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1.
Nutrients ; 13(10)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34684485

RESUMO

Cardiac hypertrophy can lead to congestive heart failure and is a leading cause of morbidity and mortality worldwide. In recent years, it has been essential to find the treatment and prevention of cardiac hypertrophy. Betulinic acid (BA), the main active ingredient in many natural products, is known to have various physiological effects. However, as the potential effect of BA on cardiac hypertrophy and consequent renal dysfunction is unknown, we investigated the effect of BA on isoprenaline (ISO)-induced cardiac hypertrophy and related signaling. ISO was known to induce left ventricular hypertrophy by stimulating the ß2-adrenergic receptor (ß2AR). ISO was injected into Sprague Dawley rats (SD rats) by intraperitoneal injection once a day for 28 days to induce cardiac hypertrophy. From the 14th day onwards, the BA (10 or 30 mg/kg/day) and propranolol (10 mg/kg/day) were administered orally. The study was conducted in a total of 5 groups, as follows: C, control; Is, ISO (10 mg/kg/day); Pr, positive-control, ISO + propranolol (10 mg/kg/day); Bl, ISO + BA (10 mg/kg/day); Bh, ISO + BA (30 mg/kg/day). As a result, the total cardiac tissue and left ventricular tissue weights of the ISO group increased compared to the control group and were significantly reduced by BA treatment. In addition, as a result of echocardiography, the effect of BA on improving cardiac function, deteriorated by ISO, was confirmed. Cardiac hypertrophy biomarkers such as ß-MHC, ANP, BNP, LDH, and CK-MB, which were increased by ISO, were significantly decreased by BA treatment. Also, the cardiac function improvement effect of BA was confirmed to improve cardiac function by inhibiting calcineurin/NFATc3 signaling. Renal dysfunction is a typical complication caused by cardiac hypertrophy. Therefore, the study of renal function indicators, creatinine clearance (Ccr) and osmolality (BUN) was aggravated by ISO treatment but was significantly restored by BA treatment. Therefore, it is thought that BA in cardiac hypertrophy can be used as valuable data to develop as a functional material effective in improving cardiac-renal dysfunction.


Assuntos
Calcineurina/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Coração/fisiopatologia , Rim/fisiopatologia , Fatores de Transcrição NFATC/metabolismo , Triterpenos Pentacíclicos/farmacologia , Transdução de Sinais , Animais , Biomarcadores/sangue , Cardiomegalia/sangue , Cardiomegalia/patologia , Fibrose , Coração/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Isoproterenol , Rim/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
2.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360761

RESUMO

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK-/- mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and ßMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.


Assuntos
Cardiomegalia/enzimologia , Diabetes Mellitus Experimental/enzimologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miocárdio/metabolismo , /metabolismo , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Volume Sistólico , Remodelação Ventricular
3.
PLoS One ; 16(8): e0255022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34339435

RESUMO

Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.


Assuntos
Cardiomiopatias/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Obesidade/tratamento farmacológico , Inibidores de Prolil-Hidrolase/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Biomarcadores/sangue , Cardiomegalia/sangue , Cardiomegalia/complicações , Cardiomegalia/fisiopatologia , Cardiomiopatias/sangue , Cardiomiopatias/complicações , Cardiomiopatias/fisiopatologia , Glucose/metabolismo , Hemoglobinas/metabolismo , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/fisiopatologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Rim/fisiopatologia , Nefropatias/sangue , Nefropatias/complicações , Nefropatias/fisiopatologia , Masculino , Obesidade/sangue , Obesidade/complicações , Obesidade/fisiopatologia , Inibidores de Prolil-Hidrolase/farmacologia , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia
4.
Cells ; 10(8)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34440871

RESUMO

Irisin is a myokine derived from the cleavage of fibronectin type III domain-containing 5. Irisin regulates mitochondrial energy, glucose metabolism, fatty acid oxidation, and fat browning. Skeletal muscle and cardiomyocytes produce irisin and affect various cardiovascular functions. In the early phase of acute myocardial infarction, an increasing irisin level can reduce endothelial damage by inhibiting inflammation and oxidative stress. By contrast, higher levels of irisin in the later phase of myocardial infarction are associated with more cardiovascular events. During different stages of heart failure, irisin has various influences on mitochondrial dysfunction, oxidative stress, metabolic imbalance, energy expenditure, and heart failure prognosis. Irisin affects blood pressure and controls hypertension through modulating vasodilatation. Moreover, irisin can enhance vasoconstriction via the hypothalamus. Because of these dual effects of irisin on cardiovascular physiology, irisin can be a critical therapeutic target in cardiovascular diseases. This review focuses on the complex functions of irisin in myocardial ischemia, heart failure, and cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Fibronectinas/metabolismo , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Cardiomegalia/fisiopatologia , Metabolismo Energético , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo
5.
Clin Sci (Lond) ; 135(14): 1631-1647, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34296750

