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2.
Ultrastruct Pathol ; 47(1): 12-21, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36588172

RESUMO

Calanus oil, an oil extracted from the marine crustacean Calanus finmarchicus, is one of the richest sources of omega-3 and poly-unsaturated fatty acids. Although calanus oil has been shown to have a significant anti-hypertensive, anti-inflammatory, anti-fibrotic and anti-obesity effects in various cardiovascular diseases, but little is known about its effect on pathological cardiac hypertrophy. Thus, the present study was carried out to evaluate the therapeutic effect of calanus oil on cardiac hypertrophy. Cardiac hypertrophy was induced by subcutaneous injections with isoproterenol (5 mg/kg b.w) for 14 consecutive days. Calanus oil (400 mg/kg) was given orally for 4 weeks. Cardiac pathological remodeling was evaluated by echocardiography, after which morphometric, biochemical, histological and ultrastructural analyses were performed. Calanus oil treatment significantly ameliorated isoproterenol-induced structural and functional alterations in echocardiography. Calanus oil also reduced the relative heart weight, significantly decreased the elevated cardiac enzymes (LDH and CK-MB) and the lipid peroxidation marker (MDA), augmented the myocardial antioxidant status (TAC), and ameliorated the histopathological and ultrastructural changes in cardiac tissues and prevented interstitial collagen deposition. The present study, for the first time, provided morphometric, biochemical, histological and ultrastructural evidences supporting the promising anti-hypertrophic effect of calanus oil against ISO-induced cardiac hypertrophy. This anti-hypertrophic effect of calanus oil is via regulating myocardial remodeling and oxidative stress. Therefore, it could be used as potential pharmacological intervention in the management of cardiac hypertrophy.


Assuntos
Miocárdio , Estresse Oxidativo , Humanos , Isoproterenol/toxicidade , Isoproterenol/metabolismo , Miocárdio/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/prevenção & controle , Cardiomegalia/patologia , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia
3.
Clin Sci (Lond) ; 137(2): 143-148, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36651286

RESUMO

The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hypertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to define the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular cardiac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated physiological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the 'RAF paradox'. Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex- and context-dependent manner.


Assuntos
Cardiomegalia , Proteínas Proto-Oncogênicas B-raf , Masculino , Camundongos , Feminino , Animais , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Cardiomegalia/patologia , Sistema de Sinalização das MAP Quinases , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno , Fibrose , Miócitos Cardíacos/metabolismo
4.
Phytomedicine ; 109: 154543, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610158

RESUMO

BACKGROUND: Cardiac hypertrophy can lead to cardiac dysfunction and is closely associated with mortality in diabetic cardiomyopathy (DCM). Astragalus polysaccharides (APS) is the main component extracted from Astragalus membranaceus (Fisch.) Bunge (AM), which exhibits anti-hypertrophic effects on cardiomyocytes in various diseases. However, whether APS exerts anti-hypertrophic effects in DCM remains unclear. PURPOSE: To investigate whether APS can attenuate cardiac hypertrophy in DCM and exert anti-hypertrophic effects by inhibiting the bone morphogenetic protein 10 (BMP10) pathway. METHODS: The anti-hypertrophic effects of APS were studied in high-glucose (HG)-stimulated H9c2 cardiomyocytes and streptozotocin (STZ)-induced DCM rats. BMP10 siRNA was used to inhibit BMP10 expression in H9c2 cardiomyocytes. Cardiac function was assessed by echocardiography. Cardiac hypertrophy was evaluated using heart weight/body weight (HW/BW), RT-PCR, hematoxylin-eosin (HE), and rhodamine phalloidin staining. Changes in hypertrophic components, including BMP10 and downstream factors, were measured using western blotting. RESULTS: In vitro, HG treatment increased the relative cell surface area of H9c2 cardiomyocytes, whereas BMP10 siRNA transfection or APS treatment alleviated the increase induced by HG. APS treatment improved the general condition, increased cardiac function, and decreased the HW/BW ratio, ANP mRNA level, and cardiomyocyte cross-sectional area of DCM rats in vivo. Molecular experiments demonstrated that APS downregulated the levels of the pro-hypertrophic protein BMP10 and its downstream proteins ALK3, BMPRII, and p-Smad1/5/8 without affecting the level of total Smad1/5/8. CONCLUSIONS: Our study demonstrates that APS can alleviate cardiac hypertrophy and protect against DCM by inhibiting activation of the BMP10 pathway. APS is a promising candidate for DCM treatment.


