and Ca(2+) sensitivity of force production. In contrast, diastolic dysfunction was observed in mRen2 compared with SD rats: early and late LV diastolic filling ratio (E/A) was lower (1.14 ± 0.04 vs. 1.87 ± 0.08, P < 0.05), LV isovolumetric relaxation time was longer (43.85 ± 0.89 vs. 28.55 ± 1.33 ms, P < 0.05), cardiomyocyte passive tension was higher (1.74 ± 0.06 vs. 1.28 ± 0.18 kN/m(2), P < 0.05), and lung weight/body weight ratio was increased (6.47 ± 0.24 vs. 5.78 ± 0.19 mg/g, P < 0.05), as was left atrial weight/body weight ratio (0.21 ± 0.03 vs. 0.14 ± 0.03 mg/g, P < 0.05). Hyperphosphorylation of titin at Ser-12742 within the PEVK domain and a twofold overexpression of protein kinase C-α in mRen2 rats were detected. Our data suggest a link between the activation of renin-angiotensin-aldosterone system and increased titin-based stiffness through phosphorylation of titin's PEVK element, contributing to diastolic dysfunction.


Assuntos
Conectina/metabolismo , Hipertensão/metabolismo , Sistema Renina-Angiotensina/fisiologia , Renina/metabolismo , Disfunção Ventricular/metabolismo , Animais , Hipertensão/genética , Hipertensão/fisiopatologia , Miócitos Cardíacos/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Renina/genética , Disfunção Ventricular/genética , Disfunção Ventricular/fisiopatologia
12.
Physiol Rep ; 4(6)2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27033451

RESUMO

Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin-3 (CAV3). We further test whether haploinsufficiency forCAV3 increases the susceptibility to high-fat-induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency forCAV3 increases susceptibility to palmitate-induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show thatCAV3 andIRdirectly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin-stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin-stimulated glucose uptake inHL-1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin-independent serine phosphorylation ofIRS-1 by 35%. In addition, we found lipid induced downregulation ofCD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss ofCAV3 interferes with downstream insulin signaling and lipid uptake, implicatingCAV3 as a regulator of theIRand regulator of lipid uptake in the heart.


Assuntos
Caveolina 3/genética , Dieta Hiperlipídica , Intolerância à Glucose/genética , Heterozigoto , Resistência à Insulina , Miócitos Cardíacos/metabolismo , Ácido Palmítico , Animais , Glicemia/metabolismo , Antígenos CD36/metabolismo , Cavéolas/metabolismo , Caveolina 3/deficiência , Linhagem Celular , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Intolerância à Glucose/induzido quimicamente , Intolerância à Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Haploinsuficiência , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Receptor de Insulina/metabolismo , Transdução de Sinais , Volume Sistólico , Fatores de Tempo , Transfecção , Disfunção Ventricular/induzido quimicamente , Disfunção Ventricular/genética , Disfunção Ventricular/fisiopatologia
13.
J Mol Cell Cardiol ; 94: 145-152, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27071338

RESUMO

Heart failure due to myocardial infarction is a major cause of mortality. The microRNA (miR) family let-7 is expressed during embryonic development and is up-regulated in differentiated cells. The aim of this study was to study the role of let-7 after acute myocardial infarction (AMI). We designed an antimiR to inhibit the highest expressed members of the let-7 family, let-7 a, b and c. Administration at day 0 and day 2 after AMI resulted in sustained knockdown of let-7 after 28days. Let-7 inhibition prevented deterioration of cardiac functions compared to control treatment which was especially due to improvements in the infarcted, apical cardiac segments. We observed higher contents of fibrosis in the border zone as well as increased numbers of cells positive for TCF21, which is also expressed in epicardial cells. Markers were augmented after let-7 inhibition and let-7 blocked EMT in epicardial cells in vitro. Lineage tracing in TCF21(iCre/+):R26R(tdT) mice showed abundant tomato positive cells in the infarct and border zone. In conclusion, let-7 inhibition resulted in functional benefits due to an increase in recruitment of epicardial cells and EMT.


