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1.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946230

RESUMO

Current knowledge on the renin-angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets.


Assuntos
Cardiopatias/patologia , MicroRNAs/metabolismo , Miocárdio/patologia , Sistema Renina-Angiotensina , Transdução de Sinais , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Fibrose , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , MicroRNAs/genética , Miocárdio/metabolismo
2.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922643

RESUMO

ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic reticulum Ca2+ overloading. The effects of IF1 on Ca2+ handling were associated with the cytosolic activation of calcium-calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial-to-nuclear crosstalk involving CaMKII.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Cardiomegalia/patologia , Mitocôndrias/patologia , Isquemia Miocárdica/patologia , Miócitos Cardíacos/patologia , Proteínas/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cardiomegalia/genética , Cardiomegalia/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas/genética , Ratos , Retículo Sarcoplasmático/metabolismo , Transdução de Sinais
3.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807195

RESUMO

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.


Assuntos
Cardiomegalia/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Metabolismo Energético , Glucose/metabolismo , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Fenilefrina/farmacologia , Fosforilação , Ratos , Transdução de Sinais/efeitos dos fármacos
4.
Oxid Med Cell Longev ; 2021: 6699054, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33824698

RESUMO

Background: Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results: Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion: Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cardiomegalia/metabolismo , Insuficiência Cardíaca/metabolismo , Interleucina-6/metabolismo , Estresse Oxidativo , Cloridrato de Raloxifeno/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Cardiomegalia/prevenção & controle , Linhagem Celular , Insuficiência Cardíaca/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitofagia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Cloridrato de Raloxifeno/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924991

RESUMO

BACKGROUND: Arterial hypertension (AH) is associated with heart and chronic kidney disease (CKD). However, the precise mechanisms of myocardial remodeling (MR) in the settings of CKD remain elusive. We hypothesized that TRPC6, calcineurin/NFAT, and Wnt/ß-catenin signaling pathways are involved in the development of MR in the background of CKD and AH. METHODS: Early CKD was induced by performing a 5/6 nephrectomy (5/6NE) in spontaneously hypertensive rats (SHR-NE). Sham-operated (SO) SHR (SHR-SO) and Wistar Kyoto (WKY-SO) rats served as controls. Systolic blood pressure (SBP), heart rate, myocardial mass index (MMI), serum creatinine, cardiomyocyte diameter (dCM), myocardial fibrosis (MF), serum and kidney α-Klotho levels, myocardial expression of calcineurin (CaN), TRPC6, and ß-catenin were measured two months after 5/6NE or SO. RESULTS: NE-induced kidney dysfunction corresponded to mild-to-moderate human CKD and was associated with an increase in FGF23 and a decrease in renal α-Klotho. The levels of SBP, MMI, dCM, and MF were higher in SHRs compared to WKY-SO as well as in SHR-NE vs. SHR-SO. The MR was associated with increased cardiomyocyte expression of CaN/NFAT and ß-catenin along with its intracellular re-distribution. TRPC6 protein levels were substantially elevated in both SHR groups with higher Trpc6 mRNA expression in SHR-NE. CONCLUSIONS: The Wnt/ß-catenin and TRPC6/CaN/NFAT hypertrophic signaling pathways seem to be involved in myocardial remodeling in the settings of AH and CKD and might be mediated by FGF23 and α-Klotho axis.


Assuntos
Cardiomegalia/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Cátion TRPC/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Calcineurina/metabolismo , Cardiomegalia/etiologia , Hipertensão/complicações , Masculino , Fatores de Transcrição NFATC/metabolismo , Nefrectomia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Insuficiência Renal Crônica/complicações , Remodelação Ventricular
6.
Oxid Med Cell Longev ; 2021: 5545261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763166