Assuntos
Astrágalo (Planta) , Diabetes Mellitus , Cardiomiopatias Diabéticas , Ratos , Animais , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Cardiomegalia/induzido quimicamente , Transdução de Sinais , Miócitos Cardíacos , Polissacarídeos/farmacologia , RNA Interferente Pequeno/farmacologia , Proteínas Morfogenéticas Ósseas/metabolismo , Diabetes Mellitus/tratamento farmacológico
5.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674423

RESUMO

The incidence of heart failure mainly resulting from cardiac hypertrophy and fibrosis increases sharply in post-menopausal women compared with men at the same age, which indicates a cardioprotective role of estrogen. Previous studies in our group have shown that the novel estrogen receptor G Protein Coupled Receptor 30 (GPR30) could attenuate myocardial fibrosis caused by ischemic heart disease. However, the role of GPR30 in myocardial hypertrophy in ovariectomized mice has not been investigated yet. In this study, female mice with bilateral ovariectomy or sham surgery underwent transverse aortic constriction (TAC) surgery. After 8 weeks, mice in the OVX + TAC group exhibited more severe myocardial hypertrophy and fibrosis than mice in the TAC group. G1, the specific agonist of GPR30, could attenuate myocardial hypertrophy and fibrosis of mice in the OVX + TAC group. Furthermore, the expression of LC3II was significantly higher in the OVX + TAC group than in the OVX + TAC + G1 group, which indicates that autophagy might play an important role in this process. An in vitro study showed that G1 alleviated AngiotensionII (AngII)-induced hypertrophy and reduced the autophagy level of H9c2 cells, as revealed by LC3II expression and tandem mRFP-GFP-LC3 fluorescence analysis. Additionally, Western blot results showed that the AKT/mTOR pathway was inhibited in the AngII group, whereas it was restored in the AngII + G1 group. To further verify the mechanism, PI3K inhibitor LY294002 or autophagy activator rapamycin was added in the AngII + G1 group, and the antihypertrophy effect of G1 on H9c2 cells was blocked by LY294002 or rapamycin. In summary, our results demonstrate that G1 can attenuate cardiac hypertrophy and fibrosis and improve the cardiac function of mice in the OVX + TAC group through AKT/mTOR mediated inhibition of autophagy. Thus, this study demonstrates a potential option for the drug treatment of pressure overload-induced cardiac hypertrophy in postmenopausal women.


Assuntos
Estenose da Valva Aórtica , Proteínas Proto-Oncogênicas c-akt , Camundongos , Feminino , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Estrogênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Estenose da Valva Aórtica/patologia , Autofagia , Fibrose , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miocárdio/metabolismo
6.
Life Sci ; 313: 121277, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36521546

RESUMO

AIMS: Prostaglandin E2 (PGE2) is a lipid hormone that signals through 4 different G-protein coupled receptor subtypes which act to regulate key physiological processes. Our laboratory has previously reported that PGE2 through its EP3 receptor reduces cardiac contractility at the level of isolated cardiomyocytes and in the isolated working heart preparation. We therefore hypothesized that cardiomyocyte specific overexpression of the PGE2 EP3 receptor further decreases cardiac function in a mouse model of heart failure produced by myocardial infarction. MAIN METHODS: Our study tested this hypothesis using EP3 transgenic mice (EP3 TG), which overexpress the porcine analogue of human EP3 in the cardiomyocytes, and their wildtype (WT) littermates. Mice were analyzed 2 wks after myocardial infarction (MI) or sham operation by echocardiography, RT-PCR, immunohistochemistry, and histology. KEY FINDINGS: We found that the EP3 TG sham controls had a reduced ejection fraction, reduced fractional shortening, and an increased left ventricular dimension at systole and diastole compared to the WT sham controls. Moreover, there was a further reduction in the EP3 TG mice after myocardial infarction. Additionally, single-cell analysis of cardiomyocytes isolated from EP3 TG mice showed reduced contractility under basal conditions. Overexpression of EP3 significantly increased cardiac hypertrophy, interstitial collagen fraction, macrophage, and T-cell infiltration in the sham operated group. Interestingly, after MI, there were no changes in hypertrophy but there were changes in collagen fraction, and inflammatory cell infiltration. SIGNIFICANCE: Overexpression of EP3 reduces cardiac function under basal conditions and this is exacerbated after myocardial infarction.