RESUMO

Raf kinases signal via extracellular signal-regulated kinases 1/2 (ERK1/2) to drive cell division. Since activating mutations in BRAF (B-Raf proto-oncogene, serine/threonine kinase) are highly oncogenic, BRAF inhibitors including dabrafenib have been developed for cancer. Inhibitors of ERK1/2 signalling used for cancer are cardiotoxic in some patients, raising the question of whether dabrafenib is cardiotoxic. In the heart, ERK1/2 signalling promotes not only cardiomyocyte hypertrophy and is cardioprotective but also promotes fibrosis. Our hypothesis is that ERK1/2 signalling is not required in a non-stressed heart but is required for cardiac remodelling. Thus, dabrafenib may affect the heart in the context of, for example, hypertension. In experiments with cardiomyocytes, cardiac fibroblasts and perfused rat hearts, dabrafenib inhibited ERK1/2 signalling. We assessed the effects of dabrafenib (3 mg/kg/d) on male C57BL/6J mouse hearts in vivo. Dabrafenib alone had no overt effects on cardiac function/dimensions (assessed by echocardiography) or cardiac architecture. In mice treated with 0.8 mg/kg/d angiotensin II (AngII) to induce hypertension, dabrafenib inhibited ERK1/2 signalling and suppressed cardiac hypertrophy in both acute (up to 7 d) and chronic (28 d) settings, preserving ejection fraction. At the cellular level, dabrafenib inhibited AngII-induced cardiomyocyte hypertrophy, reduced expression of hypertrophic gene markers and almost completely eliminated the increase in cardiac fibrosis both in interstitial and perivascular regions. Dabrafenib is not overtly cardiotoxic. Moreover, it inhibits maladaptive hypertrophy resulting from AngII-induced hypertension. Thus, Raf is a potential therapeutic target for hypertensive heart disease and drugs such as dabrafenib, developed for cancer, may be used for this purpose.


Assuntos
Antineoplásicos/farmacologia , Fibrose/tratamento farmacológico , Hipertensão/tratamento farmacológico , Imidazóis/farmacologia , Oximas/farmacologia , Animais , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Hipertensão/fisiopatologia , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
6.
Life Sci ; 284: 119664, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34090859

RESUMO

AIM: Present study focuses on the effect of daidzein in an experimental model of diabetic cardiomyopathy in rats. MATERIALS AND METHODS: Diabetes was induced in male Sprague Dawley rats by a single intraperitoneal injection of STZ at dose 55 mg/kg. Daidzein treatment was started after six weeks of diabetes induction. Animals received daidzein at a dose of 25, 50, and 100 mg/kg orally for the next four weeks. KEY FINDINGS: Diabetic control animals showed significant prolongation in QT interval, PR interval, and R wave amplitude as compared to normal control animals. Treatment with daidzein at dose 100 mg/kg significantly normalized the QT interval, PR interval, and R wave amplitude. A significant reduction in QRS duration was observed in diabetic animals. Treatment with daidzein significantly improved the QRS duration after treatment. Hemodynamic parameters like systolic pressure (SBP), diastolic pressure (DBP) and mean atrial pressure (MAP) were found to be significantly decreased in diabetic animals. Treatment with daidzein at dose 100 mg/kg significantly improved the SBP, DBP, and MAP. Daidzein treatment prevented the loss of cardiac marker enzyme from heart tissue and also increased the level of AMPK and SIRT1 in plasma. Protein expression of NOX-4 and RAC-1 was also found to be reduced in cardiac tissue of daidzein treated animals. Daidzein treatment improved oxidative defense mechanism and reduced cardiac tissue necrosis and fibrosis. SIGNIFICANCE: From the results, it can be concluded that daidzein mitigates the progression of diabetic cardiomyopathy by inhibiting NOX-4 induced oxidative stress in cardiac tissue.