RESUMO

Mitochondrial dysfunction has been suggested to be the key factor in the development and progression of cardiac hypertrophy. The onset of mitochondrial dysfunction and the mechanisms underlying the development of cardiac hypertrophy (CH) are incompletely understood. The present study is based on the use of multiple bioinformatics analyses for the organization and analysis of scRNA-seq and microarray datasets from a transverse aortic constriction (TAC) model to examine the potential role of mitochondrial dysfunction in the pathophysiology of CH. The results showed that NADH:ubiquinone oxidoreductase core subunit S1- (Ndufs1-) dependent mitochondrial dysfunction plays a key role in pressure overload-induced CH. Furthermore, in vivo animal studies using a TAC mouse model of CH showed that Ndufs1 expression was significantly downregulated in hypertrophic heart tissue compared to that in normal controls. In an in vitro model of angiotensin II- (Ang II-) induced cardiomyocyte hypertrophy, Ang II treatment significantly downregulated the expression of Ndufs1 in cardiomyocytes. In vitro mechanistic studies showed that Ndufs1 knockdown induced CH; decreased the mitochondrial DNA content, mitochondrial membrane potential (MMP), and mitochondrial mass; and increased the production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. On the other hand, Ang II treatment upregulated the expression levels of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain beta; decreased the mitochondrial DNA content, MMP, and mitochondrial mass; and increased mitochondrial ROS production in cardiomyocytes. The Ang II-mediated effects were significantly attenuated by overexpression of Ndufs1 in rat cardiomyocytes. In conclusion, our results demonstrate downregulation of Ndufs1 in hypertrophic heart tissue, and the results of mechanistic studies suggest that Ndufs1 deficiency may cause mitochondrial dysfunction in cardiomyocytes, which may be associated with the development and progression of CH.


Assuntos
Cardiomegalia/metabolismo , Potencial da Membrana Mitocondrial , Miocárdio/metabolismo , Miocárdio/patologia , NADH Desidrogenase/deficiência , Pressão , Angiotensina II , Animais , Fator Natriurético Atrial/metabolismo , Biomarcadores/metabolismo , Cardiomegalia/patologia , Constrição Patológica , Regulação para Baixo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/metabolismo , NADH Desidrogenase/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , RNA-Seq , Ratos , Análise de Célula Única
7.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668293

RESUMO

Plant-based foods, like fruits, vegetables, whole grains, legumes, nuts, seeds and other foodstuffs, have been deemed as heart healthy. The chemicals within these plant-based foods, i.e., phytochemicals, are credited with protecting the heart. However, the mechanistic actions of phytochemicals, which prevent clinical endpoints, such as pathological cardiac hypertrophy, are still being elucidated. We sought to characterize the overlapping and divergent mechanisms by which 18 selected phytochemicals prevent phenylephrine- and phorbol 12-myristate 13-acetate-mediated cardiomyocyte enlargement. Of the tested 18 compounds, six attenuated PE- and PMA-mediated enlargement of neonatal rat ventricular myocytes. Cell viability assays showed that apigenin, baicalein, berberine hydrochloride, emodin, luteolin and quercetin dihydrate did not reduce cell size through cytotoxicity. Four of the six phytochemicals, apigenin, baicalein, berberine hydrochloride and emodin, robustly inhibited stress-induced hypertrophy and were analyzed further against intracellular signaling and genome-wide changes in mRNA expression. The four phytochemicals differentially regulated mitogen-activated protein kinases and protein kinase D. RNA-sequencing further showed divergence in gene regulation, while pathway analysis demonstrated overlap in the regulation of inflammatory pathways. Combined, this study provided a comprehensive analysis of cardioprotective phytochemicals. These data highlight two defining observations: (1) that these compounds predominantly target divergent gene pathways within cardiac myocytes and (2) that regulation of overlapping signaling and gene pathways may be of particular importance for the anti-hypertrophic actions of these phytochemicals. Despite these new findings, future works investigating rodent models of heart failure are still needed to understand the roles for these compounds in the heart.


Assuntos
Cardiomegalia/tratamento farmacológico , Cardiotônicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Animais , Cardiomegalia/metabolismo , Cardiotônicos/química , Células Cultivadas , Miócitos Cardíacos/metabolismo , Compostos Fitoquímicos/química , Ratos , Ratos Sprague-Dawley
8.
Biomed Res Int ; 2021: 6615502, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33778070