Assuntos
Infarto do Miocárdio , Miócitos Cardíacos , Animais , Humanos , Camundongos , Cardiomegalia , Colágeno/farmacologia , Dinoprostona , Camundongos Transgênicos , Infarto do Miocárdio/patologia , Receptores de Prostaglandina , Suínos
7.
Function (Oxf) ; 4(1): zqac055, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36540889

RESUMO

We aimed to determine the pathophysiological impact of heart rate (HR) slowing on cardiac function. We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (Gαs) in the sinoatrial (SA) node after the addition of tamoxifen using cre-loxP technology. The addition of tamoxifen leads to bradycardia. We used this approach to examine the physiological and pathophysiological effects of HR slowing. We first looked at the impact on exercise performance by running the mice on a treadmill. After the addition of tamoxifen, mice with conditional deletion of Gαs in the SA node ran a shorter distance at a slower speed. Littermate controls preserved their exercise capacity after tamoxifen. Results consistent with impaired cardiac capacity in the mutants were also obtained with a dobutamine echocardiographic stress test. We then examined if HR reduction influenced pathological cardiac hypertrophy using two models: ligation of the left anterior descending coronary artery for myocardial infarction and abdominal aortic banding for hypertensive heart disease. In littermate controls, both procedures resulted in cardiac hypertrophy. However, induction of HR reduction prior to surgical intervention significantly ameliorated the hypertrophy. In order to assess potential protein kinase pathways that may be activated in the left ventricle by relative bradycardia, we used a phospho-antibody array and this revealed selective activation of phosphoinositide-3 kinase. In conclusion, HR reduction protects against pathological cardiac hypertrophy but limits physiological exercise capacity.


Assuntos
Bradicardia , Cardiomegalia , Camundongos , Animais , Frequência Cardíaca , Cardiomegalia/genética , Coração , Tamoxifeno/farmacologia
8.
J Cell Physiol ; 238(1): 242-256, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36538623

RESUMO

Myocardial hypertrophy is associated with a significant increase in intracellular Ca2+ , which can be induced by long-chain fatty acid. Palmitic acid methyl ester (PAME), a fatty acid ester released from adipose tissue, superior cervical ganglion, and retina, has been found to have anti-inflammation, antifibrosis, and peripheral vasodilation effects. However, the effects of PAME on cardiomyocytes are still unclear. The aim of this study was to determine whether PAME could disrupt the intracellular Ca2+ balance, leading to cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were treated with various concentrations (10-100 µM) of PAME for 1-4 days. Cytosolic Ca2+ and mitochondrial Ca2+ concentrations were examined using Fura-2 AM and Rhod-2, respectively. After treatment with PAME for 4 days, mitochondrial Ca2+ , an indicator of the state of mitochondrial permeability transition pore (MPTP), and cell death were monitored by flow cytometric analysis. ATP levels were detected using the ATP assay kit. Cardiomyocyte hypertrophy was analyzed by measuring the cardiac hypertrophy biomarker and cell area using quantitative real time-polymerase chain reaction, Western Blot analysis and immunofluorescence analysis. Our results show that PAME concentration- and time-dependently increased cytosolic and mitochondria Ca2+ through the mitochondrial calcium uniporter. Moreover, treatment with PAME for 4 days caused MPTP opening, thereby reducing ATP production and enhancing reactive oxygen species (ROS) generation, and finally led to cardiomyocyte hypertrophy. These effects caused by PAME treatment were attenuated by the G-protein coupled receptor 40 (GPR40) inhibitor. In conclusion, PAME impaired mitochondrial function, which in turn led to cardiomyocyte hypertrophy through increasing the mitochondrial Ca2+ levels mediated by activating the GPR40 signaling pathway.