Assuntos
Diabetes Mellitus Experimental/patologia , Isoflavonas/farmacologia , Miocárdio/patologia , Adenilato Quinase/metabolismo , Animais , Antioxidantes/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Cardiomegalia/sangue , Cardiomegalia/complicações , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/diagnóstico por imagem , Diabetes Mellitus Experimental/fisiopatologia , Eletrocardiografia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Isoflavonas/química , Lipídeos/sangue , Masculino , Miocárdio/enzimologia , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Sirtuína 1/metabolismo , Troponina I/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
7.
Benef Microbes ; 12(3): 283-293, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34030609

RESUMO

Escherichia coli Nissle (EcN), a probiotic bacterium protects against several disorders. Multiple reports have studied the pathways involved in cardiac hypertrophy. However, the effects of probiotic EcN against diabetes-induced cardiac hypertrophy remain to be understood. We administered five weeks old Wistar male (271±19.4 g body weight) streptozotocin-induced diabetic rats with 109 cfu of EcN via oral gavage every day for 24 days followed by subjecting the rats to echocardiography to analyse the cardiac parameters. Overexpressed interleukin (IL)-6 induced the MEK5/ERK5, JAK2/STAT3, and MAPK signalling cascades in streptozotocin-induced diabetic rats. Further, the upregulation of calcineurin, NFATc3, and p-GATA4 led to the elevation of hypertrophy markers, such as atrial and B-type natriuretic peptides. In contrast, diabetic rats supplemented with probiotic EcN exhibited significant downregulated IL-6. Moreover, the MEK5/ERK5 and JAK2/STAT3 cascades involved during eccentric hypertrophy and MAPK signalling, including phosphorylated MEK, ERK, JNK, and p-38, were significantly attenuated in diabetic rats after supplementation of EcN. Western blotting and immunofluorescence revealed the significant downregulation of NFATc3 and downstream mediators, thereby resulting in the impairment of cardiac hypertrophy. Taken together, the findings demonstrate that supplementing probiotic EcN has the potential to show cardioprotective effects by inhibiting diabetes-induced cardiomyopathies.


Assuntos
Cardiomegalia/terapia , Diabetes Mellitus Experimental/terapia , Cardiomiopatias Diabéticas/terapia , Escherichia coli/fisiologia , Interleucina-6/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Probióticos/uso terapêutico , Animais , Calcineurina/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , MAP Quinase Quinase 5/metabolismo , Masculino , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Estreptozocina
8.
J Ethnopharmacol ; 274: 114078, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-33798659

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xinyang tablet (XYT) has been traditionally used in the treatment of cardiovascular diseases (CVDs). Our previous study indicated that XYT exhibited protective effects in heart failure (HF). AIM OF THE STUDY: The aim of the present study was to determine the protective effects of XYT in pressure overload induced HF and to elucidate its underlying mechanisms of action. MATERIALS AND METHODS: We analyzed XYT content using high-performance liquid chromatography (HPLC.). Mice were subjected to transverse aortic constriction (TAC) to generate pressure overload-induced cardiac remodeling and were then orally administered XYT or URMC-099 for 1 week after the operation. HL1 mouse cardiomyoblasts were induced by lipopolysaccharides (LPS) to trigger pyroptosis and were then treated with XYT or URMC-099. We used echocardiography (ECG), hematoxylin and eosin (H&E) staining, Masson's trichrome staining and a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay to evaluate the effects of XYT. Messenger ribonucleic acid (mRNA) levels of collagen metabolism biomarkers and inflammation-related factors were detected. We determined protein levels of inflammation- and pyroptosis-related signaling pathway members via Western blot (WB). Caspase-1 activity was measured in cell lysate using a Caspase-1 Activity Assay Kit. Subsequently, to define the candidate ingredients in XYT that regulate mixed-lineage kinase-3 (MLK3), we used molecular docking (MD) to predict and evaluate binding affinity with MLK3. Finally, we screened 24 active potential compounds that regulate MLK3 via MD. RESULTS: ECG, H&E staining, Masson's trichrome staining and TUNEL assay results showed that XYT remarkably improved heart function, amelorated myocardial fibrosis and inhibited apoptosis in vivo. Moreover, it reduced expression of proteins or mRNAs related to collagen metabolism, including collagen type 1 (COL1), fibronectin (FN), alpha smooth-muscle actin (α-SMA), and matrix metalloproteinases-2 and -9 (MMP-2, MMP-9). XYT also inhibited inflammation and the induction of pyroptosis at an early stage, as well as attenuated inflammation and pyroptosis levels in vitro. CONCLUSION: Our data indicated that XYT exerted protective effects against pressure overload induced myocardial fibrosis (MF), which might be associated with the induction of pyroptosis-mediated MLK3 signaling.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cardiomegalia/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , MAP Quinase Quinase Quinases/metabolismo , Piroptose/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Pressão Sanguínea , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Ecocardiografia , Fibrose , Coração/efeitos dos fármacos , Coração/fisiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Lipopolissacarídeos , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia
9.
Environ Toxicol Pharmacol ; 85: 103653, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33812011

