Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24.271
Filtrar
1.
Cell Mol Biol (Noisy-le-grand) ; 70(8): 116-120, 2024 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-39262254

RESUMO

Pathological cardiac hypertrophy (CH) may lead to heart failure and sudden death. MicroRNAs (miRNAs) have been documented to play crucial parts in CH. The objective of this research was to discuss the potential along with molecule mechanism of miR-495-3p in CH. In vivo CH model was induced by aortic banding (AB) in rats. Cellular hypertrophy in H9c2 rat cardiomyocytes was stimulated by angiotensin II (Ang II) treatment. Haematoxylin and eosin (HE), echocardiography and immunofluorescence staining were used to examine the alterations in cardiac function. The outcomes showed that miR-495-3p expression was high in rat model as well as in Ang II-stimulated cardiomyocytes. Besides, silenced miR-495-3p attenuated CH both in vitro and in vivo. Mechanically, miR-495-3p bound to pumilio RNA binding family member 2 (Pum2) 3'UTR and silenced its expression. Rescue assays further notarized that Pum2 silence abrogated the inhibitory impacts of miR-495-3p inhibitor on CH. In a word, the present research uncovered that miR-495-3p promoted CH by targeting Pum2. Therefore, miR-495-3p may be a novel therapeutic molecule for this disease.


Assuntos
Angiotensina II , Cardiomegalia , MicroRNAs , Miócitos Cardíacos , Proteínas de Ligação a RNA , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/metabolismo , Ratos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Angiotensina II/farmacologia , Masculino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Ratos Sprague-Dawley , Linhagem Celular , Regiões 3' não Traduzidas/genética , Modelos Animais de Doenças , Sequência de Bases
2.
Int J Mol Sci ; 25(17)2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39273556

RESUMO

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KOb/c) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KOb/c mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure-volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KOb/c mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca2+ transients in paced KOb/c cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KOb/c mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues.


Assuntos
Camundongos Knockout , Simportadores de Sódio-Bicarbonato , Disfunção Ventricular Esquerda , Animais , Camundongos , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/metabolismo , Simportadores de Sódio-Bicarbonato/genética , Simportadores de Sódio-Bicarbonato/metabolismo , Miócitos Cardíacos/metabolismo , Masculino , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Cardiomegalia/patologia
3.
Cell Commun Signal ; 22(1): 438, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39261825

RESUMO

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.


Assuntos
Cardiomegalia , MAP Quinase Quinase Quinases , Proteínas de Membrana , Miócitos Cardíacos , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Masculino , Progressão da Doença , Humanos , Fenilefrina/farmacologia , Sistema de Sinalização das MAP Quinases , Estresse Oxidativo
4.
Drug Des Devel Ther ; 18: 3841-3851, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39219698

RESUMO

Introduction: Apigenin is a natural flavonoid compound with promising potential for the attenuation of myocardial hypertrophy (MH). The compound can also modulate the expression of miR-185-5p that both promote MH and suppress autophagy. The current attempts to explain the anti-MH effect of apigenin by focusing on changes in miR-185-5p-mediated autophagy. Methods: Hypertrophic symptoms were induced in rats using transverse aortic constriction (TAC) method and in cardiomyocytes using Ang II and then handled with apigenin. Changes in myocardial function and structure and cell viability and surface area were measured. The role of miR-185-5p in the anti-MH function of apigenin was explored by detecting changes in autophagic processes and miR-185-5p/SREBP2 axis. Results: TAC surgery induced weight increase, structure destruction, and collagen deposition in hearts of model rats. Ang II suppresses cardiomyocyte viability and increased cell surface area. All these impairments were attenuated by apigenin and were associated with the restored level of autophagy. At the molecular level, the expression of miR-185-5p was up-regulated by TAC, while the expression of SREBP2 was down-regulated, which was reserved by apigenin both in vivo and in vitro. The induction of miR-185-5p in cardiomyocytes could counteracted the protective effects of apigenin. Discussion: Collectively, the findings outlined in the current study highlighted that apigenin showed anti-MH effects. The effects were related to the inhibition of miR-185-5p and activation of SREBP, which contributed to the increased autophagy.