RESUMO

Cardiac hypertrophy (CH) is a common cause of sudden cardiac death and heart failure, resulting in a significant medical burden. The present study is aimed at exploring potential CH-related pathways and the key downstream effectors. The gene expression profile of GSE129090 was obtained from the Gene Expression Omnibus database (GEO), and 1325 differentially expressed genes (DEGs) were identified, including 785 upregulated genes and 540 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway enrichment analysis of DEGs were then performed. Although there were no pathways enriched by downregulated genes, many CH-related pathways were identified by upregulated genes, including PI3K-Akt signaling pathway, extracellular matrix- (ECM-) receptor interaction, regulation of actin cytoskeleton, and hypertrophic cardiomyopathy (HCM). In the deeper analysis of PI3K-Akt signaling pathway, we found all the signaling transduction pointed to B cell lymphoma-2- (Bcl-2-) mediated cell survival. We then demonstrated that PI3K-Akt signaling pathway was indeed activated in cardiac hypertrophy. Furthermore, no matter LY294002, an inhibitor of the PI3K/AKT signaling pathway, or Venetoclax, a selective Bcl-2 inhibitor, protected against cardiac hypertrophy. In conclusion, these data indicate that Bcl-2 is involved in cardiac hypertrophy as a key downstream effector of PI3K-Akt signaling pathway, suggesting a potential therapeutic target for the clinical management of cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Bases de Dados de Ácidos Nucleicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Cromonas/farmacologia , Masculino , Camundongos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/farmacologia
9.
Am J Physiol Heart Circ Physiol ; 320(4): H1456-H1469, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33635168

RESUMO

Ventricular arrhythmia (VA) is the major cause of death in patients with left ventricular (LV) hypertrophy and/or acute ischemia. We hypothesized that apamin, a blocker of small-conductance Ca2+-activated K+ (SK) channels, alters Ca2+ handling and exhibits anti-arrhythmic effects in ventricular myocardium. Spontaneous hypertensive rats were used as a model of LV hypertrophy. A dual optical mapping of membrane potential (Vm) and intracellular calcium (Cai) was performed during global hypoxia (GH) on the Langendorff perfusion system. The majority of pacing-induced VAs during GH were initiated by triggered activities. Pretreatment of apamin (100 nmol/L) significantly inhibited the VA inducibility. Compared with SK channel blockers (apamin and NS8593), non-SK channel blockers (glibenclamide and 4-AP) did not exhibit anti-arrhythmic effects. Apamin prevented not only action potential duration (APD80) shortening (-18.7 [95% confidence interval, -35.2 to -6.05] ms vs. -2.75 [95% CI, -10.45 to 12.65] ms, P = 0.04) but also calcium transient duration (CaTD80) prolongation (14.52 [95% CI, 8.8-20.35] ms vs. 3.85 [95% CI, -3.3 to 12.1] ms, P < 0.01), thereby reducing CaTD80 - APD80, which denotes "Cai/Vm uncoupling" (33.22 [95% CI, 22-48.4] ms vs. 6.6 [95% CI, 0-14.85] ms, P < 0.01). The reduction of Cai/Vm uncoupling was attributable to less prolonged Ca2+ decay constant and suppression of diastolic Cai increase by apamin. The inhibition of VA inducibility and changes in APs/CaTs parameters caused by apamin was negated by the addition of ouabain, an inhibitor of Na+/K+ pump. Apamin attenuates APD shortening, Ca2+ handling abnormalities, and Cai/Vm uncoupling, leading to inhibition of VA occurrence in hypoxic hypertrophied hearts.NEW & NOTEWORTHY We demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca2+-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca2+-activated K+ channels, especially "apamin," showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca2+ handling abnormalities, most notably the "Ca2+/voltage uncoupling."


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Sinalização do Cálcio/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , 1-Naftilamina/análogos & derivados , 1-Naftilamina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Apamina/farmacologia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Estimulação Cardíaca Artificial , Cardiomegalia/complicações , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Hipóxia/complicações , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Preparação de Coração Isolado , Masculino , Ratos Endogâmicos SHR , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Fatores de Tempo
10.
Life Sci ; 272: 119242, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607155

