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1.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540546

RESUMO

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin-angiotensin-aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/patologia , Sistema Renina-Angiotensina , Animais , Fibroblastos/patologia , Fibrose , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
2.
Hypertension ; 74(4): 843-853, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476902

RESUMO

Preterm birth is associated with proinflammatory conditions and alterations in adult cardiac shape and function. Neonatal exposure to high oxygen, a rat model of prematurity-related conditions, leads to cardiac remodeling, fibrosis, and dysfunction. TLR (Toll-like receptor) 4 signaling is a critical link between oxidative stress, inflammation, and the pathogenesis of cardiovascular diseases. The current study sought to investigate the role of TLR4 signaling in neonatal oxygen-induced cardiomyopathy. Male Sprague-Dawley pups were kept in 80% oxygen or room air from day 3 to 10 of life and treated with TLR4 antagonist lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides(LPS-RS) or saline. Echocardiography was performed at 4, 7, and 12 weeks. At 12 weeks, intraarterial blood pressure was measured before euthanization for histological and biochemical analyses. At day 10, cardiac TLR4, Il (interleukin) 18, and Il1ß expression were increased in oxygen-exposed compared with room air controls. At 4 weeks, compared with room air-saline, saline-, but not LPS-RS treated-, oxygen-exposed animals, exhibited increased left ventricle mass index, reduced ejection fraction, and cardiac output index. Findings were similar at 7 and 12 weeks. LPS-RS did not influence echocardiography in 12 weeks room air animals. Systolic blood pressure was higher in saline- but not LPS-RS treated-oxygen-exposed animals compared with room air-saline and -LPS-RS controls. LPS-RS prevented cardiac fibrosis and cardiomyocytes hypertrophy, the increased TLR4, Myd88, and Il18 gene expression, TRIF expression, and CD68+ macrophages infiltration associated with neonatal oxygen exposure, without impact in room air rats. This study indicates that neonatal exposure to high oxygen programs TLR4 activation, which contributes to cardiac remodeling and dysfunction.


Assuntos
Hiperóxia/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Lipopolissacarídeos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Animais Recém-Nascidos , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperóxia/complicações , Hiperóxia/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle
3.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434333

RESUMO

Left ventricular hypertrophy (LVH) can be adaptive, as arising from exercise, or pathological, most commonly when driven by hypertension. The pathophysiology of LVH is consistently associated with an increase in cytochrome P450 (CYP)1B1 and mitogen-activated protein kinases (MAPKs) and a decrease in sirtuins and mitochondria functioning. Treatment is usually targeted to hypertension management, although it is widely accepted that treatment outcomes could be improved with cardiomyocyte hypertrophy targeted interventions. The current article reviews the wide, but disparate, bodies of data pertaining to LVH pathoetiology and pathophysiology, proposing a significant role for variations in the N-acetylserotonin (NAS)/melatonin ratio within mitochondria in driving the biological underpinnings of LVH. Heightened levels of mitochondria CYP1B1 drive the 'backward' conversion of melatonin to NAS, resulting in a loss of the co-operative interactions of melatonin and sirtuin-3 within mitochondria. NAS activates the brain-derived neurotrophic factor receptor, TrkB, leading to raised trophic signalling via cyclic adenosine 3',5'-monophosphate (cAMP)-response element binding protein (CREB) and the MAPKs, which are significantly increased in LVH. The gut microbiome may be intimately linked to how stress and depression associate with LVH and hypertension, with gut microbiome derived butyrate, and other histone deacetylase inhibitors, significant modulators of the melatonergic pathways and LVH more generally. This provides a model of LVH that has significant treatment and research implications.