Assuntos
Apigenina , Autofagia , Cardiomegalia , MicroRNAs , Ratos Sprague-Dawley , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Apigenina/farmacologia , Autofagia/efeitos dos fármacos , Ratos , Masculino , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Sobrevivência Celular/efeitos dos fármacos
5.
Mol Biol Rep ; 51(1): 969, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39249564

RESUMO

BACKGROUND: Mitochondria are known to be involved in mediating the calorigenic effects of thyroid hormones. With an abundance of these hormones, alterations in energy metabolism and cellular respiration take place, leading to the development of cardiac hypertrophy. Vitamin D has recently gained attention due to its involvement in the regulation of mitochondrial function, demonstrating promising potential in preserving the integrity and functionality of the mitochondrial network. The present study aimed to investigate the therapeutic potential of Vitamin D on cardiac hypertrophy induced by hyperthyroidism, with a focus on the contributions of mitophagy and apoptosis as possible underlying molecular mechanisms. METHODS AND RESULTS: The rats were divided into three groups: control; hyperthyroid; hyperthyroid + Vitamin D. Hyperthyroidism was induced by Levothyroxine administration for four weeks. Serum thyroid hormones levels, myocardial damage markers, cardiac hypertrophy indices, and histological examination were assessed. The assessment of Malondialdehyde (MDA) levels and the expression of the related genes were conducted using heart tissue samples. Vitamin D pretreatment exhibited a significant improvement in the hyperthyroidism-induced decline in markers indicative of myocardial damage, oxidative stress, and indices of cardiac hypertrophy. Vitamin D pretreatment also improved the downregulation observed in myocardial expression levels of genes involved in the regulation of mitophagy and apoptosis, including PTEN putative kinase 1 (PINK1), Mitofusin-2 (MFN2), Dynamin-related Protein 1 (DRP1), and B cell lymphoma-2 (Bcl-2), induced by hyperthyroidism. CONCLUSIONS: These results suggest that supplementation with Vitamin D could be advantageous in preventing the progression of cardiac hypertrophy and myocardial damage.


Assuntos
Apoptose , Cardiomegalia , Cardiotônicos , Modelos Animais de Doenças , Hipertireoidismo , Mitofagia , Tiroxina , Vitamina D , Animais , Hipertireoidismo/complicações , Hipertireoidismo/metabolismo , Hipertireoidismo/tratamento farmacológico , Mitofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ratos , Tiroxina/farmacologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Vitamina D/farmacologia , Masculino , Cardiotônicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Malondialdeído/metabolismo , Hormônios Tireóideos/metabolismo
6.
Cell Rep ; 43(8): 114549, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39093699

RESUMO

CREB-regulated transcription co-activator (CRTC) is activated by Calcineurin (CaN) to regulate gluconeogenic genes. CaN also has roles in cardiac hypertrophy. Here, we explore a cardiac-autonomous role for CRTC in cardiac hypertrophy. In Drosophila, CRTC mutants exhibit severe cardiac restriction, myofibrillar disorganization, fibrosis, and tachycardia. Cardiac-specific CRTC knockdown (KD) phenocopies mutants, and cardiac overexpression causes hypertrophy. CaN-induced hypertrophy in Drosophila is reduced in CRTC mutants, suggesting that CRTC mediates the effects. RNA sequencing (RNA-seq) of CRTC-KD and -overexpressing hearts reveals contraregulation of metabolic genes. Genes with conserved CREB sites include the fly ortholog of Sarcalumenin, a Ca2+-binding protein. Cardiac manipulation of this gene recapitulates the CRTC-KD and -overexpression phenotypes. CRTC KD in zebrafish also causes cardiac restriction, and CRTC KD in human induced cardiomyocytes causes a reduction in Srl expression and increased action potential duration. Our data from three model systems suggest that CaN-CRTC-Sarcalumenin signaling represents an alternate, conserved pathway underlying cardiac function and hypertrophy.