RESUMO

AIMS: Recent studies have shown that enhancement of fatty acid utilization through feeding animals a high fat diet (HFD) attenuated cardiac dysfunction in heart failure (HF). Here, we aimed to examine the temporal effects of HFD feeding on cardiac function in mice with heart failure and its underlying mechanism. MAIN METHODS: Pressure overload-induced HF was established via transverse aortic constriction (TAC) surgery. After surgery, the mice were fed on either normal diet or HFD for 8 or 16 weeks. KEY FINDINGS: HFD feeding exerted opposite effects on cardiac function at different time points post-surgery. Short-term HFD feeding (8 wk) protected the heart against pressure overload, inhibiting cardiac hypertrophy and improving cardiac function, while long-term HFD feeding (16 wk) aggravated cardiac dysfunction in TAC mice. Short-term HFD feeding elevated cardiac fatty acid utilization, while long-term HFD feeding showed no significant effects on cardiac fatty acid utilization in TAC mice. Specifically, an increase in cardiac fatty acid utilization was accompanied with activated mitophagy and improved mitochondrial function. Palmitic acid treatment (400 µM, 2 h) stimulated fatty acid oxidation and mitophagy in neonatal myocytes. Mechanistically, fatty acid utilization stimulated mitophagy through upregulation of Parkin. Cardiac-specific knockdown of Parkin abolished the protective effects of short-term HFD feeding on cardiac function in TAC mice. SIGNIFICANCES: These results suggested that short-term but not long-term HFD feeding protects against pressure overload-induced heart failure through activation of mitophagy, and dietary fat intake should be used with caution in treatment of heart failure.


Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/prevenção & controle , Mitofagia/fisiologia , Animais , Pressão Sanguínea/fisiologia , Cardiomegalia/metabolismo , China , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Metabolismo Energético , Ácidos Graxos/metabolismo , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Oxirredução
11.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495819

RESUMO

High­mobility group box 1 (HMGB1) is released by necrotic cells and serves an important role in cardiovascular pathology. However, the effects of HMGB1 in cardiomyocyte hypertrophy remain unclear. Therefore, the aim of the present study was to investigate the potential role of HMGB1 in cardiomyocyte hypertrophy and the underlying mechanisms of its action. Neonatal mouse cardiomyocytes (NMCs) were co­cultured with recombinant HMGB1 (rHMGB1). Wortmannin was used to inhibit PI3K activity in cardiomyocytes. Subsequently, atrial natriuretic peptide (ANP), 14­3­3 and phosphorylated­Akt (p­Akt) protein levels were detected using western blot analysis. In addition, nuclear factor of activated T cells 3 (NFAT3) protein levels were measured by western blot analysis and observed in NMCs under a confocal microscope. The results revealed that rHMGB1 increased ANP and p­Akt, and decreased 14­3­3η protein levels. Furthermore, wortmannin abrogated the effects of rHMGB1 on ANP, 14­3­3η and p­Akt protein levels. In addition, rHMGB1 induced nuclear translocation of NFAT3, which was also inhibited by wortmannin pretreatment. The results of this study suggest that rHMGB1 induces cardiac hypertrophy by regulating the 14­3­3η/PI3K/Akt/NFAT3 signaling pathway.


Assuntos
Proteínas 14-3-3/metabolismo , Cardiomegalia/metabolismo , Proteína HMGB1/efeitos adversos , Miócitos Cardíacos/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Feminino , Proteína HMGB1/farmacologia , Camundongos , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/genética , Proteínas Recombinantes
12.
Int Heart J ; 62(1): 162-170, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33455985

RESUMO

High-mobility group box 1 (HMGB1) is increased in the myocardium under pressure overload (PO) and is involved in PO-induced cardiac remodeling. The mechanisms of the upregulation of cardiac HMGB1 expression have not been fully elucidated. In the present study, a mouse transverse aortic constriction (TAC) model was used, and an angiotensin II (Ang II) type 1 (AT1) receptor inhibitor (losartan) or Ang II type 2 (AT2) receptor inhibitor (PD123319) was administrated to mice for 14 days. Cardiac myocytes were cultured and treated with Ang II for 5 minutes to 48 hours conditionally with the blockage of the AT1 or AT2 receptor. TAC-induced cardiac hypertrophy was observed at 14 days after the operation, which was partially reversed by losartan, but not by PD123319. Similarly, the upregulated HMGB1 expression levels observed in both the serum and myocardium induced by TAC were reduced by losartan. Elevated cardiac HMGB1 protein levels, but not mRNA or serum levels, were significantly decreased by PD123319. Furthermore, HMGB1 expression levels in culture media and cardiac myocytes were increased following Ang II treatment in vitro, positively associated with the duration of treatment. Similarly, Ang II-induced upregulation of HMGB1 in vitro was inhibited by both losartan and PD123319. These results suggest that upregulation of HMGB1 in serum and myocardium under PO, which are partially derived from cardiac myocytes, may be induced by Ang II via the AT1 and AT2 receptors. Additionally, amelioration of PO-induced cardiac hypertrophy following losartan treatment may be associated with the reduction of HMGB1 expression through the AT1 receptor.