Assuntos
Citocromo P-450 CYP1B1/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Animais , Citocromo P-450 CYP1B1/genética , Microbioma Gastrointestinal/fisiologia , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Melatonina/metabolismo , Mitocôndrias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Sirtuínas/metabolismo
4.
Hum Exp Toxicol ; 38(10): 1183-1194, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256679

RESUMO

Heart failure (HF) is a leading cause of hospitalization across the world and is known to cause ill-health and heavy economic losses. In the present study, a rat model of isoproterenol (ISO, 85 mg/kg subcutaneously for two subsequent days) induced HF was developed. ISO induces HF by its direct effect, that is, rise in left ventricular end-diastolic pressure (mechanical) and indirectly by altering the baroreflex (neural), electrocardiography (electrical), and development of oxidative stress and hyperlipidemia (chemical). Fenofibrate, a hypolipidemic drug, which ameliorates myocardial energy metabolism was seen to improve the both ISO-induced oxidative stress and lipid profile and consequently improved Baroreflex Sensitivity (BRS), partial ventricular functions, and cardiac hypertrophy. Therefore, our result suggests that fenofibrate treatment protected the heart by alleviating the ISO-induced effects, that is, neural, mechanical, electrical, and chemical alterations.


Assuntos
Barorreflexo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fenofibrato/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipolipemiantes/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Eletrocardiografia/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , NADPH Oxidases/genética , Ratos Wistar
5.
Cell Mol Life Sci ; 76(23): 4705-4724, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31350618

RESUMO

Following the serendipitous discovery of the ageing suppressor, αKlotho (αKl), several decades ago, a growing body of evidence has defined a pivotal role for its various forms in multiple aspects of vertebrate physiology and pathology. The transmembrane form of αKl serves as a co-receptor for the osteocyte-derived mineral regulator, fibroblast growth factor (FGF)23, principally in the renal tubules. However, compelling data also suggest that circulating soluble forms of αKl, derived from the same source, may have independent homeostatic functions either as a hormone, glycan-cleaving enzyme or lectin. Chronic kidney disease (CKD) is of particular interest as disruption of the FGF23-αKl axis is an early and common feature of disease manifesting in markedly deficient αKl expression, but FGF23 excess. Here we critically discuss recent findings in αKl biology that conflict with the view that soluble αKl has substantive functions independent of FGF23 signalling. Although the issue of whether soluble αKl can act without FGF23 has yet to be resolved, we explore the potential significance of these contrary findings in the context of CKD and highlight how this endocrine pathway represents a promising target for novel anti-ageing therapeutics.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Nefropatias/patologia , Animais , Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/genética , Glucuronidase/química , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Nefropatias/metabolismo , Domínios Proteicos , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais
6.
Am J Physiol Regul Integr Comp Physiol ; 316(6): R776-R782, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042418

RESUMO

Exercise promotes physiological cardiac hypertrophy and activates the renin-angiotensin system (RAS), which plays an important role in cardiac physiology, both through the classical axis [angiotensin II type 1 receptor (AT1R) activated by angiotensin II (ANG II)] and the alternative axis [proto-oncogene Mas receptor (MASR) activated by angiotensin-(1-7)]. However, very intense exercise could have deleterious effects on the cardiovascular system. We aimed to analyze the cardiac hypertrophy phenotype and the classical and alternative RAS axes in the myocardium of mice submitted to swimming exercises of varying volume and intensity for the development of cardiac hypertrophy. Male Balb/c mice were divided into three groups, sedentary, swimming twice a day without overload (T2), and swimming three times a day with a 2% body weight overload (T3), totaling 6 wk of training. Both training groups developed similar cardiac hypertrophy, but only T3 mice improved their oxidative capacity. We observed that T2 had increased levels of MASR, which was followed by the activation of its main downstream protein AKT; meanwhile, AT1R and its main downstream protein ERK remained unchanged. Furthermore, no change was observed regarding the levels of angiotensin peptides, in either group. In addition, we observed no change in the ratio of expression of the myosin heavy chain ß-isoform to that of the α-isoform. Fibrosis was not observed in any of the groups. In conclusion, our results suggest that increasing exercise volume and intensity did not induce a pathological hypertrophy phenotype, but instead improved the oxidative capacity, and this process might have the participation of the RAS alternative axis.


Assuntos
Cardiomegalia/metabolismo , Miocárdio/metabolismo , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Cardiomegalia/fisiopatologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Fragmentos de Peptídeos/metabolismo , Condicionamento Físico Animal , Receptor Tipo 1 de Angiotensina/metabolismo , Natação , Remodelação Ventricular/fisiologia
7.
PLoS One ; 14(5): e0216359, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31067252

RESUMO

BACKGROUND: Left ventricular hypertrophy (LVH) has been associated with oxidative stress, although not with the protein thiolation index (PTI). This study explored the potential use of PTI as a biomarker of oxidative stress in patients with LVH. METHODS: We recruited 70 consecutive patients (n = 35 LVH and n = 35 non-LVH) based on an echocardiography study in our institution (left ventricular mass indexed to body surface area). Plasma levels of both S-thiolated protein and total thiols were measured as biomarkers of oxidative stress by spectrophotometry, and PTI was calculated as the molar ratio between S-thiolated proteins and the total thiol concentration. RESULTS: Values for plasma S-thiolated proteins were higher in patients with LVH than in the control group (P = 0.01). There were no differences in total thiols between the LVH group and the control group. Finally, PTI was higher in patients with LVH than in the control group (P = 0.001). The area under the ROC curve was 0.75 (95% CI, 0.63-0.86; P<0.001), sensitivity was 70.6%, and specificity was 68.6%, thus suggesting that PTI could be used to screen for LVH. A multivariable logistic regression model showed a positive association (P = 0.02) between PTI and LVH (OR = 1.24 [95% CI, 1.03-1.49]) independently of gender (OR = 3.39 [95% CI, 0.60-18.91]), age (OR = 1.03 [95% CI, 0.96-1.10]), smoking (OR = 5.15 [95% CI, 0.51-51.44]), glucose (OR = 0.99 [95% CI, 0.97-1.01]), systolic arterial pressure (OR = 1.10 [CI 1.03-1.17]), diastolic arterial pressure (OR = 0.94 [CI 0.87-1.02]), dyslipidemia (OR = 1.46 [95% CI, 0.25-8.55]), estimated glomerular filtration rate (OR = 0.98 [95% CI, 0.96-1.01]), body mass index (OR = 1.03 [95% CI, 0.90-1.10]), and valvular and/or coronary disease (OR = 5.27 [95% CI, 1.02-27.21]). CONCLUSIONS: The present study suggests that PTI could be a new biomarker of oxidative stress in patients with LVH.


Assuntos
Proteínas Sanguíneas/metabolismo , Hipertrofia Ventricular Esquerda/diagnóstico , Compostos de Sulfidrila/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo
8.
Ther Adv Cardiovasc Dis ; 13: 1753944719841795, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31088231

RESUMO

BACKGROUND: Pressure-overload left-ventricular hypertrophy (LVH) is an increasingly prevalent pathological condition of the myocardial muscle and an independent risk factor for a variety of cardiac diseases. We investigated changes in expression levels of proangiogeneic genes in a small animal model of LVH. METHODS: Myocardial hypertrophy was induced by transaortic constriction (TAC) in C57BL/6 mice and compared with sham-operated controls. The myocardial expression levels of vascular endothelial growth factor (VEGF), its receptors (KDR and FLT-1), stromal-cell-derived factor 1 (SDF1) and the transcription factors hypoxia-inducible factor-1 and 2 (HIF1 and HIF2) were analyzed by quantitative polymerase chain reaction over the course of 25 weeks. Histological sections were stained for caveolin-1 to visualize endothelial cells and determine the capillary density. The left-ventricular morphology and function were assessed weekly by electrocardiogram-gated magnetic resonance imaging. RESULTS: The heart weight of TAC animals increased significantly from week 4 to 25 ( p = 0.005) compared with sham-treated animals. At 1 day after TAC, the expression of VEGF and SDF1 also increased, but was downregulated again after 1 week. The expression of HIF2 was significantly downregulated after 1 week and remained at a lower level in the subsequent weeks. The expression level of FLT-1 was also significantly decreased 1 week after TAC. HIF-1 and KDR showed similar changes compared with sham-operated animals. However, the expression levels of HIF1 after 4 and 8 weeks were significantly decreased compared with day 1. KDR changes were significantly decreased after 1, 2, 4, 8 and 25 weeks compared with week 3. After 4 weeks post-TAC, the size of the capillary vessels increased ( p = 0.005) while the capillary density itself decreased (TAC: 2143 ± 293 /mm2 versus sham: 2531 ± 321 /mm2; p = 0.021). Starting from week 4, the left-ventricular ejection fraction decreased compared with controls ( p = 0.049). CONCLUSIONS: The decrease in capillary density in the hypertrophic myocardium appears to be linked to the dysregulation in the expression of proangiogeneic factors. The results suggest that overcoming this dysregulation may lead to reconstitution of capillary density in the hypertrophic heart, and thus be beneficial for cardiac function and survival.


Assuntos
Proteínas Angiogênicas/metabolismo , Capilares/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Neovascularização Fisiológica , Proteínas Angiogênicas/genética , Animais , Capilares/patologia , Capilares/fisiopatologia , Técnicas de Imagem de Sincronização Cardíaca , Modelos Animais de Doenças , Eletrocardiografia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Imagem por Ressonância Magnética , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Transdução de Sinais , Fatores de Tempo , Função Ventricular Esquerda , Remodelação Ventricular
9.
Circ Arrhythm Electrophysiol ; 12(5): e007224, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31023060

RESUMO

BACKGROUND: The interaction between regional left ventricular (LV) myocardial work and metabolism in remodeled hearts has not yet been well established. Our aim was to investigate the effect of inhomogeneous LV work distribution on regional metabolism and remodeling in our animal model with reversible dyssynchrony due to pacing. METHODS: In 12 sheep, 8 weeks of right atrial and right ventricular free wall (DDD) pacing lead to LV dilatation, a thinned septum, and thickened lateral wall. Left bundle branch block-like dyssynchrony caused by DDD pacing could be acutely reverted by right atrial pacing (AAI) only. Invasive hemodynamics and echocardiography were used to assess regional work by stress-strain loop area and compared with regional glucose metabolism measured by 18F-fluorodeoxyglucose positron emission tomography with and without improved spatial resolution by motion and anatomy correction on gated reconstructions. RESULTS: Glucose metabolism by positron emission tomography with anatomic correction on gated positron emission tomography reconstruction showed a different regional distribution than with clinical reconstructions and correlated best and significantly with regional myocardial work. At baseline, work was homogeneously distributed with normal conduction (AAI pacing), whereas during dyssynchrony (DDD pacing), the lateral wall was more loaded, and the septum was unloaded. After 8 weeks of remodeling under DDD pacing, however, an almost homogeneous work distribution was found with DDD pacing, whereas with AAI pacing, the thin septum showed exaggerated loading and the lateral walls a low load. Our experimental observations were confirmed in 5 patient responders to cardiac resynchronization therapy. CONCLUSIONS: Regional LV glucose metabolism closely correlates with regional work. Our data indicate that regionally different LV remodeling after exposure to inhomogeneous loading conditions, such as during LV dyssynchrony, is an adaptive process that helps to equilibrate work distribution. Correction of the inhomogeneous loading conditions, such as during cardiac resynchronization therapy, then triggers a reverse LV remodeling through the same mechanism.


Assuntos
Metabolismo Energético , Hipertrofia Ventricular Esquerda/fisiopatologia , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Remodelação Ventricular , Adaptação Fisiológica , Animais , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Feminino , Fluordesoxiglucose F18/administração & dosagem , Glucose/metabolismo , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Carneiro Doméstico , Fatores de Tempo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo
10.
Basic Res Cardiol ; 114(3): 21, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30915659

RESUMO

Inhibition of the Ca2+-dependent proteases calpains attenuates post-infarction remodeling and heart failure. Recent data suggest that calpain activity is elevated in non-ischemic cardiomyopathies and that upregulation of the key cardiac G-protein-coupled receptor kinase 2 (GRK2) signaling hub promotes cardiac hypertrophy. However, the functional interactions between calpains and GRK2 in this context have not been explored. We hypothesized that calpain modulates GRK2 levels in myocardial hypertrophy of non-ischemic cause, and analyzed the mechanisms involved and the potential therapeutic benefit of inhibiting calpain activity in this situation. The oral calpain inhibitor SNJ-1945 was administered daily to male Sprague-Dawley rats or wild-type and hemizygous GRK2 mice treated with 5 mg/Kg/day isoproterenol intraperitoneally for 1 week. In isoproterenol-treated animals, calpains 1 and 2 were overexpressed in myocardium and correlated with increased calpain activity and ventricular hypertrophy. Oral co-administration of SNJ-1945 attenuated calpain activation and reduced heart hypertrophy as assessed using morphological and biochemical markers. Calpain activation induced by isoproterenol increased GRK2 protein levels, while genetic downregulation of GRK2 expression prevented isoproterenol-mediated hypertrophy independently of calpain inhibition. GRK2 upregulation was associated to calpain-dependent degradation of the GRK2 ubiquitin ligase MDM2 and to enhanced NF-κB-dependent GRK2 gene expression in correlation with calpain-mediated IĸB proteolysis. These results demonstrate that calpain mediates isoproterenol-induced myocardial hypertrophy by modulating GRK2 protein content through mechanisms involving the control of GRK2 stability and expression. Sustained calpain inhibition attenuates isoproterenol-induced myocardial hypertrophy and could be an effective therapeutic strategy to limit ventricular remodeling of non-ischemic origin.


Assuntos
Calpaína/metabolismo , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Carbamatos , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/induzido quimicamente , Isoproterenol , Masculino , Ratos Sprague-Dawley , Regulação para Cima
11.
Biol Sex Differ ; 10(1): 8, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728084

RESUMO

BACKGROUND: Maladaptive remodeling in pressure overload (PO)-induced left ventricular hypertrophy (LVH) may lead to heart failure. Major sex differences have been reported in this process. The steroid hormone 17ß-estradiol, along with its receptors ERα and ERß, is thought to be crucial for sex differences and is expected to be protective, but this may not hold true for males. Increasing evidence demonstrates a major role for microRNAs (miRNAs) in PO-induced LVH. However, little is known about the effects of biological sex and ERß on cardiac miRNA regulation and downstream mitochondrial targets. We aimed at the analysis of proteins involved in mitochondrial metabolism testing the hypothesis that they are the target of sex-specific miRNA regulation. METHODS: We employed the transverse aortic constriction model in mice and assessed the levels of five mitochondrial proteins, i.e., Auh, Crat, Decr1, Hadha, and Ndufs4. RESULTS: We found a significant decrease of the mitochondrial proteins primarily in the male overloaded heart compared with the corresponding control group. Following computational analysis to identify miRNAs putatively targeting these proteins, our in vitro experiments employing miRNA mimics demonstrated the presence of functional target sites for miRNAs in the 3'-untranslated region of the messenger RNAs coding for these proteins. Next, we assessed the levels of the functionally validated miRNAs under PO and found that their expression was induced only in the male overloaded heart. In contrast, there was no significant effect on miRNA expression in male mice with deficient ERß. CONCLUSION: We put forward that the male-specific induction of miRNAs and corresponding downregulation of downstream protein targets involved in mitochondrial metabolism may contribute to sex-specific remodeling in PO-induced LVH.


Assuntos
Pressão Sanguínea , MicroRNAs/metabolismo , Proteínas Mitocondriais/genética , Miocárdio/metabolismo , Caracteres Sexuais , Animais , Linhagem Celular , Receptor beta de Estrogênio/genética , Feminino , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
12.
Cardiovasc Diabetol ; 18(1): 13, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696455

RESUMO

BACKGROUND: The diabetic heart undergoes remodelling contributing to an increased incidence of heart failure in individuals with diabetes at a later stage. The molecular regulators that drive this process in the diabetic heart are still unknown. METHODS: Real-time (RT) PCR analysis was performed to determine the expression of cardiac specific microRNA-208a in right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic patients undergoing coronary artery bypass graft surgery. To determine the time-dependent changes, cardiac tissue were collected from type 2 diabetic mice at different age groups. A western blotting analysis was conducted to determine the expression of contractile proteins α- and ß-myosin heavy chain (MHC) and thyroid hormone receptor-α (TR-α), the negative regulator of ß-MHC. To determine the beneficial effects of therapeutic modulation of miR-208a, high glucose treated adult mouse HL-1 cardiomyocytes were transfected with anti-miR-208a. RESULTS: RT-PCR analysis showed marked upregulation of miR-208a from early stages of diabetes in type 2 diabetic mouse heart, which was associated with a marked increase in the expression of pro-hypertrophic ß-MHC and downregulation of TR-α. Interestingly, upregulation of miR-208a preceded the switch of α-/ß-MHC isoforms and the development of diastolic and systolic dysfunction. We also observed significant upregulation of miR-208a and modulation of miR-208a associated proteins in the type 2 human diabetic heart. Therapeutic inhibition of miR-208a activity in high glucose treated HL-1 cardiomyocytes prevented the activation of ß-MHC and hence the hypertrophic response. CONCLUSION: Our results provide the first evidence that early modulation of miR-208a in the diabetic heart induces alterations in the downstream signaling pathway leading to cardiac remodelling and that therapeutic inhibition of miR-208a may be beneficial in preventing diabetes-induced adverse remodelling of the heart.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , MicroRNAs/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Transdução de Sinais , Fatores de Tempo , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismo
13.
Cardiovasc Toxicol ; 19(1): 72-81, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30128816

RESUMO

Heart failure-associated morbidity and mortality is largely attributable to extensive and unregulated cardiac remodelling. Roselle (Hibiscus sabdariffa) calyces are enriched with natural polyphenols known for antioxidant and anti-hypertensive effects, yet its effects on early cardiac remodelling in post myocardial infarction (MI) setting are still unclear. Thus, the aim of this study was to investigate the actions of roselle extract on cardiac remodelling in rat model of MI. Male Wistar rats (200-300 g) were randomly allotted into three groups: Control, MI, and MI + Roselle. MI was induced with isoprenaline (ISO) (85 mg/kg, s.c) for two consecutive days followed by roselle treatment (100 mg/kg, orally) for 7 days. Isoprenaline administration showed changes in heart weight to body weight (HW/BW) ratio. MI was especially evident by the elevated cardiac injury marker, troponin-T, and histological observation. Upregulation of plasma levels and cardiac gene expression levels of inflammatory cytokines such as interleukin (IL)-6 and IL-10 was seen in MI rats. A relatively high percentage of fibrosis was observed in rat heart tissues with over-expression of collagen (Col)-1 and Col-3 genes following isoprenaline-induced MI. On top of that, cardiomyocyte areas were larger in heart tissues of MI rats with upregulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression, indicating cardiac hypertrophy. Interestingly, roselle supplementation attenuated elevation of plasma troponin-T, IL-6, IL10, and gene expression level of IL-10. Furthermore, reduction of cardiac fibrosis and hypertrophy were observed. In conclusion, roselle treatment was able to limit early cardiac remodelling in MI rat model by alleviating inflammation, fibrosis, and hypertrophy; hence, the potential application of roselle in early adjunctive treatment to prevent heart failure.


Assuntos
Fármacos Cardiovasculares/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Hibiscus , Hipertrofia Ventricular Esquerda/prevenção & controle , Infarto do Miocárdio/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Fármacos Cardiovasculares/isolamento & purificação , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Modelos Animais de Doenças , Fibrose , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hibiscus/química , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Mediadores da Inflamação/sangue , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Isoproterenol , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Ratos Wistar , Troponina T/sangue
14.
Int J Cardiovasc Imaging ; 35(3): 469-479, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30328027

RESUMO

Hemodialysis patients have conditions that increase cardiac output (CO), including arteriovenous fistula, fluid retention, vasodilator use, and anemia. We sought to determine the relationships between these factors and CO and to evaluate the effects of the high-output states on ventricular morphology, function, and myocardial energetics in hemodialysis patients, using noninvasive load-insensitive indices. Cardiovascular function was assessed in hemodialysis patients with high output [ejection fraction ≥ 50%, cardiac index (CI) > 3.5 L/min/m2, n = 30], those with normal output (CI < 3.0 L/min/m2, n = 161), and control subjects without hemodialysis (n = 155). As compared to control subjects and hemodialysis patients with normal CI, patients with elevated CI were anemic and displayed decreased systemic vascular resistance index (SVRI), excessive left ventricular (LV) contractility, larger LV volume, and tachycardia. Lower hemoglobin levels were correlated with decreased SVRI, excessive LV contractility, and higher heart rate, while estimated plasma volume and interdialytic weight gain were associated with larger LV volume, thus increasing CO. High output patients displayed markedly increased pressure-volume area (PVA) and PVA/stroke volume ratio, which were correlated directly with CO. The use of combination vasodilator therapy (angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker and calcium channel blocker) was not associated with high-output states. In conclusion, anemia and fluid retention are correlated with increased CO in hemodialysis patients. The high-output state is also associated with excessive myocardial work and energy cost.


Assuntos
Débito Cardíaco Elevado/fisiopatologia , Débito Cardíaco , Metabolismo Energético , Nefropatias/terapia , Contração Miocárdica , Miocárdio/metabolismo , Diálise Renal , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Idoso , Anemia/etiologia , Anemia/fisiopatologia , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Débito Cardíaco Elevado/diagnóstico por imagem , Débito Cardíaco Elevado/etiologia , Débito Cardíaco Elevado/metabolismo , Estudos Transversais , Ecocardiografia , Feminino , Deslocamentos de Líquidos Corporais , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Japão , Nefropatias/complicações , Nefropatias/diagnóstico por imagem , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Vasodilatadores/uso terapêutico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Equilíbrio Hidroeletrolítico , Desequilíbrio Hidroeletrolítico/etiologia , Desequilíbrio Hidroeletrolítico/fisiopatologia
15.
ESC Heart Fail ; 6(1): 154-163, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30378291

RESUMO

AIMS: In hypertrophy and heart failure, the proarrhythmic persistent Na+ current (INaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel NaV 1.8 in human hypertrophied myocardium. METHODS AND RESULTS: Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of NaV 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, NaV 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent INaL was significantly reduced after addition of novel NaV 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 µM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of NaV 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca2+ leak and SR-Ca2+ spark frequency after exposure to both NaV 1.8 inhibitors. CONCLUSIONS: We show for the first time that the neuronal sodium channel NaV 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of NaV 1.8 reduced augmented INaL , abbreviated the action potential duration, and decreased the SR-Ca2+ leak. The findings of our study suggest that NaV 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.


Assuntos
Regulação da Expressão Gênica , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/genética , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/genética , RNA/genética , Potenciais de Ação , Idoso , Western Blotting , Diástole , Feminino , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Miócitos Cardíacos/patologia , Canal de Sódio Disparado por Voltagem NAV1.8/biossíntese , Técnicas de Patch-Clamp , Reação em Cadeia da Polimerase em Tempo Real , Retículo Sarcoplasmático/metabolismo
16.
J Biol Chem ; 294(7): 2543-2554, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30523159

RESUMO

Myocyte enhancer factor 2 (MEF2) transcription factors are key regulators of the development and adult phenotype of diverse tissues, including skeletal and cardiac muscles. Controlled by multiple post-translational modifications, MEF2D is an effector for the Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN, PP2B, and PPP3). CaN-catalyzed dephosphorylation promotes the desumoylation and acetylation of MEF2D, increasing its transcriptional activity. Both MEF2D and CaN bind the scaffold protein muscle A-kinase-anchoring protein ß (mAKAPß), which is localized to the nuclear envelope, such that C2C12 skeletal myoblast differentiation and neonatal rat ventricular myocyte hypertrophy are inhibited by mAKAPß signalosome targeting. Using immunoprecipitation and DNA-binding assays, we now show that the formation of mAKAPß signalosomes is required for MEF2D dephosphorylation, desumoylation, and acetylation in C2C12 cells. Reduced MEF2D phosphorylation was coupled to a switch from type IIa histone deacetylase to p300 histone acetylase binding that correlated with increased MEF2D-dependent gene expression and ventricular myocyte hypertrophy. Together, these results highlight the importance of mAKAPß signalosomes for regulating MEF2D activity in striated muscle, affirming mAKAPß as a nodal regulator in the myocyte intracellular signaling network.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Calcineurina/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Proteínas de Ancoragem à Quinase A/genética , Animais , Calcineurina/genética , Linhagem Celular , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patologia , Miócitos Cardíacos/patologia , Fosforilação , Ratos
17.
J Clin Invest ; 129(2): 531-545, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30422822

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.