Assuntos
Cálcio , Mitocôndrias , Palmitatos , Receptores Acoplados a Proteínas G , Animais , Ratos , Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Palmitatos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Células Cultivadas
9.
Pharmacol Res ; 187: 106607, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36509316

RESUMO

BACKGROUND: As a pathological myocardial remodeling process in a variety of cardiovascular diseases, cardiac hypertrophy still has no effective treatment. Human mesenchymal stem cells (hMSCs) derived extracellular vesicles (EVs) has been recognized as a promising treatment strategy for cardiac disease. METHODS: In this study, the inhibitory effects on cardiac hypertrophy are compared between normoxia-conditioned hMSC-derived EVs (Nor-EVs) and hypoxia-conditioned hMSC-derived EVs (Hypo-EVs) in neonatal rat cardiomyocytes (NRCMs) after angiotensin II (Ang II) stimulation and in a mouse model of transverse aortic constriction (TAC). RESULTS: We demonstrate that Hypo-EVs exert an increased inhibitory effect on cardiac hypertrophy compared with Nor-EVs. Parkinson disease protein 7 (PARK7/DJ-1) is identify as a differential protein between Nor-EVs and Hypo-EVs by quantitative proteomics analysis. Results show that DJ-1, which is rich in Hypo-EVs, alleviates mitochondrial dysfunction and excessive mitochondrial reactive oxygen species (mtROS) production as an antioxidant. Mechanistic studies demonstrate for the first time that DJ-1 may suppress cardiac hypertrophy by inhibiting the activity of proteasome subunit beta type 10 (PSMB10) through a direct physical interaction. This interaction can inhibit angiotensin II type 1 receptor (AT1R)-mediated signaling pathways resulting in cardiac hypertrophy through alleviating ubiquitination degradation of AT1R-associated protein (ATRAP). CONCLUSIONS: When taken together, our study suggests that Hypo-EVs have significant potential as a novel therapeutic agent for the treatment of cardiac hypertrophy.


Assuntos
Vesículas Extracelulares , Células-Tronco Mesenquimais , Camundongos , Ratos , Humanos , Animais , Cardiomegalia/metabolismo , Proteólise , Transdução de Sinais , Vesículas Extracelulares/metabolismo , Miócitos Cardíacos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Desglicase DJ-1/metabolismo , Proteína Desglicase DJ-1/farmacologia
10.
Pharm Biol ; 61(1): 61-68, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36548192

RESUMO

CONTEXT: Andrographolide (Andr) is a bioactive Andr diterpenoid extracted from herbaceous Andrographis paniculata (Burm. F.) Wall. ex Nees (Acanthaceae). Andr can relieve cardiac dysfunction in mice by inhibiting the mitogen-activated protein kinases (MAPK) pathway. OBJECTIVE: This study investigates the efficacy and underlying mechanism of Andr on cardiac hypertrophy in mice. MATERIALS AND METHODS: Male C57 mice (20-25 g, 6-8 weeks) were divided into four groups (n = 10 mice/group) as sham group (sham operation), transverse aortic constriction (TAC) model group, TAC + Andr 100 mg/kg group and TAC + Andr 200 mg/kg group. Andr groups were given intragastric administration of Andr (100 and 200 mg/kg) once a day for 14 consecutive days. An in vitro hypertrophy model was established by adding 1 µM of Ang II to H9c2 cells for 48 h induction. RESULTS: In TAC-mice, Andr improved echocardiographic indices [reduced LVESD (30.4% or 37.1%) and LVEDD (24.8% or 26.4%), increased EF (22.9% or 42.6%) and FS (25.4% or 52.2%)], reduced BNP (11.5% or 23.6%) and Ang II levels (10.3% or 32.8%), attenuates cardiac fibrosis and reduces cardiac cell apoptosis in TAC mice. In vitro, Andr attenuated cardiomyocyte hypertrophy and decreased the protein expression of GRP78 (67.8%), GRP94 (47.6%), p-PERK (44.9%) and CHOP (66.8%) in Ang-II-induced H9c2 cells and reversed after endoplasmic reticulum (ER) stress agonist Tunicamycin (TN) treatment. DISCUSSION AND CONCLUSIONS: Andr was found to be an anti-hypertrophic regulator, which could attenuate cardiac hypertrophy by suppressing ER stress. It may be a new therapeutic drug for cardiac hypertrophy.


Assuntos
Cardiomegalia , Diterpenos , Animais , Masculino , Camundongos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Estresse do Retículo Endoplasmático , Fibrose , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia
11.
Cell Death Dis ; 13(12): 1073, 2022 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-36572672

RESUMO

The failing heart is characterized by an increase in glucose uptake and glycolytic rates that is not accompanied by a concomitant increase in glucose oxidation. Lower coupling of glucose oxidation to glycolysis possibly owes to unchanged or reduced pyruvate oxidation in mitochondria. Therefore, increasing pyruvate oxidation may lead to new therapies for heart disease. Dihydrolipoamide dehydrogenase (DLD) is a component of the pyruvate dehydrogenase complex (PDH). DLD mutations or defects are closely associated with metabolic diseases. However, few studies explore the effects of DLD mutants or acylation status on PDH activity and pyruvate metabolism. P300 is protein 2-hydroxyisobutyryltransferases in cells, and P300-dependent lysine 2-hydroxyisobutyrylation of glycolytic enzymes affects glucose metabolism. However, there are no relevant reports on the effect of 2-hydroxyisobutyrylation on the energy metabolism of heart failure, and it is worth further in-depth study. In this study, we showed that 2-hydroxyisobutyrylation is an essential protein translational modification (PTM) that regulates the activity of pyruvate dehydrogenase complex (PDHc). In a mouse model of transverse aortic constriction (TAC)-induced cardiac hypertrophy, the 2-hydroxyisobutylation of DLD was significantly increased, related to the decrease in PDH activity. In addition, our data provide clear evidence that DLD is a direct substrate of P300. As one of the main active ingredients of ginseng, ginsenoside Rg3 (Rg3) can reduce the 2-hydroxyisobutylation levels of DLD and restore the PDH activity by inhibiting the acyltransferase activity of P300, thereby producing beneficial effects whenever the heart is injured. Therefore, this study suggests a novel strategy for reversing myocardial hypertrophy.


Assuntos
Di-Hidrolipoamida Desidrogenase , Ácido Pirúvico , Camundongos , Animais , Di-Hidrolipoamida Desidrogenase/genética , Complexo Piruvato Desidrogenase/metabolismo , Cardiomegalia/genética , Glucose/metabolismo
12.
Stem Cell Res Ther ; 13(1): 529, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36544188

RESUMO

BACKGROUND: Tissue organoids generated from human pluripotent stem cells are valuable tools for disease modelling and to understand developmental processes. While recent progress in human cardiac organoids revealed the ability of these stem cell-derived organoids to self-organize and intrinsically formed chamber-like structure containing a central cavity, it remained unclear the processes involved that enabled such chamber formation. METHODS: Chambered cardiac organoids (CCOs) differentiated from human embryonic stem cells (H7) were generated by modulation of Wnt/ß-catenin signalling under fully defined conditions, and several growth factors essential for cardiac progenitor expansion. Transcriptomic profiling of day 8, day 14 and day 21 CCOs was performed by quantitative PCR and single-cell RNA sequencing. Endothelin-1 (EDN1) known to induce oxidative stress in cardiomyocytes was used to induce cardiac hypertrophy in CCOs in vitro. Functional characterization of cardiomyocyte contractile machinery was performed by immunofluorescence staining and analysis of brightfield and fluorescent video recordings. Quantitative PCR values between groups were compared using two-tailed Student's t tests. Cardiac organoid parameters comparison between groups was performed using two-tailed Mann-Whitney U test when sample size is small; otherwise, Welch's t test was used. Comparison of calcium kinetics parameters derived from the fluorescent data was performed using two-tailed Student's t tests. RESULTS: Importantly, we demonstrated that a threshold number of cardiac progenitor was essential to line the circumference of the inner cavity to ensure proper formation of a chamber within the organoid. Single-cell RNA sequencing revealed improved maturation over a time course, as evidenced from increased mRNA expression of cardiomyocyte maturation genes, ion channel genes and a metabolic shift from glycolysis to fatty acid ß-oxidation. Functionally, CCOs recapitulated clinical cardiac hypertrophy by exhibiting thickened chamber walls, reduced fractional shortening, and increased myofibrillar disarray upon treatment with EDN1. Furthermore, electrophysiological assessment of calcium transients displayed tachyarrhythmic phenotype observed as a consequence of rapid depolarization occurring prior to a complete repolarization. CONCLUSIONS: Our findings shed novel insights into the role of progenitors in CCO formation and pave the way for the robust generation of cardiac organoids, as a platform for future applications in disease modelling and drug screening in vitro.


Assuntos
Doenças Cardiovasculares , Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Humanos , Doenças Cardiovasculares/metabolismo , Cálcio/metabolismo , Organoides/metabolismo , Diferenciação Celular/fisiologia , Miócitos Cardíacos/metabolismo , Cardiomegalia/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo
13.
BMJ Case Rep ; 15(12)2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36535739

RESUMO

The neonatal form of carnitine palmitoyltransferase II (CPT II) deficiency is a rare lethal inherited disorder of fatty acid oxidation. Carnitine essentially transfers long-chain fatty acids across the mitochondrial membranes for ß-oxidation, where CPT II plays a key role. CPT II deficiency phenotypical forms include lethal neonatal, severe infantile and myopathic forms. We present a term small-for-gestational-age neonate with hypoglycaemia, seizures, refractory cardiac arrhythmias and intracranial haemorrhage. Plasma acylcarnitine profile and the genetic study confirmed CPT II deficiency. Additionally, likely pathogenic variants in the SLC22A5 gene point to primary carnitine deficiency. Antenatal findings of polycystic kidney disease and cardiomegaly were confirmed postnatally. All supportive measures, including extracorporeal life support, failed to improve the clinical course, and the baby succumbed. Major renal, cerebral and cardiac anomalies were reported with CPT II deficiency. In our case, fetal polycystic nephromegaly and cardiomegaly with parental consanguinity should have signalled the possibility of this disorder.


Assuntos
Carnitina O-Palmitoiltransferase , Erros Inatos do Metabolismo Lipídico , Lactente , Recém-Nascido , Humanos , Feminino , Gravidez , Carnitina O-Palmitoiltransferase/genética , Erros Inatos do Metabolismo Lipídico/genética , Ácidos Graxos , Cardiomegalia , Feto , Carnitina , Membro 5 da Família 22 de Carreadores de Soluto
14.
Front Endocrinol (Lausanne) ; 13: 1029750, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568083

RESUMO

Introduction: Quercetin (Que) is a potent anti-inflammatory and antioxidant flavonoid with cardioprotective potential. However, very little is known about the signaling pathways and gene regulatory proteins Que may interfere with, especially in diabetic cardiomyopathy. Therefore, we aimed to study the potential cardioprotective effects of Que on the cardiac phenotype of type 2 diabetes mellitus (T2DM) accompanied by obesity. Methods: For this experiment, we used Zucker Diabetic Fatty rats (fa/fa) and their age-matched lean controls (fa/+) that were treated with either vehicle or 20 mg/kg/day of Que for 6 weeks. Animals underwent echocardiographic (echo) examination before the first administration of Que and after 6 weeks. Results: After the initial echo examination, the diabetic rats showed increased E/A ratio, a marker of left ventricular (LV) diastolic dysfunction, in comparison to the control group which was selectively reversed by Que. Following the echo analysis, Que reduced LV wall thickness and exhibited an opposite effect on LV luminal area. In support of these results, the total collagen content measured by hydroxyproline assay was decreased in the LVs of diabetic rats treated with Que. The follow-up immunoblot analysis of proteins conveying cardiac remodeling pathways revealed that Que was able to interfere with cardiac pro-hypertrophic signaling. In fact, Que reduced relative protein expression of pro-hypertrophic transcriptional factor MEF2 and its counter-regulator HDAC4 along with pSer246-HDAC4. Furthermore, Que showed potency to decrease GATA4 transcription factor, NFAT3 and calcineurin, as well as upstream extracellular signal-regulated kinase Erk5 which orchestrates several pro-hypertrophic pathways. Discussion: In summary, we showed for the first time that Que ameliorated pro-hypertrophic signaling on the level of epigenetic regulation and targeted specific upstream pathways which provoked inhibition of pro-hypertrophic signals in ZDF rats. Moreover, Que mitigated T2DM and obesity-induced diastolic dysfunction, therefore, might represent an interesting target for future research on novel cardioprotective agents.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Disfunção Ventricular Esquerda , Ratos , Animais , Quercetina/farmacologia , Quercetina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Epigênese Genética , Ratos Zucker , Cardiomegalia/genética , Disfunção Ventricular Esquerda/complicações , Obesidade/complicações
15.
J Am Heart Assoc ; 11(24): e027363, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36515236

RESUMO

Background Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high-output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. Methods and Results We sought to systematically characterize high-output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain-of-function variants in ABCC9, which encodes cardiovascular KATP (ATP-sensitive potassium) channel subunits. We studied the cardiovascular phenotype longitudinally in 31 subjects with CS with confirmed ABCC9 variants (median [interquartile range] age 8 years [3-32 years], body mass index 19.9 [16.5-22.9], 16 male subjects). Subjects with CS presented with significant left ventricular hypertrophy (left ventricular mass index 86.7 [57.7-103.0] g/m2 in CS, n=30; 26.6 [24.1-32.8] g/m2 in controls, n=17; P<0.0001) and low blood pressure (systolic 94.5 [90-103] mm Hg in CS, n=17; 109 [98-115] mm Hg in controls, n=17; P=0.0301; diastolic 60 [56-66] mm Hg in CS, n=17; 69 [65-72] mm Hg in control, n=17; P=0.0063). Most (21/31) subjects with CS exhibited eccentric hypertrophy with normal left ventricular wall thickness. Congestive heart failure symptoms were evident in 4 of the 5 subjects with CS aged >40 years on long-term follow-up. Conclusions The data define the natural history of high-output cardiac hypertrophy resulting from decreased systemic vascular resistance in subjects with CS, a defining population for long-term consequences of high-output hypertrophy caused by low systemic vascular resistance, and the potential for progression to high-output heart failure.


Assuntos
Cardiomegalia , Insuficiência Cardíaca , Hipertricose , Hipertrofia Ventricular Esquerda , Osteocondrodisplasias , Humanos , Masculino , Trifosfato de Adenosina , Cardiomegalia/genética , Insuficiência Cardíaca/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/complicações , Canais KATP , Fenótipo , Resistência Vascular , Feminino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Osteocondrodisplasias/genética , Hipertricose/genética
16.
Cell Mol Biol (Noisy-le-grand) ; 68(7): 85-89, 2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-36495513

RESUMO

An experiment was carried out to investigate the effect of hesperetin on isoproterenol-induced H9C2 cardiomyocyte hypertrophy and its possible mechanism. For this aim, H9C2 cardiomyocytes were coincubated with different concentrations of hesperetin (0.125, 0.25, 0.5, 1µmol/L) and isoproterenol to detect the changes in the area of H9C2 cells, the expression of cardiac hypertrophy marker ß-MHC mRNA and autophagy marker LC3II; H9C2 cells were coincubated with hesperetin and isoproterenol at the optimal intervention concentration, and the intervention time was set to 6h, 12h, 24h, respectively, and the changes of H9C2 cell area, ß-MHC mRNA and LC3II expression were detected. Results showed that hesperetin could reduce isoproterenol-induced H9C2 cardiomyocyte area enlargement; hesperetin can reduce ß-MHC mRNA expression in isoproterenol-induced H9C2 cardiomyocyte; hesperetin can increase the expression level of LC3II in isoproterenol-induced H9C2 cardiomyocyte. Conclusion Hesperetin may improve the hypertrophy of H9C2 cardiomyocytes induced by isoproterenol by activating autophagy.


Assuntos
Cardiomegalia , Miócitos Cardíacos , Humanos , Isoproterenol/toxicidade , Miócitos Cardíacos/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Autofagia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Sci Rep ; 12(1): 19130, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352008

RESUMO

The computer-aided diagnosis (CAD) for chest X-rays was developed more than 50 years ago. However, there are still unmet needs for its versatile use in our medical fields. We planned this study to develop a multipotent CAD model suitable for general use including in primary care areas. We planned this study to solve the problem by using computed tomography (CT) scan with its one-to-one matched chest X-ray dataset. The data was extracted and preprocessed by pulmonology experts by using the bounding boxes to locate lesions of interest. For detecting multiple lesions, multi-object detection by faster R-CNN and by RetinaNet was adopted and compared. A total of twelve diagnostic labels were defined as the followings: pleural effusion, atelectasis, pulmonary nodule, cardiomegaly, consolidation, emphysema, pneumothorax, chemo-port, bronchial wall thickening, reticular opacity, pleural thickening, and bronchiectasis. The Faster R-CNN model showed higher overall sensitivity than RetinaNet, nevertheless the values of specificity were opposite. Some values such as cardiomegaly and chemo-port showed excellent sensitivity (100.0%, both). Others showed that the unique results such as bronchial wall thickening, reticular opacity, and pleural thickening can be described in the chest area. As far as we know, this is the first study to develop an object detection model for chest X-rays based on chest area defined by CT scans in one-to-one matched manner, preprocessed and conducted by a group of experts in pulmonology. Our model can be a potential tool for detecting the whole chest area with multiple diagnoses from a simple X-ray that is routinely taken in most clinics and hospitals on daily basis.