Assuntos
Angiotensina II/farmacologia , Proteína HMGB1/efeitos dos fármacos , Losartan/farmacologia , Miocárdio/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/patologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Estudos de Casos e Controles , Constrição , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Losartan/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/farmacologia , Regulação para Cima , Vasoconstritores/farmacologia
13.
Life Sci ; 267: 118984, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33383049

RESUMO

An increase in oxidative stress is an important pathological mechanism of heart injury induced by doxorubicin (DOX). Tranilast is an anti-allergy drug that has been shown to possess good antioxidant activity in previous studies. The overexpression and secretion of chymase by mast cells (MCs) increase the pathological overexpression of angiotensin II (Ang II), which plays a crucial role in myocardial hypertrophy and the deterioration of heart disease. The MC stabilizer tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid; tran) prevents mast cells from degranulating, which may reduce DOX-induced Ang II synthesis. Therefore, in the present study, we hypothesized that tranilast will protect rats from DOX-induced myocardial damage via its antioxidant activity, thereby inhibiting Ang II expression. Thirty male Wistar rats were divided into three groups (n = 10 in each group) that received DOX, a combination of DOX and tranilast or saline (the control group) to test this hypothesis. Tranilast suppressed chymase expression, reduced Ang II levels and prevented the myocardial hypertrophy and the deterioration of heart function induced by DOX. Based on the findings of the present study, the suppression of chymase-dependent Ang-II production and the direct effect of tranilast on the inhibition of apoptosis and fibrosis because of its antioxidant stress capacity may contribute to the protective effect of tranilast against DOX-induced myocardial hypertrophy.


Assuntos
Angiotensina II/efeitos dos fármacos , Cardiomegalia/metabolismo , Doxorrubicina/efeitos adversos , ortoaminobenzoatos/farmacologia , Angiotensina II/biossíntese , Angiotensina II/metabolismo , Animais , Antioxidantes/farmacologia , Cardiomegalia/tratamento farmacológico , Doxorrubicina/farmacologia , Fibrose , Cardiopatias/etiologia , Masculino , Mastócitos/efeitos dos fármacos , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , ortoaminobenzoatos/metabolismo
14.
FASEB J ; 35(1): e21240, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33377257

RESUMO

Signal transducers and transcriptional activation 1 (Stat1) is a member of the STATs family, and its role in various biological responses, including cell proliferation, differentiation, migration, apoptosis, and immune regulation has been extensively studied. We aimed to investigate its role in pathological cardiac hypertrophy, which is currently poorly understood. Experiments using H9C2 cardiomyocytes, Stat1, and IfngR cardiomyocyte-specific knockout mice revealed that Stat1 had a protective effect on cardiac hypertrophy. Using transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice, we analyzed the degree of hypertrophy using echocardiography, pathology, and at the molecular level. Mice lacking Stat1 had more pronounced cardiac hypertrophy and fibrosis than wild-type TAC mice. Analysis of the molecular mechanisms suggested that Stat1 downregulated the mRNA levels of hypertrophy and fibrosis markers to inhibit cardiac hypertrophy, and promotes mitochondrial fission through the Ucp2/P-Drp1 pathway, enhancing mitochondrial function, and increasing compensatory myocardial ATP production in the compensatory phase for cardiac hypertrophy inhibition. Overall, this comprehensive analysis revealed that Stat1 inhibits cardiac hypertrophy by downregulating hypertrophic and fibrotic marker genes and enhancing the mitochondrial function to enhance cardiomyocyte function through the Ucp2/P-Drp1 signaling pathway.