RESUMO

Ambient air fine particulate matter (PM2.5) may increase cardiovascular disease risks. In this study, we investigated the miR-208/GATA4/myosin heavy chain (MHC) regulation mechanisms on cardiac injury in rats after PM2.5 exposure via an animal inhalation device. The results showed that PM2.5 exposure for 2 months caused pathological heart injury, reduced nucleus-cytoplasm ratio, and increased the levels of CK-MB and cTnI, showing cardiac hypertrophy. Oxidative stress and inflammatory responses were also observed in rats' hearts exposed to PM2.5. Of note, PM2.5 exposure for 2-month significantly elevated GATA4 and ß-MHC mRNA and protein expression compared with the corresponding controls, along with the high-expression of miR-208b. The ratios of ß-MHC/α-MHC expression induced by PM2.5 were remarkably raised in comparison to their controls. It suggested that the up-regulation of miR-208b/ß-MHC and GATA4 and the conversion from α-MHC to ß-MHC may be the important causes of cardiac hypertrophy in rats incurred by PM2.5.


Assuntos
Poluentes Atmosféricos/toxicidade , Cardiomegalia , Traumatismos Cardíacos , Material Particulado/toxicidade , Animais , Miosinas Cardíacas/genética , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Traumatismos Cardíacos/genética , Traumatismos Cardíacos/metabolismo , Traumatismos Cardíacos/patologia , Traumatismos Cardíacos/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , MicroRNAs , Miocárdio/patologia , Cadeias Pesadas de Miosina/genética , Ratos Sprague-Dawley
10.
Cells ; 10(4)2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916597

RESUMO

Cardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population's rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, autophagy inducer rapamycin has been described to exert cardioprotective effects, it remains to be shown whether these effects can be attributed to improved cardiomyocyte autophagy and contractility. In vivo hypertrophy was induced by transverse aortic constriction (TAC), with mice receiving daily rapamycin injections beginning six weeks after surgery for four weeks. Echocardiographic analysis demonstrated TAC-induced HF and protein analyses showed abundance of modified proteins in TAC-hearts after 10 weeks, both reduced by rapamycin. In vitro, cardiomyocyte hypertrophy was mimicked by endothelin 1 (ET-1) and autophagy manipulated by silencing Atg5 in neonatal cardiomyocytes. ET-1 and siAtg5 decreased Atg5-Atg12 and LC3-II, increased natriuretic peptides, and decreased amplitude and early phase of contraction in cardiomyocytes, the latter two evaluated using ImageJ macro Myocyter recently developed by us. ET-1 further decreased cell contractility in control but not in siAtg5 cells. In conclusion, ET-1 decreased autophagy and cardiomyocyte contractility, in line with siAtg5-treated cells and the results of TAC-mice demonstrating a crucial role for autophagy in cardiomyocyte contractility and cardiac performance.


Assuntos
Autofagia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Contração Miocárdica , Miocárdio/patologia , Miócitos Cardíacos/patologia , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/metabolismo , Cardiomegalia/complicações , Cardiomegalia/diagnóstico por imagem , Ecocardiografia , Endotelina-1/metabolismo , Inativação Gênica , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Pressão , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos
11.
Biomed Pharmacother ; 138: 111316, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33684689