Assuntos
Cardiomegalia , Proteínas de Drosophila , Fatores de Transcrição , Peixe-Zebra , Animais , Cardiomegalia/metabolismo , Cardiomegalia/genética , Cardiomegalia/patologia , Peixe-Zebra/metabolismo , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais , Calcineurina/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética
7.
FASEB J ; 38(15): e23851, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39108204

RESUMO

Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.


Assuntos
Antígeno CTLA-4 , Insuficiência Cardíaca , Camundongos Endogâmicos C57BL , Células Th17 , Animais , Células Th17/imunologia , Células Th17/metabolismo , Camundongos , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Masculino , Interleucina-17/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR4/antagonistas & inibidores , Diferenciação Celular , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/etiologia
8.
JCI Insight ; 9(17)2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39088268

RESUMO

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either KATP GOF or acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cantú syndrome.


Assuntos
Endotélio Vascular , Hipertricose , Mitocôndrias , Osteocondrodisplasias , Ácido Peroxinitroso , Espécies Reativas de Oxigênio , Vasodilatação , Animais , Camundongos , Hipertricose/genética , Hipertricose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ácido Peroxinitroso/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Mitocôndrias/metabolismo , Vasodilatação/genética , Receptores de Sulfonilureias/metabolismo , Receptores de Sulfonilureias/genética , Cálcio/metabolismo , Masculino , Vasoconstrição , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Canais KATP/metabolismo , Canais KATP/genética , Humanos , Modelos Animais de Doenças , Mutação com Ganho de Função , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/genética
9.
Environ Res ; 261: 119781, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39142458

RESUMO

Bisphenol S (BPS) is widely used in the manufacture products and increase the risk of cardiovascular diseases. The effect of the association between obesity and BPS on cardiac outcomes is still unknown. Male C57BL/6 mice were divided into standard chow diet (SC; 15 kJ/g), standard chow diet + BPS (SCB), high-fat diet (HF; 21 kJ/g), and high-fat diet + BPS (HFB). Over 12 weeks, the groups were exposed to BPS through drinking water (dose: 25 µg/kg/day) and/or a HF diet. We evaluated: body mass (BM), total cholesterol, systolic blood pressure (SBP), left ventricle (LV) mass, and cardiac remodeling. In the SCB group, BM, total cholesterol, and SBP increase were augmented in relation to the SC group. In the HF and HFB groups, these parameters were higher than in the SC and SCB groups. Cardiac hypertrophy was evidenced by augmented LV mass and wall thickness, and ANP protein expression in all groups in comparison to the SC group. Only the HFB group had a thicker LV wall than SCB and HF groups, and increased cardiomyocyte area when compared with SC and SCB groups. Concerning cardiac fibrosis, SCB, HF, and HFB groups presented higher interstitial collagen area, TGFß, and α-SMA protein expression than the SC group. Perivascular collagen area was increased only in the HF and HFB groups than SC group. Higher IL-6, TNFα, and CD11c protein expression in all groups than the SC group evidenced inflammation. All groups had elevated CD36 and PPARα protein expression in relation to the SC group, but only HF and HFB groups promoted cardiac steatosis with increased perilipin 5 protein expression than the SC group. BPS exposure alone promoted cardiac remodeling with pathological concentric hypertrophy, fibrosis, and inflammation. Diet-induced remodeling is aggravated when associated with BPS, with marked hypertrophy, alongside fibrosis, inflammation, and lipid accumulation.