Assuntos
Transição Epitelial-Mesenquimal , Regulação da Expressão Gênica , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Disfunção Ventricular/genética , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem da Célula , Transição Epitelial-Mesenquimal/genética , Fibrose , Masculino , Camundongos , Camundongos Transgênicos , MicroRNAs/química , Infarto do Miocárdio/patologia
14.
Antioxid Redox Signal ; 25(2): 78-88, 2016 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-27000416

RESUMO

AIM: We evaluated the effect of thioredoxin1 (Trx1) system on postischemic ventricular and mitochondrial dysfunction using transgenic mice overexpressing cardiac Trx1 and a dominant negative (DN-Trx1) mutant (C32S/C35S) of Trx1. Langendorff-perfused hearts were subjected to 15 min of ischemia followed by 30 min of reperfusion (R). We measured left ventricular developed pressure (LVDP, mmHg), left ventricular end diastolic pressure (LVEDP, mmHg), and t63 (relaxation index, msec). Mitochondrial respiration, SERCA2a, phospholamban (PLB), and phospholamban phosphorylation (p-PLB) Thr17 expression (Western blot) were also evaluated. RESULTS: At 30 min of reperfusion, Trx1 improved contractile state (LVDP: Trx1: 57.4 ± 4.9 vs. Wt: 27.1 ± 6.3 and DN-Trx1: 29.2 ± 7.1, p < 0.05); decreased myocardial stiffness (LVEDP: Wt: 24.5 ± 4.8 vs. Trx1: 11.8 ± 2.9, p < 0.05); and improved the isovolumic relaxation (t63: Wt: 63.3 ± 3.2 vs. Trx1: 51.4 ± 1.9, p < 0.05). DN-Trx1 mice aggravated the myocardial stiffness and isovolumic relaxation. Only the expression of p-PLB Thr17 increased at 1.5 min R in Wt and DN-Trx1 groups. At 30 min of reperfusion, state 3 mitochondrial O2 consumption was impaired by 13% in Wt and by 33% in DN-Trx1. ADP/O ratios for Wt and DN-Trx1 decrease by 25% and 28%, respectively; whereas the Trx1 does not change after ischemia and reperfusion (I/R). Interestingly, baseline values of complex I activity were increased in Trx1 mice; they were 24% and 47% higher than in Wt and DN-Trx1 mice, respectively (p < 0.01). INNOVATION AND CONCLUSION: These results strongly suggest that Trx1 ameliorates the myocardial effects of I/R by improving the free radical-mediated damage in cardiac and mitochondrial function, opening the possibility of new therapeutic strategies in coronary artery disease. Antioxid. Redox Signal. 25, 78-88.


Assuntos
Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/metabolismo , Tiorredoxinas/metabolismo , Disfunção Ventricular/metabolismo , Animais , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/genética , Miocárdio Atordoado/genética , Consumo de Oxigênio , Tiorredoxinas/genética , Disfunção Ventricular/genética
15.
J Mol Cell Cardiol ; 93: 18-31, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26906634

RESUMO

BACKGROUND: Adiponectin (APN), an adipose-derived adipokine, alleviates lipopolysaccharide (LPS)-induced injury in multiple organs including hearts although the underlying mechanism in endotoxemia remains elusive. This study was designed to examine the role of adiponectin in LPS-induced cardiac anomalies and inflammation as well as the underlying mechanism with a focus on autophagy - a conserved machinery for bulk degradation of intracellular components. METHODS AND RESULTS: Wild-type (WT) and APN(-/-) mice were challenged with LPS (4mg/kg) or saline for 6h. Echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were evaluated. Markers of autophagy, apoptosis and inflammation including LC3B, p62, Beclin1, AMPK, mTOR, ULK, Caspase 3, Bcl-2, Bax, TLR4, TRAF6, MyD88, IL-1B, TNFα, HMGB1, JNK and IκB were examined using Western blot or RT-PCR. Our results showed that LPS challenge reduced fractional shortening, compromised cardiomyocyte contractile capacity, intracellular Ca(2+) handling properties, apoptosis and inflammation, which were accentuated by adiponectin ablation. Adiponectin ablation unmasked the LPS-induced cardiac remodeling (left ventricular end systolic diameter) and prolongation of cell shortening. The detrimental effects of adiponectin ablation were associated with dampened autophagy in response to LPS through an AMPK-mTOR-ULK1-dependent mechanism. In vivo administration of AMPK activator AICAR or the autophagy inducer rapamycin effectively attenuated or obliterated LPS-induced and adiponectin deficiency-accentuated responses without affecting TLR4, TRAF6 and MyD88. CONCLUSIONS: The findings suggest that AMPK and autophagy may play a permissive role in the adiponectin deficiency-exacerbated cardiac dysfunction, apoptosis and inflammation under LPS challenge possibly at the post-TLR4 receptor level.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/deficiência , Autofagia , Endotoxemia/genética , Endotoxemia/metabolismo , Miocardite/etiologia , Miocardite/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Cálcio/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Morte Celular , Modelos Animais de Doenças , Endotoxemia/complicações , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Knockout , Miocardite/diagnóstico , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ribonucleotídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Disfunção Ventricular/diagnóstico , Disfunção Ventricular/genética , Disfunção Ventricular/fisiopatologia
16.
Am J Physiol Heart Circ Physiol ; 310(6): H655-66, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26801308