Assuntos
Cardiomegalia/metabolismo , Mitocôndrias Cardíacas/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Linhagem Celular , Modelos Animais de Doenças , Dinaminas/genética , Dinaminas/metabolismo , Fibrose , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/patologia , Fator de Transcrição STAT1/genética , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo
15.
PLoS Comput Biol ; 16(12): e1008490, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33338038

RESUMO

Cardiac hypertrophy is a context-dependent phenomenon wherein a myriad of biochemical and biomechanical factors regulate myocardial growth through a complex large-scale signaling network. Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of ß-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model's predictions on the role of CaMKII-Gßγ and CaN-Gßγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. CLASSED is a systematic approach for developing context-specific large-scale signaling networks, yielding insights into new-found crosstalks in ß-adrenergic cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Simulação por Computador , Receptores Adrenérgicos beta/metabolismo , Animais , Células Cultivadas , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
16.
Life Sci ; 260: 118378, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32898528

RESUMO

AIMS: Pathological cardiac hypertrophy (CH) is one of the main risk factors for heart failure and cardiac death. Mitochondrial dysfunction and oxidative stress often occur in hypertrophic cardiomyocytes. It was recently proposed that deficiency or decreased activity of glucose-6-phosphate dehydrogenase (G6PD) may be related to the development of CH. This study aimed to investigate the expression of G6PD in CH and its regulatory role in mitochondrial dysfunction and oxidative stress of CH cells. MAIN METHODS: Phenylephrine (PE) was used to create an in vitro model of CH. Using RT-qPCR and western blotting, the expression levels of target mRNAs and proteins were measured. ELISA assays and commercial kits based on spectrophotometry or colorimetry were used to measure mitochondrial function and oxidative stress. TargetScan and luciferase reporter gene assays were utilized for combination prediction and validation. CCK-8 and TUNEL kit were used to determine cell viability and apoptosis. KEY FINDINGS: The results showed that G6PD overexpression attenuated the decreases of mitochondrial respiration, ATP, ATP synthetase and mitochondrial membrane potential induced by PE, as well as the increases of LDH release and apoptosis. Besides, PE elevated ROS activity, NO and MDA contents, and reduced SOD, CAT levels and cell viability. These effects were hindered by G6PD overexpression. MiR-24 was found to directly bind to G6PD at the motif of CUGAGCC and regulated its expression, furtherly, influenced the G6PD-mediated mitochondrial dysfunction and oxidative stress of CH cells. SIGNIFICANCE: Generally, our study demonstrated that miR-24/G6PD regulates mitochondrial dysfunction and oxidative stress in CH cells, representing a new sight for CH therapy.


Assuntos
Cardiomegalia/patologia , Glucosefosfato Desidrogenase/metabolismo , MicroRNAs/genética , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/efeitos adversos , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiotônicos/efeitos adversos , Glucosefosfato Desidrogenase/genética , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
17.
PLoS One ; 15(7): e0232507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645007

RESUMO

Sex-related differences in cardiovascular diseases are highly complex in humans and model-dependent in experimental laboratory animals. The objective of this work was to comprehensively investigate key sex differences in the response to acute and prolonged adrenergic stimulation in C57Bl/6NCrl mice. Cardiac function was assessed by trans-thoracic echocardiography before and after acute adrenergic stimulation (a single sub-cutaneous dose of isoproterenol 10 mg/kg) in 15 weeks old male and female C57Bl/6NCrl mice. Thereafter, prolonged adrenergic stimulation was achieved by sub-cutaneous injections of isoproterenol 10 mg/kg/day for 14 days in male and female mice. Cardiac function and morphometry were assessed by trans-thoracic echocardiography on the 15th day. Thereafter, the mice were euthanized, and the hearts were collected. Histopathological analysis of myocardial tissue was performed after staining with hematoxylin & eosin, Masson's trichrome and MAC-2 antibody. Gene expression of remodeling and fibrotic markers was assessed by real-time PCR. Cardiac function and morphometry were also measured before and after isoproterenol 10 mg/kg/day for 14 days in groups of gonadectomized male and female mice and sham-operated controls. In the current work, there were no statistically significant differences in the positive inotropic and chronotropic effects of isoproterenol between male and female C57Bl/6NCrl. After prolonged adrenergic stimulation, there was similar degree of cardiac dysfunction, cardiac hypertrophy, and myocardial fibrosis in male and female mice. Similarly, prolonged isoproterenol administration induced hypertrophic and fibrotic genes in hearts of male and female mice to the same extent. Intriguingly, gonadectomy of male and female mice did not have a significant impact on isoproterenol-induced cardiac dysfunction as compared to sham-operated animals. The current work demonstrated lack of significant sex-related differences in isoproterenol-induced cardiac hypertrophy, dysfunction, and fibrosis in C57Bl/6NCrl mice. This study suggests that female sex may not be sufficient to protect the heart in this model of isoproterenol-induced cardiac dysfunction and underscores the notion that sexual dimorphism in cardiovascular diseases is highly model-dependent.