Assuntos
Cardiomegalia , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Fenóis , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Camundongos , Fenóis/toxicidade , Remodelação Ventricular/efeitos dos fármacos , Sulfonas
10.
Proc Natl Acad Sci U S A ; 121(36): e2322726121, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39159386

RESUMO

Constricting pythons, known for their ability to consume infrequent, massive meals, exhibit rapid and reversible cardiac hypertrophy following feeding. Our primary goal was to investigate how python hearts achieve this adaptive response after feeding. Isolated myofibrils increased force after feeding without changes in sarcomere ultrastructure and without increasing energy cost. Ca2+ transients were prolonged after feeding with no changes in myofibril Ca2+ sensitivity. Feeding reduced titin-based tension, resulting in decreased cardiac tissue stiffness. Feeding also reduced the activity of sirtuins, a metabolically linked class of histone deacetylases, and increased chromatin accessibility. Transcription factor enrichment analysis on transposase-accessible chromatin with sequencing revealed the prominent role of transcription factors Yin Yang1 and NRF1 in postfeeding cardiac adaptation. Gene expression also changed with the enrichment of translation and metabolism. Finally, metabolomics analysis and adenosine triphosphate production demonstrated that cardiac adaptation after feeding not only increased energy demand but also energy production. These findings have broad implications for our understanding of cardiac adaptation across species and hold promise for the development of innovative approaches to address cardiovascular diseases.


Assuntos
Boidae , Cardiomegalia , Epigênese Genética , Animais , Cardiomegalia/metabolismo , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Boidae/fisiologia , Boidae/genética , Período Pós-Prandial/fisiologia , Metabolismo Energético , Miofibrilas/metabolismo , Cálcio/metabolismo , Adaptação Fisiológica , Miocárdio/metabolismo , Reprogramação Metabólica
11.
J Cell Mol Med ; 28(16): e70022, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39205384

RESUMO

Under the long-term pressure overload stimulation, the heart experiences embryonic gene activation, leading to myocardial hypertrophy and ventricular remodelling, which can ultimately result in the development of heart failure. Identifying effective therapeutic targets is crucial for the prevention and treatment of myocardial hypertrophy. Histone lysine lactylation (HKla) is a novel post-translational modification that connects cellular metabolism with epigenetic regulation. However, the specific role of HKla in pathological cardiac hypertrophy remains unclear. Our study aims to investigate whether HKla modification plays a pathogenic role in the development of cardiac hypertrophy. The results demonstrate significant expression of HKla in cardiomyocytes derived from an animal model of cardiac hypertrophy induced by transverse aortic constriction surgery, and in neonatal mouse cardiomyocytes stimulated by Ang II. Furthermore, research indicates that HKla is influenced by glucose metabolism and lactate generation, exhibiting significant phenotypic variability in response to various environmental stimuli. In vitro experiments reveal that exogenous lactate and glucose can upregulate the expression of HKla and promote cardiac hypertrophy. Conversely, inhibition of lactate production using glycolysis inhibitor (2-DG), LDH inhibitor (oxamate) and LDHA inhibitor (GNE-140) reduces HKla levels and inhibits the development of cardiac hypertrophy. Collectively, these findings establish a pivotal role for H3K18la in pathological cardiac hypertrophy, offering a novel target for the treatment of this condition.


Assuntos
Cardiomegalia , Histonas , Ácido Láctico , Miócitos Cardíacos , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Histonas/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Camundongos , Ácido Láctico/metabolismo , Processamento de Proteína Pós-Traducional , Modelos Animais de Doenças , Glucose/metabolismo , Masculino , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Glicólise
12.
Sci Rep ; 14(1): 19839, 2024 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-39191928