RESUMO

"Obesity cardiomyopathy" effects have been widely described; however, the specific contribution of metabolic changes and altered adipokine secretion are still uncharacterized. Moreover, a diagnosis based on body mass index might not be the most accurate to identify increased adiposity and its outcomes. In this study, we aimed to determine the impact of a Western-type diet [hypercaloric diet (HCD)] ingestion on biventricular structure and function, as well as the metabolic and endocrine changes that occur before the establishment of overt obesity. Wistar rats were fed for 6 wk with a regular diet or HCD. At the end of the protocol, metabolic tests, cardiac structure, and functional evaluation were performed, and blood and tissue samples collected to perform histological, molecular biology, and functional studies. The animals that ingested the HCD presented increased adiposity and larger adipocyte cross-sectional area, but similar body weight compared with the regular diet group. At the cardiac level, HCD induced biventricular cardiomyocyte hypertrophy, fibrosis, increased stiffness, and impaired relaxation. Galectin-3 plasma expression was likewise elevated in the same animals. The nutritional modulation also altered the secretory pattern of the adipose tissue, originating a proinflammatory systemic environment. In this study, we observed that before "clinical" overweight or frank obesity is established, the ingestion of a HCD-induced cardiac remodeling manifests by increased biventricular stiffness and diastolic dysfunction. The mechanism triggering the cardiac alterations appears to be the proinflammatory environment promoted by the adipose tissue dysfunction. Furthermore, galectin-3, a profibrotic molecule, might be a potential biomarker for the myocardial alterations promoted by the HCD before overweight or obesity.


Assuntos
Adipócitos/patologia , Cardiomiopatias/patologia , Dieta Ocidental , Galectina 3/genética , Resistência à Insulina , Miocárdio/patologia , Miócitos Cardíacos/patologia , RNA Mensageiro/metabolismo , Disfunção Ventricular/patologia , Remodelação Ventricular , Tecido Adiposo , Animais , Peso Corporal , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Tamanho Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Diástole , Ecocardiografia , Matriz Extracelular/patologia , Fibrose , Galectina 3/metabolismo , Teste de Tolerância a Glucose , Inflamação , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leptina/genética , Leptina/metabolismo , Miocárdio/metabolismo , Obesidade , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Resistina/genética , Resistina/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Disfunção Ventricular/diagnóstico por imagem , Disfunção Ventricular/genética
17.
Eur J Hum Genet ; 24(5): 666-71, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26419279

RESUMO

Dilated cardiomyopathy (DCM) and malignant ventricular arrhythmias are important causes of congestive heart failure, heart transplantation, and sudden cardiac death in young patients. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line that has a pivotal role in maintaining adult cardiac structure and function. The putative mutation p.(D117N) in Cypher/ZASP has been suggested to cause systolic dysfunction, dilated left ventricle with hypertrabeculated myocardium, and intraventricular conduction disturbance, based on two reported sporadic cases. In two unrelated Bedouin families, one with pediatric DCM and the other with DCM and ventricular arrhythmias at young adulthood searching for the causative mutation by exome sequencing we identified the p.(D117N) variant in Cypher/ZASP. However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations. Furthermore, the carrier frequency in the Bedouin population of origin is estimated to be 5.2%, which is much higher than the incidence of idiopathic DCM in this population. Thus, our data support the notion that the p.(D117N) variant in Cypher/ZASP is not a causative mutation in the families tested by us. The results also indicates that at least in some cases, the p.(D117N) in Cypher/ZASP is not a causative mutation and the role of D117N in Cypher/ZASP in cardiac pathologies should be further clarified and re-evaluated.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/genética , Proteínas com Domínio LIM/genética , Polimorfismo de Nucleotídeo Único , Disfunção Ventricular/genética , Adolescente , Adulto , Árabes , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Linhagem
18.
PLoS One ; 10(2): e0115822, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25671318