RESUMO

BACKGROUND: Cardiovascular diseases are the leading cause of death globally, and they are causing enormous socio-economic burden to the developed and developing countries. Allyl Methyl Sulfide (AMS) is a novel cardioprotective metabolite identified in the serum of rats after raw garlic administration. The present study explored the cardioprotective effect of AMS on thoracic aortic constriction (TAC)-induced cardiac hypertrophy and heart failure model in rats. METHODS: Thoracic aortic constriction (TAC) by titanium ligating clips resulted in the development of pressure overload-induced cardiac hypertrophy and heart failure model. Four weeks prior to TAC and for 8 weeks after TAC, Sprague Dawley (SD) rats were administered with AMS (25 and 50 mg/kg/day) or Enalapril (10 mg/kg/day). RESULTS: We have observed AMS (25 and 50 mg/kg/day) intervention significantly improved structural and functional parameters of the heart. mRNA expression of fetal genes i.e., atrial natriuretic peptide (ANP), alpha skeletal actin (α-SA) and beta myosin heavy chain (ß-MHC) were reduced in AMS treated TAC hearts along with decrease in perivascular and interstitial fibrosis. AMS attenuated lipid peroxidation and improved protein expression of endogenous antioxidant enzymes i.e., catalase and manganese superoxide dismutase (MnSOD) along with electron transport chain (ETC) complex activity. AMS increased mitochondrial fusion proteins i.e., mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy protein (OPA1), and reduced fission protein i.e., dynamin-related protein 1 (DRP1). Preliminary study suggests that AMS intervention upregulated genes involved in mitochondrial bioenergetics in normal rats. Further, in-vitro studies suggest that AMS reduced mitochondrial reactive oxygen species (ROS), preserved mitochondrial membrane potential and oxygen consumption rate (OCR) in isoproterenol-treated cardiomyoblast. CONCLUSION: This study demonstrated that AMS protected cardiac remodelling, LV dysfunction and fibrosis in pressure overload-induced cardiac hypertrophy and heart failure model by improving endogenous antioxidants and mitochondrial function.


Assuntos
Compostos Alílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Mitocôndrias Cardíacas/efeitos dos fármacos , Sulfetos/uso terapêutico , Compostos Alílicos/farmacologia , Animais , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , Cardiotônicos/farmacologia , Linhagem Celular , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Masculino , Mitocôndrias Cardíacas/fisiologia , Ratos , Ratos Sprague-Dawley , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Sulfetos/farmacologia
12.
Theranostics ; 11(8): 3830-3838, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664864

RESUMO

Anti-angiogenics drugs in clinical use for cancer treatment induce cardiotoxic side effects. The endothelin axis is involved in hypertension and cardiac remodelling, and addition of an endothelin receptor antagonist to the anti-angiogenic sunitinib was shown to reduce cardiotoxicity of sunitinib in mice. Here, we explored further the antidote effect of the endothelin receptor antagonist macitentan in sunitinib-treated animals on cardiac remodeling. Methods: Tumor-bearing mice treated per os daily by sunitinib or vehicle were imaged before and after 1, 3 and 6 weeks of treatment by positron emission tomography using [18F]fluorodeoxyglucose and by echocardiography. Non-tumor-bearing animals were randomly assigned to be treated per os daily by vehicle or sunitinib or macitentan or sunitinib+macitentan, and imaged by echocardiography after 5 weeks. Hearts were harvested for histology and molecular analysis at the end of in vivo exploration. Results: Sunitinib treatment increases left ventricular mass and ejection fraction and induces cardiac fibrosis. Sunitinib also induces an early increase in cardiac uptake of [18F]fluorodeoxyglucose, which is significantly correlated with increased left ventricular mass at the end of treatment. Co-administration of macitentan prevents sunitinib-induced hypertension, increase in ejection fraction and cardiac fibrosis, but fails to prevent increase of the left ventricular mass. Conclusion: Early metabolic changes predict sunitinib-induced cardiac remodeling. Endothelin blockade can prevent some but not all cardiotoxic side-effects of sunitinib, in particular left ventricle hypertrophy that appears to be induced by sunitinib through an endothelin-independent mechanism.


Assuntos
Cardiomegalia/induzido quimicamente , Endotelinas/fisiologia , Sunitinibe/toxicidade , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/administração & dosagem , Feminino , Fibrose , Glicólise/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Medicina de Precisão , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologia
13.
Theranostics ; 11(10): 4710-4727, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754023