Assuntos
Atelectasia Pulmonar , Tomografia Computadorizada por Raios X , Humanos , Raios X , Tomografia Computadorizada por Raios X/métodos , Radiografia , Cardiomegalia
18.
Commun Biol ; 5(1): 1251, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36380187

RESUMO

Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and α myosin heavy chain R403Q (R403Q-αMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-αMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirm the above-described pathways and the effectiveness of AG-825 Treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models.


Assuntos
Cardiomiopatia Hipertrófica , Proteoma , Camundongos , Animais , Proteoma/metabolismo , Fosforilação , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Cardiomegalia , Serina/metabolismo , Treonina/metabolismo , Tirosina/metabolismo
19.
J Am Heart Assoc ; 11(22): e027004, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36370010

RESUMO

Background SENP1 (sentrin/small ubiquitin-like modifier-specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload-induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac-specific SENP1 knockdown markedly exacerbated transverse aortic constriction-induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus-mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1-JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte-specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy-promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post-transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload-induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.


Assuntos
Cardiomegalia , Remodelação Ventricular , Animais , Humanos , Camundongos , Ratos , Cardiomegalia/genética , Cardiomegalia/prevenção & controle , Cardiomegalia/metabolismo , Cisteína Endopeptidases/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Remodelação Ventricular/fisiologia
20.
J Tradit Chin Med ; 42(6): 892-899, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36378046

RESUMO

OBJECTIVE: To investigate whether peroxisome proliferator-activated receptor γ-coactivator-1α/nuclear respiratory factor 1 (PGC-1α/NRF1) activity can protect mitochondrial function in the setting of cardiac hypertrophy and improve cardiomyocyte energy metabolism. METHODS: Cardiac hypertrophy was modeled in H9c2 cells treated with isoproterenol (ISO) to assess the effects of Shenge San (, SGS) on cell viability and mitochondrial membrane potential. We assessed mitochondrial complex mRNA levels and mitochondrial oxidative phosphorylation factor mRNA and protein levels. RESULTS: Compared with the 100 µM ISO group, cell size was significantly decreased in the 0.3 mg/mL SGS and 20 µM ZLN005 (PGC-1α activator) groups ( < 0.01). Compared with the SGS (0.3) +ISO group, we observed lower phosphorylated adenosine monophosphate-activated kinase (AMPK) protein levels in the ISO and ZLN005+SGS+ISO groups ( < 0.01). Compared with the compound C group, SGS significantly increased PGC-1α expression in ISO-induced cardiac hypertrophy cells ( < 0.01), and this was inhibited by compound C pretreatment ( < 0.05). Compared with the ISO group, the mitochondrial red-green fluorescence ratio increased in the 0.3 mg/mL SGS group ( < 0.05). mRNA levels of cytochrome c oxidase subunit 1 (CO1) in the ISO and compound C groups were lower than those in control group ( 0.01), and the mRNA levels of CO1 and ATP8 were significantly lower in the ISO and compound C groups versus control ( 0.01). Compared with the SGS (0.3) +ISO group, ATP synthetase subunit 8 (ATP8) mRNA was significantly decreased in the ISO group ( < 0.01) and compound C+SGS+ISO group ( < 0.05). Compared with the SGS (0.3) +ISO group, NRF1 mRNA levels were significantly decreased ( < 0.05) in the ISO and compound C+SGS+ISO groups. CONCLUSIONS: SGS can attenuate ISO-induced cardiomyocyte hypertrophy, restore the decrease in mitochondrial membrane potential, and upregulate PGC-1α/NRF1 levels. Notably, these effects can be blocked by AMPK inhibitor-compound C.


Assuntos
Proteínas Quinases Ativadas por AMP , Miócitos Cardíacos , Humanos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/farmacologia , Transdução de Sinais , Mitocôndrias , Isoproterenol/efeitos adversos , Isoproterenol/metabolismo , Cardiomegalia/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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