Assuntos
Cardiopatias/fisiopatologia , Caracteres Sexuais , Animais , Biomarcadores/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Isoproterenol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia
18.
J Pharmacol Sci ; 144(1): 30-42, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32665128

RESUMO

To understand the mechanism underlying the regression of cardiac hypertrophy, we investigated the pathological changes after isoproterenol (ISO) withdrawal in ISO-induced cardiomyopathy models in rats and neonatal cardiomyocytes. Cardiac hypertrophy was induced in rats by two weeks of ISO administration; however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group). The remaining hypertrophy in the ISO-wdr group was accompanied by a sustained increase in the level of phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the CaV1.2 channel and amounts of CaMKII bound with HDAC4 and CaV1.2 were not recovered in the ISO-wdr group. The results in cardiomyocyte models were similar to those seen in rat models. Losartan, metoprolol or amlodipine neither ameliorated the increase in atrial natriuretic peptide nor inhibited the increase in p-CaMKII and bound CaMKII. In contrast, autocamtide-2-related inhibitor peptide, a CaMKII inhibitor, reduced these increases. This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with CaV1.2 could be potential targets to achieve effective regression of cardiac hypertrophy.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomegalia/genética , Cardiomegalia/metabolismo , Isoproterenol/efeitos adversos , Animais , Canais de Cálcio Tipo L/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Modelos Animais de Doenças , Histona Desacetilases/metabolismo , Masculino , Terapia de Alvo Molecular , Miócitos Cardíacos/metabolismo , Fosforilação , Ligação Proteica , Ratos Sprague-Dawley
19.
Clin Exp Hypertens ; 42(7): 675-679, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-32478610

RESUMO

BACKGROUND: Bromocriptine, a dopamine agonist, used for the treatment of hyperprolactinemia, type 2 diabetes, ovarian hyper-stimulation syndrome, has also effects on the cardiac remodeling process, but the mechanism of action is unknown. The aim of this work was to determinate the effect during hypertrophic process through molecular mechanisms that include prolactin receptor (Prlr) and receptor of dopamine 2 (D2 r) expression. METHODS: We used a model of cardiac hypertrophy induced by an aortocaval fistula (ACF) surgery in rats. Protein concentrations of D2 r and Prlr were determined by western blotting. The treatment consisted in water (control), captopril (50 mg/kg/day), bromocriptine (3 mg/kg/day), and ACF group (n = 6 per group). RESULTS: Our results showed that bromocriptine treatment decreases the hypertrophy index. Treatment with bromocriptine increases the protein expression of Prlr and D2 r in the cardiac tissue of rats with cardiac hypertrophy. CONCLUSIONS: We concluded that bromocriptine has a protective effect on cardiac hypertrophy, and due to this effect, it may modulate the expression of Prlr and D2 r, which are involved in the development of cardiac hypertrophy.


Assuntos
Bromocriptina/farmacologia , Cardiomegalia/metabolismo , Agonistas de Dopamina/farmacologia , Miocárdio/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores da Prolactina/metabolismo , Animais , Bromocriptina/metabolismo , Bromocriptina/uso terapêutico , Cardiomegalia/prevenção & controle , Masculino , Ratos , Receptores de Dopamina D2/agonistas
20.
Nat Commun ; 11(1): 2551, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439985

RESUMO

Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show that Dio2 is a direct transcriptional target of FoxO1, and the FoxO1-Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restricted FoxO1 knockout mice, we unveil an essential role for the FoxO1-Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1-Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.


Assuntos
Proteína Forkhead Box O1/metabolismo , Iodeto Peroxidase/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Hormônios Tireóideos/metabolismo , Animais , Animais Recém-Nascidos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Iodeto Peroxidase/antagonistas & inibidores , Iodeto Peroxidase/genética , Camundongos , Camundongos Knockout , Ratos , Transdução de Sinais , Remodelação Ventricular
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