RESUMO

The compound NS5806 is a Kv4 channel modulator. This study investigated the chronic effects of NS5806 on cardiac hypertrophy induced by transverse aortic constriction (TAC) in mice in vivo and on neonatal rat ventricular cardiomyocyte hypertrophy induced by endothelin-1 (ET-1) in vitro. Four weeks after TAC, NS5806 was administered by gavage for 4 weeks. Echocardiograms revealed pronounced left ventricular (LV) hypertrophy in TAC-treated mice compared with sham mice. NS5806 attenuated LV hypertrophy, as manifested by the restoration of LV wall thickness and weight and the reversal of contractile dysfunction in TAC-treated mice. NS5806 also blunted the TAC-induced increases in the expression of cardiac hypertrophic and fibrotic genes, including ANP, BNP and TGF-ß. Electrophysiological recordings revealed a significant prolongation of action potential duration and QT intervals, accompanied by an increase in susceptibility to ventricular arrhythmias in mice with cardiac hypertrophy. However, NS5806 restored these alterations in electrical parameters and thus reduced the incidence of mouse sudden death. Furthermore, NS5806 abrogated the downregulation of the Kv4 protein in the hypertrophic myocardium but did not influence the reduction in Kv4 mRNA expression. In addition, NS5806 suppressed in vitro cardiomyocyte hypertrophy. The results provide novel insight for further ion channel modulator development as a potential treatment option for cardiac hypertrophy.


Assuntos
Cardiomegalia , Miócitos Cardíacos , Canais de Potássio Shal , Animais , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Canais de Potássio Shal/metabolismo , Canais de Potássio Shal/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/tratamento farmacológico , Masculino , Ratos , Camundongos Endogâmicos C57BL , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Modelos Animais de Doenças , Compostos de Fenilureia , Tetrazóis
13.
Cells ; 13(16)2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39195232

RESUMO

From birth to adulthood, the mammalian heart grows primarily through increasing cardiomyocyte (CM) size, which is known as maturational hypertrophic growth. The Hippo-YAP signaling pathway is well known for regulating heart development and regeneration, but its roles in CM maturational hypertrophy have not been clearly addressed. Vestigial-like 4 (VGLL4) is a crucial component of the Hippo-YAP pathway, and it functions as a suppressor of YAP/TAZ, the terminal transcriptional effectors of this signaling pathway. To develop an in vitro model for studying CM maturational hypertrophy, we compared the biological effects of T3 (triiodothyronine), Dex (dexamethasone), and T3/Dex in cultured neonatal rat ventricular myocytes (NRVMs). The T3/Dex combination treatment stimulated greater maturational hypertrophy than either the T3 or Dex single treatment. Using T3/Dex treatment of NRVMs as an in vitro model, we found that activation of VGLL4 suppressed CM maturational hypertrophy. In the postnatal heart, activation of VGLL4 suppressed heart growth, impaired heart function, and decreased CM size. On the molecular level, activation of VGLL4 inhibited the PI3K-AKT pathway, and disrupting VGLL4 and TEAD interaction abolished this inhibition. In conclusion, our data suggest that VGLL4 suppresses CM maturational hypertrophy by inhibiting the YAP/TAZ-TEAD complex and its downstream activation of the PI3K-AKT pathway.


Assuntos
Cardiomegalia , Miócitos Cardíacos , Fatores de Transcrição , Animais , Ratos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Dexametasona/farmacologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Tri-Iodotironina/farmacologia , Proteínas de Sinalização YAP/metabolismo
14.
Cell Mol Life Sci ; 81(1): 359, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158709

RESUMO

Infiltration of monocyte-derived macrophages plays a crucial role in cardiac remodeling and dysfunction. The serum and glucocorticoid-inducible protein kinase 3 (SGK3) is a downstream factor of PI3K signaling, regulating various biological processes via an AKT-independent signaling pathway. SGK3 has been implicated in cardiac remodeling. However, the contribution of macrophagic SGK3 to hypertensive cardiac remodeling remains unclear. A cardiac remodeling model was established by angiotensin II (Ang II) infusion in SGK3-Lyz2-CRE (f/f, +) and wild-type mice to assess the function of macrophagic SGK3. Additionally, a co-culture system of SGK3-deficient or wild-type macrophages and neonatal rat cardiomyocytes (CMs) or neonatal rat fibroblasts (CFs) was established to evaluate the effects of SGK3 and the underlying mechanisms. SGK3 levels were significantly elevated in both peripheral blood mononuclear cells and serum from patients with heart failure. Macrophage SGK3 deficiency attenuated Ang II-induced macrophage infiltration, myocardial hypertrophy, myocardial fibrosis, and mitochondrial oxidative stress. RNA sequencing suggested Ndufa13 as the candidate gene in the effect of SGK3 on Ang II-induced cardiac remolding. Downregulation of Ndufa13 in CMs and CFs prevented the suppression of cardiac remodeling caused by SGK3 deficiency in macrophages. Mechanistically, the absence of SGK3 led to a reduction in IL-1ß secretion by inhibiting the NLRP3/Caspase-1/IL-1ß pathway in macrophages, consequently suppressing upregulated Ndufa13 expression and mitochondrial oxidative stress in CMs and CFs. This study provides new evidence that SGK3 is a potent contributor to the pathogenesis of hypertensive cardiac remodeling, and targeting SGK3 in macrophages may serve as a potential therapy for cardiac remodeling.