RESUMO

Background: Telomere shortening and dysfunction may cause metabolic disorders, tissue damage and age-dependent pathologies. However, little is known about the association of telomere-associated protein Rap1 with mitochondrial energy metabolism and cardiac aging. Methods: Echocardiography was performed to detect cardiac structure and function in Rap1+/+ and Rap1-/- mice at different ages (3 months, 12 months and 20 months). Telomere length, DNA damage, cardiac senescence and cardiomyocyte size were analyzed using the real-time PCR, Western blotting, senescence associated ß-galactosidase assay and wheat germ agglutinin staining, respectively. Western blotting was also used to determine the level of cardiac fatty acid metabolism related key enzymes in mouse and human myocardium. Chromatin immunoprecipitation assay was used to verify the direct link between p53 and PPARα. The p53 inhibitor, Pifithrin-α and PPARα activator WY14643 were utilized to identify the effects of Rap1/p53/PPARα signaling pathway. Results: Telomere was shortened concomitant with extensive DNA damage in aged Rap1-/- mouse hearts, evidenced by reduced T/S ratios and increased nuclear γH2AX. Meanwhile, the aging-associated phenotypes were pronounced as reflected by altered mitochondrial ultrastructure, enhanced senescence, cardiac hypertrophy and dysfunction. Mechanistically, acetylated p53 and nuclear p53 was enhanced in the Rap1-/- mouse hearts, concomitant with reduced PPARα. Importantly, p53 directly binds to the promoter of PPARα in mouse hearts and suppresses the transcription of PPARα. In addition, aged Rap1-/- mice exhibited reduced cardiac fatty acid metabolism. Pifithrin-α alleviated cardiac aging and enhanced fatty acid metabolism in the aged Rap1-/- mice. Activating PPARα with WY14643 in primarily cultured Rap1-/- cardiomyocytes restored maximal oxygen consumption rates. Reduced Rap1 expression and impaired p53/PPARα signaling also presented in aged human myocardium. Conclusion: In summary, Rap1 may link telomere biology to fatty acid metabolism and aging-related cardiac pathologies via modulating the p53/PPARα signaling pathway, which could represent a therapeutic target in preventing/attenuating cardiac aging.


Assuntos
Envelhecimento/genética , Cardiomegalia/genética , Senescência Celular/genética , Miócitos Cardíacos/metabolismo , PPAR alfa/genética , Proteínas de Ligação a Telômeros/genética , Proteína Supressora de Tumor p53/genética , Animais , Benzotiazóis/farmacologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Dano ao DNA , Ecocardiografia , Ácidos Graxos/metabolismo , Cardiopatias/diagnóstico por imagem , Cardiopatias/genética , Cardiopatias/fisiopatologia , Histonas/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Teste de Campo Aberto , PPAR alfa/metabolismo , Proliferadores de Peroxissomos/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Telômero/metabolismo , Homeostase do Telômero , Proteínas de Ligação a Telômeros/metabolismo , Tolueno/análogos & derivados , Tolueno/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo
14.
Oxid Med Cell Longev ; 2021: 8875729, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688395

RESUMO

Global consumption of high-fat diets (HFD) is associated with an increased incidence of cardiometabolic syndrome and cardiac injury, warranting identification of cardioprotective strategies. Cardioprotective effects of quercetin (Q) have mostly been evaluated in ischemic heart disease models and attributed to senolysis. We hypothesized that Q could alleviate murine cardiac damage caused by HFD by restoring the myocardial microcirculation. C57BL/6J mice were fed standard chow or HFD for 6 months and then treated with Q (50 mg/kg) or vehicle 5-day biweekly for 10 additional weeks. Left ventricular (LV) cardiac function was studied in vivo using magnetic resonance imaging, and intramyocardial fat deposition, microvascular density, oxidative stress, and senescence were analyzed ex vivo. Additionally, direct angiogenic effects of Q were studied in vitro in HUVECs. HFD increased body weight, heart weight, total cholesterol, and triglyceride levels, whereas Q normalized heart weight and triglycerides. LV ejection fraction was lower in HFD vs. control mice (56.20 ± 15.8% vs. 73.38 ± 5.04%, respectively, P < 0.05), but improved in HFD + Q mice (67.42 ± 7.50%, P < 0.05, vs. HFD). Q also prevented cardiac fat accumulation and reduced HFD-induced cardiac fibrosis, cardiomyocyte hypertrophy, oxidative stress, and vascular rarefaction. Cardiac senescence was not observed in any group. In vitro, ox-LDL reduced HUVEC tube formation activity, which Q effectively improved. Quercetin may directly induce angiogenesis and decrease myocardial oxidative stress, which might account for its cardioprotective effects in the murine HFD-fed murine heart independently from senolytic activity. Furthermore, its beneficial effects might be partly attributed to a decrease in plasma triglycerides and intramyocardial fat deposition.