RESUMO

The functional importance of threonine 5 (T5) in modulating the activity of sarcolipin (SLN), a key regulator of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) pump was studied using a transgenic mouse model with cardiac specific expression of threonine 5 to alanine mutant SLN (SLNT5A). In these transgenic mice, the SLNT5A protein replaces the endogenous SLN in atria, while maintaining the total SLN content. The cardiac specific expression of SLNT5A results in severe cardiac structural remodeling accompanied by bi-atrial enlargement. Biochemical analyses reveal a selective downregulation of SR Ca2+ handling proteins and a reduced SR Ca2+ uptake both in atria and in the ventricles. Optical mapping analysis shows slower action potential propagation in the transgenic mice atria. Doppler echocardiography and hemodynamic measurements demonstrate a reduced atrial contractility and an impaired diastolic function. Together, these findings suggest that threonine 5 plays an important role in modulating SLN function in the heart. Furthermore, our studies suggest that alteration in SLN function can cause abnormal Ca2+ handling and subsequent cardiac remodeling and dysfunction.


Assuntos
Proteínas Musculares/genética , Mutação , Miocárdio/metabolismo , Miocárdio/patologia , Proteolipídeos/genética , Treonina/genética , Disfunção Ventricular/genética , Remodelação Ventricular/genética , Animais , Cálcio/metabolismo , Diástole/genética , Expressão Gênica , Átrios do Coração/metabolismo , Hemodinâmica , Camundongos , Camundongos Transgênicos , Proteínas Musculares/metabolismo , Especificidade de Órgãos/genética , Proteolipídeos/metabolismo , Retículo Sarcoplasmático/metabolismo , Treonina/metabolismo
19.
Toxicol Sci ; 143(2): 374-84, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25370841

RESUMO

Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardiomyocytes treated with sorafenib. Reactive oxygen species (ROS) production significantly increased in both species of human cardiomyocytes and zebrafish exposed to sorafenib and STC1 knockdown compared with the controls. Finally, we found that forced expression of stc1 normalized impairment, decreasing the longitudinal dimensions in zebrafish treated with sorafenib. Our study demonstrated that STC1 plays a protective role against ventricular dysfunction and ROS overproduction, which are induced by sorafenib treatment. We discovered for the first time that STC1 downregulation is responsible for sorafenib-induced cardiotoxicity through activated ROS generation.


Assuntos
Antineoplásicos/efeitos adversos , Glicoproteínas/genética , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Disfunção Ventricular/induzido quimicamente , Adulto , Animais , Cardiotoxicidade , Regulação para Baixo , Coração/fisiopatologia , Humanos , Miócitos Cardíacos/metabolismo , Niacinamida/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Sorafenibe , Disfunção Ventricular/genética , Disfunção Ventricular/metabolismo , Peixe-Zebra
20.
J Am Heart Assoc ; 3(6): e001263, 2014 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-25389285

RESUMO

BACKGROUND: Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM. METHODS AND RESULTS: We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions. CONCLUSIONS: Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.


Assuntos
Cardiomiopatia Hipertrófica/metabolismo , Diferenciação Celular , Endotelina-1/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miofibrilas/efeitos dos fármacos , Animais , Fenômenos Biomecânicos , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Relação Dose-Resposta a Droga , Interação Gene-Ambiente , Genótipo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miofibrilas/metabolismo , Miofibrilas/patologia , Fenótipo , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Disfunção Ventricular/genética , Disfunção Ventricular/metabolismo , Disfunção Ventricular/patologia , Disfunção Ventricular/fisiopatologia , Gravação em Vídeo
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