Assuntos
Angiotensina II , Macrófagos , Miócitos Cardíacos , Estresse Oxidativo , Proteínas Serina-Treonina Quinases , Remodelação Ventricular , Animais , Angiotensina II/farmacologia , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Transdução de Sinais , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Camundongos Knockout , Células Cultivadas
15.
JCI Insight ; 9(16)2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39171530

RESUMO

Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.


Assuntos
Modelos Animais de Doenças , Frataxina , Ataxia de Friedreich , Proteínas de Ligação ao Ferro , NAD , Animais , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/patologia , Ataxia de Friedreich/genética , Proteínas de Ligação ao Ferro/genética , Proteínas de Ligação ao Ferro/metabolismo , Camundongos , Humanos , NAD/metabolismo , Fenótipo , Masculino , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Mononucleotídeo de Nicotinamida/farmacologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Compostos de Piridínio , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
16.
J Pharmacol Sci ; 156(2): 142-148, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39179333

RESUMO

The hallmark of pathological cardiac hypertrophy is the decline in myocardial contractility caused by an energy deficit resulting from metabolic abnormalities, particularly those related to glucose metabolism. Here, we aim to explore whether D-Allose, a rare sugar that utilizes the same transporters as glucose, may restore metabolic equilibrium and reverse cardiac hypertrophy. Isolated neonatal rat cardiomyocytes were stimulated with phenylephrine and treated with D-Allose simultaneously for 48 h. D-Allose treatment resulted in a pronounced reduction in cardiomyocyte size and cardiac remodelling markers accompanied with a dramatic reduction in the level of intracellular glucose in phenylephrine-stimulated cells. The metabolic flux analysis provided further insights revealing that D-Allose exerted a remarkable inhibition of glycolysis as well as glycolytic capacity. Furthermore, in mice subjected to a 14-day continuous infusion of isoproterenol (ISO) to induce cardiac hypertrophy, D-Allose treatment via drinking water notably reduced ISO-induced cardiac hypertrophy and remodelling markers, with minimal effects on ventricular wall thickness observed in echocardiographic analyses. These findings indicate that D-Allose has the ability to attenuate the progression of cardiomyocyte hypertrophy by decreasing intracellular glucose flux and inhibiting glycolysis.


Assuntos
Cardiomegalia , Glucose , Glicólise , Isoproterenol , Miócitos Cardíacos , Fenilefrina , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Glicólise/efeitos dos fármacos , Glucose/metabolismo , Fenilefrina/farmacologia , Masculino , Células Cultivadas , Camundongos Endogâmicos C57BL , Ratos , Camundongos , Modelos Animais de Doenças , Ratos Sprague-Dawley
17.
Eur J Pharmacol ; 981: 176876, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39127302