Assuntos
Dieta Hiperlipídica , Comportamento Alimentar , Coração/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Quercetina/farmacologia , Sístole/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Senescência Celular/efeitos dos fármacos , Fibrose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos
15.
Clin Exp Hypertens ; 43(5): 428-435, 2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-33688765

RESUMO

Salt-inducible kinases (SIKs) represent a subfamily of AMPK family kinases. SIK1 has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. SIK2, as an isoform of the SIK family, modulates various biological functions and acts as a signal transmitter in various pathways. To evaluate the role of both SIK1 and SIK2 isoforms in blood pressure (BP), body fluid regulation and cardiac hypertrophy development, we made use of constitutive sik1-/- (SIK1-KO), sik2-/- (SIK2-KO), double sik1-/-sik2-/- (double SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) or chronic high-salt (HS, 8% NaCl) diet intake for 12 weeks.Mice, under a standard diet intake, had similar and normal BP. On a chronic HS intake, SIK1-KO and double SIK1*2-KO mice showed increased BP, but not WT and SIK2-KO mice. A chronic HS intake led to the development of cardiac left ventricle hypertrophy (LVH) in normotensive WT and hypertensive SIK1-KO mice, but not in SIK2-KO mice. Double SIK1*2-KO mice under standard diet intake show normal BP but an increased LV mass. Remarkably, in response to a dietary stress condition, there is an increase in BP but LVH remained unchanged in double SIK1*2-KO mice.In summary, SIK1 isoform is required for maintaining normal BP in response to HS intake. LVH triggered by HS intake requires SIK2 isoform and is independent of high BP.


Assuntos
Cardiomegalia/fisiopatologia , Hipertensão/fisiopatologia , /metabolismo , Animais , Glicemia/metabolismo , Pressão Sanguínea , Peso Corporal , Cardiomegalia/sangue , Hipertensão/sangue , Testes de Função Renal , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamanho do Órgão , Isoformas de Proteínas/metabolismo , Cloreto de Sódio na Dieta
16.
Virchows Arch ; 479(1): 79-94, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33740097

RESUMO

Since cardiac hypertrophy may be considered a cause of death at autopsy, its assessment requires a uniform approach. Common terminology and methodology to measure the heart weight, size, and thickness as well as a systematic use of cut off values for normality by age, gender, and body weight and height are needed. For these reasons, recommendations have been written on behalf of the Association for European Cardiovascular Pathology. The diagnostic work up implies the search for pressure and volume overload conditions, compensatory hypertrophy, storage and infiltrative disorders, and cardiomyopathies. Although some gross morphologic features can point to a specific diagnosis, systematic histologic analysis, followed by possible immunostaining and transmission electron microscopy, is essential for a final diagnosis. If the autopsy is carried out in a general or forensic pathology service without expertise in cardiovascular pathology, the entire heart (or pictures) together with mapped histologic slides should be sent for a second opinion to a pathologist with such an expertise. Indication for postmortem genetic testing should be integrated into the multidisciplinary management of sudden cardiac death.


Assuntos
Cardiomegalia/patologia , Miocárdio/patologia , Autopsia , Cardiomegalia/genética , Cardiomegalia/mortalidade , Cardiomegalia/fisiopatologia , Causas de Morte , Testes Genéticos , Humanos , Tamanho do Órgão , Valor Preditivo dos Testes , Fatores de Risco , Terminologia como Assunto
17.
J Exp Med ; 218(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33635944

RESUMO

Meteorin-like/Meteorin-ß (Metrnl/Metrnß) is a secreted protein produced by skeletal muscle and adipose tissue that exerts metabolic actions that improve glucose metabolism. The role of Metrnß in cardiac disease is completely unknown. Here, we show that Metrnß-null mice exhibit asymmetrical cardiac hypertrophy, fibrosis, and enhanced signs of cardiac dysfunction in response to isoproterenol-induced cardiac hypertrophy and aging. Conversely, adeno-associated virus-mediated specific overexpression of Metrnß in the heart prevents the development of cardiac remodeling. Furthermore, Metrnß inhibits cardiac hypertrophy development in cardiomyocytes in vitro, indicating a direct effect on cardiac cells. Antibody-mediated blockage of Metrnß in cardiomyocyte cell cultures indicated an autocrine action of Metrnß on the heart, in addition to an endocrine action. Moreover, Metrnß is highly produced in the heart, and analysis of circulating Metrnß concentrations in a large cohort of patients reveals that it is a new biomarker of heart failure with an independent prognostic value.


Assuntos
Cardiomegalia/genética , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Fatores de Crescimento Neural/genética , Animais , Animais Recém-Nascidos , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Cardiomegalia/fisiopatologia , Cardiotônicos/metabolismo , Células Cultivadas , Ecocardiografia , Regulação da Expressão Gênica , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fatores de Crescimento Neural/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo
18.
Circ Heart Fail ; 14(2): e007279, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33517669

RESUMO

BACKGROUND: Mineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored. METHODS: Male mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry. RESULTS: Deletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction. CONCLUSIONS: These results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC, thereby improving cardiac blood supply in the setting of pressure overload-induced hypertrophy, which in turn mitigates the adverse cardiac remodeling that contributes to HF progression and symptoms.