Assuntos
Células Endoteliais/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Lamina Tipo A/biossíntese , Mecanotransdução Celular , Miocárdio/metabolismo , Elementos de Resposta , Transativadores/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/patologia , Fibrose , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Lamina Tipo A/genética , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Óxido Nítrico/biossíntese , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo III/biossíntese , Óxido Nítrico Sintase Tipo III/genética , Transativadores/genética
18.
Cardiovasc Res ; 115(1): 71-82, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931050

RESUMO

Aims: Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results: Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions: Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Insuficiência Cardíaca/terapia , Hipertrofia Ventricular Esquerda/terapia , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/metabolismo , Terapêutica com RNAi , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Calcineurina/metabolismo , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/metabolismo , Neovascularização Fisiológica , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Transdução de Sinais , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
19.
Cardiovasc Diabetol ; 17(1): 160, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591063

RESUMO

BACKGROUND: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. METHODS: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-ß1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. RESULTS: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway. CONCLUSIONS: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Piperidinas/farmacologia , Uracila/análogos & derivados , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Diástole/efeitos dos fármacos , Fibrose , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Fator 1 Nuclear Respiratório/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Uracila/farmacologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
20.
J Mol Cell Cardiol ; 124: 1-11, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30267750

RESUMO

Cardiac tyhrotropin-releasing hormone (TRH) is overexpressed in the hypertrophied left ventricle (LV) of spontaneously hypertensive rats (SHR) and its inhibition prevents both hypertrophy and fibrosis. In a normal heart, the TRH increase induces fibrosis and hypertrophy opening the question of whether TRH could be a common mediator of left ventricular hypertrophy (LVH). We used angiotensin II (AngII) as an inductor of LVH to evaluate if the blockade of LV-TRH prevents hypertrophy and fibrosis in mice. We challenged C57BL/6 adult male mice with an infusion of AngII (osmotic pumps; 2 mg/kg.day) to induce LVH. Groups of mice were injected with an intracardiac siRNA-TRH or scrambled siRNA (siRNA-Con). Body weight, water intake and systolic arterial blood pressure (SABP) were measured daily. AngII significantly increased water intake and SABP (p < .05). Cardiac hypertrophy (heart weight/body weight) was evident in the group with the normal cardiac TRH system. In fact, it was found an AngII-induced increase of TRH precursor mRNA (p < .05) in conjunction with elevated TRH levels measured by immunohistochemistry and western blot. These changes were not observed in the AngII + siRNA-TRH group. Furthermore, AngII increased significantly (p < .05) BNP (hypertrophic marker), collagens I and III and TGF-ß (fibrosis markers) expression in the group with the native cardiac TRH system. These increases were attenuated in the groups with the TRH system blocked despite the high blood pressure. Similar and stronger results were observed "in vitro" with NIH3T3 and H9C2 cell culture models, where, when the TRH system is blocked, AngII stimulus was not able to induce the markers of its fibrotic and hypertrophic effects, so we believe that these effects are independent of any other physiological modifications. Our results point out that cardiac TRH is required for AngII-induced hypertrophic and fibrotic effects.


Assuntos
Angiotensina II/metabolismo , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Miocárdio/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , Angiotensina II/administração & dosagem , Animais , Pressão Sanguínea , Peso Corporal/efeitos dos fármacos , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ingestão de Líquidos/efeitos dos fármacos , Fibrose , Perfilação da Expressão Gênica , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Imuno-Histoquímica , Camundongos , Miocárdio/patologia , Células NIH 3T3 , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos
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