RESUMO

Baicalin, a flavonoid glycoside from Scutellaria baicalensis Georgi., exerts anti-hypertensive effects. The present study aimed to assess the cardioprotective role of baicalin and explore its potential mechanisms. Network pharmacology analysis pointed out a total of 477 potential targets of baicalin were obtained from the PharmMapper and SwissTargetPrediction databases, while 11,280 targets were identified associating with hypertensive heart disease from GeneCards database. Based on the above 382 common targets, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed enrichment in the regulation of cardiac hypertrophy, cardiac contraction, cardiac relaxation, as well as the mitogen-activated protein kinase (MAPK) and other signaling pathways. Moreover, baicalin treatment exhibited the amelioration of increased cardiac index and pathological alterations in angiotensin II (Ang II)-infused C57BL/6 mice. Furthermore, baicalin treatment demonstrated a reduction in cell surface area and a down-regulation of hypertrophy markers (including atrial natriuretic peptide and brain natriuretic peptide) in vivo and in vitro. In addition, baicalin treatment led to a decrease in the expression of phosphorylated c-Jun N-terminal kinase (p-JNK)/JNK, phosphorylated p38 (p-p38)/p38, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK in the cardiac tissues of Ang II-infused mice and Ang II-stimulated H9c2 cells. These findings highlight the cardioprotective effects of baicalin, as it alleviates hypertensive cardiac injury, cardiac hypertrophy, and the activation of the MAPK pathway.


Assuntos
Angiotensina II , Cardiomegalia , Flavonoides , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Animais , Flavonoides/farmacologia , Angiotensina II/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Masculino , Farmacologia em Rede , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Linhagem Celular , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico
18.
Function (Oxf) ; 5(5)2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38984978

RESUMO

Cantú syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by gain-of-function (GoF) variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels and is characterized by low systemic vascular resistance, as well as tortuous, dilated, vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell autonomously within vascular smooth muscle cells (VSMCs) or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. Whole-cell voltage clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild-type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were similar to those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs and suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs .


Assuntos
Hipertricose , Células-Tronco Pluripotentes Induzidas , Canais KATP , Músculo Liso Vascular , Miócitos de Músculo Liso , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Músculo Liso Vascular/metabolismo , Hipertricose/genética , Hipertricose/metabolismo , Hipertricose/fisiopatologia , Hipertricose/patologia , Animais , Camundongos , Miócitos de Músculo Liso/metabolismo , Canais KATP/genética , Canais KATP/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Osteocondrodisplasias/fisiopatologia , Mutação , Diferenciação Celular/genética , Técnicas de Patch-Clamp , Cardiomegalia , Receptores de Sulfonilureias
19.
Med Sci (Paris) ; 40(6-7): 534-543, 2024.
Artigo em Francês | MEDLINE | ID: mdl-38986098

RESUMO

Cyclic nucleotide phosphodiesterases (PDEs) modulate neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple isoforms of PDEs with different enzymatic properties and subcellular locally regulate cyclic nucleotide levels and associated cellular functions. This organisation is severely disrupted during hypertrophy and heart failure (HF), which may contribute to disease progression. Clinically, PDE inhibition has been seen as a promising approach to compensate for the catecholamine desensitisation that accompanies heart failure. Although PDE3 inhibitors such as milrinone or enoximone can be used clinically to improve systolic function and relieve the symptoms of acute CHF, their chronic use has proved detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as potential new targets for the treatment of HF, each with a unique role in local cyclic nucleotide signalling pathways. In this review, we describe cAMP and cGMP signalling in cardiomyocytes and present the different families of PDEs expressed in the heart and their modifications in pathological cardiac hypertrophy and HF. We also review results from preclinical models and clinical data indicating the use of specific PDE inhibitors or activators that may have therapeutic potential in CI.