Assuntos
Insuficiência Cardíaca/genética , Miócitos de Músculo Liso/metabolismo , Receptores de Mineralocorticoides/genética , Remodelação Ventricular/genética , Animais , Aorta/cirurgia , Pressão Arterial , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Constrição Patológica , Modelos Animais de Doenças , Ecocardiografia , Técnicas de Inativação de Genes , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia
19.
J Cell Physiol ; 236(9): 6581-6596, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33615478

RESUMO

Aerobic exercise increases M2 AChR, which thus improves cardiac function in cardiovascular disease (CVD) rats. This study aimed to determine whether aerobic exercise could ameliorate pressure overload-induced heart hypertrophy through M2 AChR, and to elucidate the underlying mechanisms of action. Mice were used to establish the myocardial hypertrophy model by transverse aortic constriction (TAC), and subjected to 2, 4, and 8 weeks of moderate-intensity aerobic exercise and choline intervention (14 mg/kg/day). Our results showed that 4 and 8 weeks of exercise and choline intervention reduced excessive mitochondrial fission and autophagy of myocardial mitochondria, thereby improving the ultrastructure and function of mitochondria after TAC. Moreover, 8-week exercise and choline intervention have enhanced parasympathetic function and promoted the expression of M2 AChR. In addition, 8-week exercise and choline intervention also inhibited the protein expression of myocardial MFN2, PERK/eIF2α/ATF4, and NLRP3/caspase-1/IL-1ß signaling pathways, thereby effectively reducing mitochondrial fusion, endoplasmic reticulum stress, and inflammation. Taken together, these data suggest that pressure overload led to cardiac hypertrophy, cardiac dysfunction, and decreased parasympathetic function in cardiac tissues. Aerobic exercise attenuated cardiac dysfunction by modulating the expression of proteins involved in mitochondrial quality control, and induced endoplasmic reticulum stress and inflammation, thereby reducing cardiac hypertrophy and improving cardiac function in impaired heart tissues following TAC, which was likely mediated by M2 AChR activation.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/patologia , Estresse do Retículo Endoplasmático , Mitocôndrias Cardíacas/metabolismo , Condicionamento Físico Animal , Animais , Fator Natriurético Atrial/metabolismo , Autofagia , Cardiomegalia/fisiopatologia , Constrição Patológica , Diástole , Fibrose , Testes de Função Cardíaca , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/ultraestrutura , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Cadeias Pesadas de Miosina/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Ratos , Receptor Muscarínico M2 , Transdução de Sinais , Sístole
20.
J Mol Cell Cardiol ; 154: 115-123, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33582159

RESUMO

The role of DNA methylation in cardiomyocyte physiology and cardiac disease remains a matter of controversy. We have recently provided evidence for an important role of DNMT3A in human cardiomyocyte cell homeostasis and metabolism, using engineered heart tissue (EHT) generated from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes carrying a knockout of the de novo DNA methyltransferase DNMT3A. Unlike isogenic control EHT, knockout EHT displayed morphological abnormalities such as lipid accumulations inside cardiomyocytes associated with impaired mitochondrial metabolism, as well as functional defects and impaired glucose metabolism. Here, we analyzed the role of DNMT3A in the setting of cardiac hypertrophy. We induced hypertrophic signaling by treatment with 50 nM endothelin-1 and 20 µM phenylephrine for one week and assessed EHT contractility, morphology, DNA methylation, and gene expression. While both knockout EHTs and isogenic controls showed the expected activation of the hypertrophic gene program, knockout EHTs were protected from hypertrophy-related functional impairment. Conversely, hypertrophic treatment prevented the metabolic consequences of a loss of DNMT3A, i.e. abolished lipid accumulation in cardiomyocytes likely by partial normalization of mitochondrial metabolism and restored glucose metabolism and metabolism-related gene expression of knockout EHT. Together, these data suggest an important role of DNA methylation not only for cardiomyocyte physiology, but also in the setting of cardiac disease.


Assuntos
Cardiomegalia/etiologia , Cardiomegalia/metabolismo , DNA (Citosina-5-)-Metiltransferases/deficiência , Metabolismo Energético , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Biomarcadores , Cardiomegalia/fisiopatologia , Metilação de DNA , Epigênese Genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica/genética
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