Title: Les phosphodiestérases des nucléotides cycliques - Cibles thérapeutiques dans l'hypertrophie et l'insuffisance cardiaques. Abstract: Les phosphodiestérases des nucléotides cycliques (PDE) modulent la régulation neuro-hormonale de la fonction cardiaque en dégradant l'AMPc et le GMPc. Dans les cardiomyocytes, de multiples isoformes de PDE, aux propriétés enzymatiques et aux localisations subcellulaires différentes, régulent localement les niveaux de nucléotides cycliques et les fonctions cellulaires associées. Cette organisation est fortement perturbée au cours de l'hypertrophie et de l'insuffisance cardiaque à fraction d'éjection réduite (IC), ce qui peut contribuer à la progression de la maladie. Sur le plan clinique, l'inhibition des PDE a été considérée comme une approche prometteuse pour compenser la désensibilisation aux catécholamines qui accompagne l'IC. Bien que des inhibiteurs de la PDE3, tels que la milrinone ou l'énoximone, puissent être utilisés cliniquement pour améliorer la fonction systolique et soulager les symptômes de l'IC aiguë, leur utilisation chronique s'est avérée préjudiciable. D'autres PDE, telles que les PDE1, PDE2, PDE4, PDE5, PDE9 et PDE10, sont apparues comme de nouvelles cibles potentielles pour le traitement de l'IC, chacune ayant un rôle unique dans les voies de signalisation locales des nucléotides cycliques. Dans cette revue, nous décrivons la signalisation de l'AMPc et du GMPc dans les cardiomyocytes et présentons les différentes familles de PDE exprimées dans le cœur ainsi que leurs modifications dans l'hypertrophie cardiaque pathologique et dans l'IC. Nous évaluons également les résultats issus de modèles précliniques ainsi que les données cliniques indiquant l'utilisation d'inhibiteurs ou d'activateurs de PDE spécifiques qui pourraient avoir un potentiel thérapeutique dans l'IC.


Assuntos
Cardiomegalia , Insuficiência Cardíaca , Inibidores de Fosfodiesterase , Humanos , Cardiomegalia/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Animais , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Terapia de Alvo Molecular/métodos , GMP Cíclico/metabolismo , GMP Cíclico/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , AMP Cíclico/metabolismo , AMP Cíclico/fisiologia , Diester Fosfórico Hidrolases/metabolismo , Diester Fosfórico Hidrolases/fisiologia
20.
J Cell Mol Med ; 28(14): e18546, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39046458

RESUMO

Heart failure (HF) prognosis depends on various regulatory factors; microRNA-128 (miR-128) is identified as a regulator of cardiac fibrosis, contributing to HF. MyoD family inhibitor (MDFI), which is reported to be related with Wnt/ß-catenin pathway, is supposed to be regulated by miR-128. This study investigates the interaction between miR-128 and MDFI in cardiomyocyte development and elucidates its role in heart injury. Gene expression profiling assessed miR-128's effect on MDFI expression in HF using qPCR and Western blot analysis. Luciferase assays studied the direct interaction between miR-128 and MDFI. MTT, transwell, and immunohistochemistry evaluated the effects of miR-128 and MDFI on myocardial cells in mice HF. Genescan and luciferase assays validated the interaction between miR-128 and MDFI sequences. miR-128 mimics significantly reduced MDFI expression at mRNA and protein levels with decrease rate of 55%. Overexpression of miR-128 promoted apoptosis with the increase rate 65% and attenuated cardiomyocyte proliferation, while MDFI upregulation significantly enhanced proliferation. Elevated miR-128 levels upregulated Wnt1 and ß-catenin expression, whereas increased MDFI levels inhibited these expressions. Histological analysis with haematoxylin and eosin staining revealed that miR-128 absorption reduced MDFI expression, hindering cell proliferation and cardiac repair, with echocardiography showing corresponding improvements in cardiac function. Our findings suggest miR-128 interacts with MDFI, playing a crucial role in HF management by modulating the Wnt1/ß-catenin pathway. Suppression of miR-128 could promote cardiomyocyte proliferation, highlighting the potential value of the miR-128/MDFI interplay in HF treatment.


Assuntos
Apoptose , Cardiomegalia , Proliferação de Células , Insuficiência Cardíaca , MicroRNAs , Miócitos Cardíacos , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Apoptose/genética , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proliferação de Células/genética , Camundongos , Masculino , Humanos , Via de Sinalização Wnt/genética , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL , beta Catenina/metabolismo , beta Catenina/genética , Proteína Wnt1/metabolismo , Proteína Wnt1/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA