RESUMO
Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30 min followed by 4 h reperfusion. The mice were treated with NG-R1 (25 mg/kg, i.p.) every 2 h for 3 times starting 30 min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25 µM) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor ß-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.
Assuntos
Ginsenosídeos , Traumatismo por Reperfusão Miocárdica , Camundongos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Ginsenosídeos/metabolismo , Miocárdio , Miócitos Cardíacos , ApoptoseRESUMO
BACKGROUND: Drug-coated balloon (DCB) is a novel and effective device for coronary artery disease patients with in-stent restenosis (ISR). However, the incidence and possible influencing factors associated with binary restenosis have not yet been adequately assessed. METHODS: The data are extracted from a prospective, multicenter, randomized controlled trial. A total of 211 patients with ISR were enrolled at 13 centers from August 2017 to October 2018 and treated with DCB. At the 9-month coronary angiographic follow-up, patients were divided into restenosis and non-restenosis groups, and demographic data, lesion features, and laboratory tests were retrospectively reviewed. Furthermore, logistic regression analysis was used to identify possible influencing factors. RESULTS: All patients successfully underwent treatment, and 166 patients with 190 lesions took part in angiography follow-ups at 9 months. Of these, 41 patients with 44 target lesions developed restenosis following treatment, and the incidence of ISR was 24.7%. There were significant differences in the average length of target lesions and the number of multivessel lesions and fasting plasma glucose (FBG) between the two groups (p < 0.05). Demographic data, cardiac risk factors, left ventricular ejection fractions (LVEF), blood routine tests, biochemical tests, and other features of devices and lesions showed no difference. Logistic regression analyses showed that FBG > 6.1 mmol/L (OR: 7.185 95% CI: 2.939-17.567 P < 0.001) and length of lesion (OR:1.046 95% CI: 1.001-1.093 P = 0.046) were associated risk factors. CONCLUSIONS: The longer length of lesions, more target lesions and FBG > 6.1 mmol/L per individual may be characteristics of patients showing ISR following treatment. Studies with larger sample size, and more complete follow-up data are needed in the future to expend on these findings. TRIAL REGISTRATION: No.: NCT04213378, first posted date (30/12/2019).
Assuntos
Angioplastia com Balão , Reestenose Coronária , Humanos , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/epidemiologia , Reestenose Coronária/etiologia , Incidência , Estudos Retrospectivos , Estudos Prospectivos , Angioplastia com Balão/efeitos adversos , Constrição Patológica/complicaçõesRESUMO
OBJECTIVES: This study sought to compare the efficacy and clinical safety of the LONGTY drug-coated balloon (DCB) with those of SeQuent Please DCB in patients with in-stent restenosis (ISR). BACKGROUND: Although DCB technologies have evolved, little is known about the clinical efficacy of the new-generation LONGTY DCB. METHODS: This was a prospective, multicenter, randomized, noninferiority trial comparing LONGTY DCB with SeQuent Please DCB in patients with ISR. The primary endpoint was target lesion late lumen loss at 9 months' follow-up. RESULTS: A total of 211 patients with ISR from 13 Chinese sites were included (LONGTY DCB, n = 105; SeQuent Please DCB, n = 106). Device success was achieved in all patients. At the 9 month angiographic follow-up, target lesion late lumen loss was 0.35 ± 0.42 mm with LONGTY and 0.38 ± 0.45 mm with SeQuent Please (p for noninferiority <.001). The target lesion revascularization rates at 1 year were similar in both DCB groups (15.24 vs. 13.21%; p = .673). Over an extended follow-up of 2 years, the clinical endpoints, including cardiac death, myocardial infarction, and thrombus rate, were extremely low and similar in both groups. CONCLUSIONS: In this multicenter, head-to-head, randomized trial, the new-generation LONGTY DCB was noninferior to the SeQuent Please DCB for the primary endpoint of target lesion late lumen loss at 9 months.
Assuntos
Angioplastia Coronária com Balão , Fármacos Cardiovasculares , Reestenose Coronária , Stents Farmacológicos , Angioplastia Coronária com Balão/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , China , Materiais Revestidos Biocompatíveis , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/etiologia , Reestenose Coronária/terapia , Humanos , Paclitaxel/efeitos adversos , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Transforming growth factor ß-activated protein kinase 1 (TAK1) involves in various biological responses and is a key regulator of cell death. However, the role of TAK1 on acute myocardial ischaemia/reperfusion (MI/R) injury is unknown. We observed that TAK1 activation increased significantly after MI/R and hypoxia/reoxygenation (H/R), and we hypothesized that TAK1 has an important role in MI/R injury. Mice (TAK1 inhibiting by 5Z-7-oxozeaenol or silencing by AAV9 vector) were exposed to MI/R injury. Primary cardiomyocytes (TAK1 silencing by siRNA; and overexpressing TAK1 by adenovirus vector) were used to induce H/R injury model in vitro. Inhibition of TAK1 significantly decreased MI/R-induced myocardial infarction area, reduced cell death and improved cardiac function. Mechanistically, TAK1 silencing suppressed MI/R-induced myocardial oxidative stress and attenuated endoplasmic reticulum (ER) stress both in vitro and in vivo. In addition, the inhibition of ROS by NAC partially reversed the damage of TAK1 in vitro. Our study presents the first direct evidence that inhibition of TAK1 mitigated MI/R injury, and TAK1 mediated ROS/ER stress/apoptosis signal pathway is important for the pathogenesis of MI/R injury.
Assuntos
Estresse do Retículo Endoplasmático , MAP Quinase Quinase Quinases/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Animais , Animais Recém-Nascidos , Apoptose , Regulação para Baixo , Ativação Enzimática , Inativação Gênica , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the clinic, with the characteristics of occult onset, rapid progression, and high degree of malignancy. Alpha fetoprotein (AFP) is the most important biomarker of HCC, which is widely used in early screening, diagnosis, and prognosis observation. A series of immunoassays have been developed and frequently used in the detection of AFP based on antibodies. Unfortunately, the shortcomings of antibodies, such as thermal unstable and fluctuant activity by batches, lead to the inaccuracy in the detection of AFP. In this study, aptamers instead of antibodies were adopted as the specific recognition element for AFP, aiming to seek an alternative strategy to immunoassays. An AFP-specific ssDNA aptamer was grafted to magnetic nanoparticles (Fe3O4@SiO2) via avidin-biotin interaction, and the resultant aptamer functionalized magnetic nanoparticles (Ap-MNPs) were adequately characterized and tested. The Ap-MNPs in solution exhibited a fast response to the outer magnetic field, and can be completely separated in several minutes. It was found that Ap-MNPs have good specificity to the target AFP, as the recovery of AFP (87.0%) was much higher than the competitive proteins IgG (38.9%), HSA (18.5%), and FIB (11.4%). A convenient and efficient label-free detection method of AFP in serum was developed based on Ap-MNPs in combination with high-performance liquid chromatography. The linearity of this method was over a range of 1-50 µg ml-1 with a correlation coefficient of 0.9999, and the limit of detection was 0.27 µg ml-1. This study indicated that aptamers are an ideal tool for the recognition and detection of biomarkers, and thus will find wide applications in clinical practice.
Assuntos
Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , Carcinoma Hepatocelular/sangue , DNA de Cadeia Simples/química , Neoplasias Hepáticas/sangue , Nanopartículas de Magnetita/química , alfa-Fetoproteínas/análise , Aptâmeros de Nucleotídeos/sangue , Biomarcadores/sangue , Técnicas Biossensoriais/instrumentação , Humanos , Nanotecnologia/métodosRESUMO
BACKGROUND: Breast cancer (BC) displays striking genetic, epigenetic and phenotypic diversity. N6-methyladenosine (m6A) in mRNA has emerged as a crucial epitranscriptomic modification that controls cancer self-renewal and cell fate. However, the key enzymes of m6A expression and function in human breast carcinogenesis remain unclear. METHODS: The expression of m6A methylases (METTL3, METTL14 and WTAP) and demethylases (FTO and ALKBH5) were analyzed by using ONCOMINE and The Cancer Genome Atlas databases and in 36 pairs of BC and adjacent non-cancerous tissue. The level of m6A in BC patients was detected by ELISA, and the function of m6A was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and transwell assay. The database of bc-GenExMiner v4.0, Kaplan-Meier Plotter and cBioPortal were queried for correlation, mutation and prognosis analysis of BC. RESULTS: The m6A methylases and demethylases were dysregulated in several major malignant tumors. Specifically, the expression of all m6A methylases was reduced in BC as compared with normal controls, but the demethylase ALKBH5 was induced in ONCOMINE databases and confirmed in clinical patients. METTL14 expression was positively correlated with METTL3 expression, and both showed high expression in normal breast-like and luminal-A and -B BC. Functionally, reducing m6A expression by overexpressing METTL14 and/or knockdown of ALKBH5 could inhibit breast cell viability, colony formation and cell migration. Furthermore, Kaplan-Meier, meta-analysis and univariate Cox assay showed that the expression of m6A members including METTL3, METTL14, WTAP and FTO but not their gene mutation and amplification, was tightly associated with cancer progression and poor survival. CONCLUSIONS: Changes of m6A modulators reduced m6A may promote tumorigenesis and predict poor prognosis in BC.
Assuntos
Adenosina/análogos & derivados , Neoplasias da Mama/patologia , Metiltransferases/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Adenosina/metabolismo , Adulto , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carcinogênese/genética , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Progressão da Doença , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metilação , Metiltransferases/genética , Pessoa de Meia-Idade , Mutação , Oxirredutases N-Desmetilantes/genética , Prognóstico , RNA Mensageiro/metabolismoRESUMO
The tumor suppressor p53 is recognized as the guardian of the genome in cell cycle and cell death. P53 expression increases as cardiac hypertrophy worsens to heart failure, suggesting that p53 may play important role in cardiac remodeling. In the present study, deletion of p53 in the mice heart would ameliorate cardiac hypertrophy induced by pressure overload. The role of p53 on heart was investigated using in vivo models. Cardiac hypertrophy in mice was induced by transverse aortic banding surgery. The extent of cardiac hypertrophy was examined by echocardiography, as well as pathological and molecular analyses of heart tissue. Global knockout of p53 in the mice reduced the hypertrophic response and markedly reduced cardiac apoptosis, and fibrosis. Ejection fraction of heart was also improved in hearts without p53 in response to pressure overload. Protein determination further suggested loss of p53 expression markedly increased Hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) expression. The study indicated p53 deteriorated cardiac functions and cardiac hypertrophy, apoptosis, and fibrosis by partially inhibition of HIF1α and VEGF.
Assuntos
Cardiomegalia/genética , Genes p53/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Remodelação Ventricular/fisiologia , Animais , Cardiomegalia/etiologia , Ecocardiografia , Fibrose/diagnóstico por imagem , Fibrose/genética , Regulação da Expressão Gênica , Marcadores Genéticos , Coração/diagnóstico por imagem , Masculino , Camundongos Knockout , Miocárdio/patologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Ventricular/genéticaRESUMO
We investigated the role of tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) on pressure overload-induced cardiac hypertrophy and the underlying molecular mechanisms by using a TRADD deficiency mice model. 6-8 weeks wild-type and TRADD knockout mice were performed to transverse aorta constriction (TAC) or sham operation (6-8 mice for each group). 14 days after TAC, cardiac function was measured by echocardiography, as well as by pathological and molecular analyses of heart samples. The expressions of cardiac hypertrophic and fibrotic markers were detected by qPCR. Phosphorylated and total TAK1, Akt, and p38 MAPK levels were examined by Western blotting. The ratios of lung or heart/body weight, wall thickness/chamber diameter of left ventricular and cross area of cardiomyocyte were significantly reduced in TRADD knockout (KO) mice than those of wild-type mice after TAC. Moreover, cardiac hypertrophic and fibrotic markers were downregulated in TRADD knockout mice than those of wild-type mice following TAC. Protein expression analysis showed phosphorylated TAK1, p38 MAPK and AKT were upregulated after TAC in both wild-type and TRADD KO mice, phosphorylation of TAK1 and p38 MAPK was reduced more remarkably after TRADD deficiency, while phosphorylated AKT expression was similar between TRADD KO and wild-type mice following TAC. Our data suggest that TRADD KO blunts pressure overload-induced cardiac hypertrophy through mediating TAK1/p38 MAPK but not AKT phosphorylation in mice.
Assuntos
Cardiomegalia/etiologia , MAP Quinase Quinase Quinases/metabolismo , Proteína de Domínio de Morte Associada a Receptor de TNF/deficiência , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Pressão Sanguínea/fisiologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Domínio de Morte Associada a Receptor de TNF/genética , Proteína de Domínio de Morte Associada a Receptor de TNF/metabolismo , Remodelação Ventricular/fisiologiaRESUMO
Increased oxidative stress and cardiac inflammation have been implicated in the pathogenesis of diabetic cardiomyopathy (DCM). We previously found that a novel chalcone derivative, L6H9, was able to reduce LPS-induced inflammatory response in macrophages. This study was designed to investigate its protective effects on DCM and the underlying mechanisms. H9C2 cells were cultured with DMEM containing 33 mmol/L of glucose in the presence or absence of L6H9. Pretreatment with L6H9 significantly reduced high glucose-induced inflammatory cytokine expression, ROS level increase, mitochondrial dysfunction, cell apoptosis, fibrosis, and hypertrophy in H9c2 cells, which may be mediated by NF-κB inhibition and Nrf2 activation. In mice with STZ-induced diabetes, oral administration of L6H9 at 20 mg/kg/day for 8 weeks significantly decreased the cardiac cytokine and ROS level, accompanied by decreasing cardiac apoptosis and hypertrophy, and, finally, improved histological abnormalities and fibrosis, without affecting the hyperglycemia. L6H9 also attenuated the diabetes-induced NF-κB activation and Nrf2 decrease in diabetic hearts. These results strongly suggest that L6H9 may have great therapeutic potential in the treatment of DCM via blockage of inflammation and oxidative stress. This study also provides a deeper understanding of the regulatory role of Nrf2 and NF-κB in DCM, indicating that they may be important therapeutic targets for diabetic complications.
Assuntos
Antioxidantes/farmacologia , Chalconas/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/uso terapêutico , Apoptose , Linhagem Celular , Chalconas/uso terapêutico , Cardiomiopatias Diabéticas/metabolismo , Hiperglicemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RatosRESUMO
Obesity and increased free fatty acid (FFA) level are tightly linked, leading to the development of cardiovascular disorders. Curcumin is a natural product from Curcuma longa with multiple bioactivities and is known to have cardioprotective effects in several cellular and animal models. The current study was designed to evaluate the cardioprotective effects of curcumin and demonstrate the underlying mechanism in FFA-induced cardiac injury. Using cell culture studies and high fat in vivo model, we explored the mechanistic basis of anti-inflammatory and antioxidant activities of curcumin. We observed that palmitate (PA) treatment in cardiac derived H9C2 cells induced a marked increase in reactive oxygen species, inflammation, apoptosis and hypertrophy. All of these changes were effectively suppressed by curcumin treatment. In addition, oral administration of curcumin at 50mg/kg completely suppressed high fat diet-induced oxidative stress, inflammation, apoptosis, fibrosis, hypertrophy and tissue remodeling in mice. The beneficial actions of curcumin are closely associated with its ability to increase Nrf2 expression and inhibit NF-κB activation. Thus, both in vitro and in vivo studies showed a promising role of curcumin as a cardioprotective agent against palmitate and high fat diet mediated cardiac dysfunction. We indicated the regulatory roles of Nrf2 and NF-κB in obesity-induced heart injury, and suggested that they may be important therapeutic targets in the treatment of obesity-related disorders.
Assuntos
Cardiotônicos/uso terapêutico , Curcumina/farmacologia , Ácidos Graxos não Esterificados/efeitos adversos , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiomegalia/complicações , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiotônicos/farmacologia , Linhagem Celular , Curcumina/administração & dosagem , Curcumina/uso terapêutico , Dieta Hiperlipídica , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Palmitatos/efeitos adversos , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Vascular endothelial growth factor (VEGF) inhibition has previously been shown to have damaging effects on the heart. Because the role of Flt-1 (a phosphotyrosine kinase receptor for VEGF) in cardiac function and hypertrophy is unclear, we generated mice lacking Flt-1 only in their cardiomyocytes (Flt-1 KO). The hearts from 8- to 10-week-old mice were measured by using echocardiography and histology. No significant differences were seen in fraction shortening, cross-sectional area of cardiomyocytes, and interstitial collagen fraction between littermate controls and KO mice at baseline. To test the hypothesis that Flt-1 is involved in cardiac remodeling, we performed transverse aorta constriction (TAC) by ligating the transverse ascending aorta. Four weeks after TAC, echocardiography of the mice was performed, and the hearts were excised for pathological analysis and Western blotting. No difference in mortality was found between Flt-1 KO mice and controls; however, KO mice showed a greater cardiomyocyte cross-sectional area and interstitial collagen fraction than controls. Western blotting indicated that AKT was activated less in Flt-1 KO hearts after TAC compared with that in control hearts. Thus, Flt-1 deletion in cardiomyocytes increased hypertrophy, fibrosis, and regression of AKT phosphorylation. Our study suggests that Flt-1 plays a critical role in cardiac hypertrophy induced by pressure overload via the activation of AKT, which seems to be cardioprotective.
Assuntos
Cardiomegalia/patologia , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Constrição Patológica , Ecocardiografia/métodos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Camundongos Knockout , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiênciaRESUMO
Cellular FLICE-like inhibitory protein (Flip) is a negative regulator of nuclear factor κB signaling which has been shown previously to complicate with cardiac hypertrophy. In the present study, we tested the hypothesis that the knockout of Flip would increase cardiac hypertrophy in vivo and in vitro. The effects of Flip knockout on cardiac hypertrophy were investigated using in vitro and in vivo models. Flip was downregulated in transverse aortic constriction (TAC)-induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 1 h. An in vivo, heart hypertrophy model, was performed by TAC in Flip knockdown and sham mice. The extent of hypertrophy of heart was quantitated by echocardiography, and further confirmed by pathological and molecular examination of heart tissue samples. Conditional knockout of Flip in the murine heart increases the hypertrophic response induced by TAC, whereas cardiac function was preserved with reduced Flip levels in response to hypertrophic stimuli. Western blot experiments further showed Flip knockout activated markedly ASK1/P38 signaling cascades in vivo and in vitro. In conclusion, Flip preserves cardiac functions and inhibits cardiac hypertrophy partially by blocking ASK1/P38 signaling.
Assuntos
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Cardiomegalia/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Cardiomegalia/genética , Cardiomegalia/patologia , Modelos Animais de Doenças , MAP Quinase Quinase Quinase 5/genética , Camundongos , Camundongos Knockout , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
BACKGROUND: Balloon burst during transcatheter aortic valve replacement (TAVR) is serious complication. This study pioneers a novel approach by combining image observation and computer simulation validation to unravel the mechanism of balloon burst in a patient with bicuspid aortic valve (BAV) stenosis. METHOD: A new computational model for balloon pre-dilatation was developed by incorporating the element failure criteria according to the Law of Laplace. The effects of calcification and aortic tissue material parameters, friction coefficients, balloon types and aortic anatomy classification were performed to validate and compare the expansion behavior and rupture mode of actual balloon. RESULTS: Balloon burst was dissected into three distinct stages based on observable morphological changes. The mechanism leading to the complete transverse burst of the non-compliant balloon initiated at the folding edges, where contacted with heavily calcified masses at the right coronary sinus, resulting in high maximum principal stress. Local sharp spiked calcifications facilitated rapid crack propagation. The elastic moduli of calcification significantly influenced balloon expansion behavior and crack morphology. The simulation case of the calcific elastic modulus was set at 12.6 MPa could closely mirror clinical appearance of expansion behavior and crack pattern. Furthermore, the case of semi-compliant balloons introduced an alternative rupture mechanism as pinhole rupture, driven by local sharp spiked calcifications. CONCLUSIONS: The computational model of virtual balloons could effectively simulate balloon dilation behavior and burst mode during TAVR pre-dilation. Further research with a larger cohort is needed to investigate the balloon morphology during pre-dilation by using this method to guide prosthesis sizing for potential favorable outcomes.
Assuntos
Estenose da Valva Aórtica , Calcinose , Doenças das Valvas Cardíacas , Próteses Valvulares Cardíacas , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/métodos , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Dilatação , Simulação por Computador , Análise de Elementos Finitos , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Calcinose/diagnóstico por imagem , Calcinose/cirurgia , Resultado do Tratamento , Desenho de PróteseRESUMO
BACKGROUND: Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear. METHODS: A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway. RESULTS: Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3). CONCLUSIONS: Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.
Assuntos
Insuficiência Cardíaca , MicroRNAs , Miocardite , Camundongos , Animais , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Insuficiência Cardíaca/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Miócitos Cardíacos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Cardiomegalia/patologia , Miocardite/genética , Miocardite/prevenção & controle , Inflamação/patologia , Modelos Animais de Doenças , FibroseRESUMO
Ubiquitin-specific protease 22 (USP22) is a member of the ubiquitin specific protease family (ubiquitin-specific protease, USPs), the largest subfamily of deubiquitinating enzymes, and plays an important role in the treatment of tumors. USP22 is also expressed in the heart. However, the role of USP22 in heart disease remains unclear. In this study, we found that USP22 was elevated in hypertrophic mouse hearts and in angiotensin II (Ang II)-induced cardiomyocytes. The inhibition of USP22 expression with adenovirus significantly rescued hypertrophic phenotype and cardiac dysfunction induced by pressure overloaded. Consistent with in vivo study, silencing by USP22 shRNA expression in vitro had similar results. Molecular analysis revealed that transforming growth factor-ß-activating protein 1 (TAK1)-(JNK1/2)/P38 signaling pathway and HIF-1α was activated in the Ang II-induced hypertrophic cardiomyocytes, whereas HIF-1α expression was decreased after the inhibition of USP22. Inhibition of HIF-1α expression reduces TAK1 expression. Co-immunoprecipitation and ubiquitination studies revealed the regulatory mechanism between USP22 and HIF1α.Under hypertrophic stress conditions, USP22 enhances the stability of HIF-1α through its deubiquitination activity, which further activates the TAK1-(JNK1/2)/P38 signaling pathway to lead to cardiac hypertrophy. Inhibition of HIF-1α expression further potentiates the in vivo pathological effects caused by USP22 deficiency. In summary, this study suggests that USP22, through HIF-1α-TAK1-(JNK1/2)/P38 signaling pathway, may be potential targets for inhibiting pathological cardiac hypertrophy induced by pressure overload.
Assuntos
Cardiomegalia , MAP Quinase Quinase Quinases , Animais , Camundongos , Cardiomegalia/metabolismo , MAP Quinase Quinase Quinases/genética , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/farmacologiaRESUMO
BACKGROUND: Ischemic cardiomyopathy (ICM) is associated with electrical and structural remodelling, leading to arrhythmias. Caveolin-1 (Cav1) is a membrane protein involved in the pathogenesis of ischemic injury. Cav1 deficiency has been associated with arrhythmogenicity. The current study aimed to determine how Cav1 overexpression inhibits arrhythmias and cardiac remodelling in ICM. METHODS: ICM was modelled using left anterior descending (LAD) artery ligation for 4 weeks. Cardiac-specific Cav1 overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodelling were investigated using the intramyocardial injection of an adeno-associated virus serotype 9 (AAV-9) system, carrying a specific sequence expressing Cav1 (AAVCav1) under the cardiac troponin T (cTnT) promoter. RESULTS: Cav1 overexpression decreased susceptibility to arrhythmias by upregulating gap junction connexin 43 (CX43) and reducing spontaneous irregular proarrhythmogenic Ca2+ waves in ventricular cardiomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca2+ cycling through normalizing Ca2+-handling protein levels and improving Ca2+ homeostasis. Masson stain and immunoblotting revealed that the deposition of excessive fibrosis was attenuated by Cav1 overexpression, inhibiting the transforming growth factor-ß (TGF-ß)/Smad2 signalling pathway. Coimmunoprecipitation assays demonstrated that the interaction between Cav1 and cSrc modulated CX43 expression and Ca2+-handling protein levels. CONCLUSIONS: Cardiac-specific overexpression of Cav1 attenuated ventricular arrhythmia, improved Ca2+ cycling, and attenuated cardiac remodelling. These effects were attributed to modulation of CX43, normalized Ca2+-handling protein levels, improved Ca2+ homeostasis, and attenuated cardiac fibrosis.
Assuntos
Cardiomiopatias , Caveolina 1 , Isquemia Miocárdica , Animais , Ratos , Arritmias Cardíacas/etiologia , Cardiomiopatias/patologia , Caveolina 1/genética , Caveolina 1/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Isquemia Miocárdica/complicações , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Remodelação VentricularRESUMO
Immunotherapy has greatly improved the clinical benefits of cancer treatment, especially in melanoma. Ferroptosis is a novel mechanism of cell death which relates to immunity. This study aimed at understanding the potential link between ferroptosis and cancer immunocompetent in melanoma using multiple bioinformatics analyses. By the WGCNA assay, we first constructed a key module-gene of ferroptosis, which was strongly correlated with the diagnosis, prognosis, and infiltration of immune cells in melanoma. The elevated module-gene could effectively distinguish melanoma from normal tissues and acted as a good prognostic marker. The module-gene of ferroptosis was positively correlated with the infiltration of immune cells. In particular, the module was positively correlated with the expression of PD-L1 and sensitively increased after effective anti-PD-1 treatment. Furthermore, the differential expression of the module-gene between normal and tumor tissues was observed in pan-cancer. The similarity correlations of the module-gene with infiltration of immune cells and the expressions of PD-L1 were confirmed in the pan-cancer level. Our study demonstrated that the key module-gene of ferroptosis was closely related with diagnosis, prognosis, and anti-immune response in melanoma, as well as in pan-cancer.
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Atherosclerosis (AS) is the leading cause of cardiovascular diseases (CVDs) with a high rate of mortality worldwide. Plasma cell-free DNA (cfDNA), mainly originating from apoptosis, necrosis, and active secretion, has been recognized as a promising biomarker for the diagnosis and prognosis of multiple cancers, whereas there are no reports about cfDNA in CVDs. Here, we found an increased quantity and decreased integrity of cfDNA (cfDI) in the serum from AS patients compared with normal controls. Moreover, the reduced cfDI is inversely correlated with serum LDL levels, carotid plaque size, and carotid plaque thickness in the progression of AS. Consistently, in vivo experiments confirmed that the release and cleavage of cfDNA were increased concomitantly with the development and progression of AS in ApoE-/- mice. Our study sheds light on the potential of cfDNA and cfDI as molecular biomarkers for detecting and monitoring AS.
Assuntos
Aterosclerose , Ácidos Nucleicos Livres , Animais , Camundongos , Apolipoproteínas E/genética , Aterosclerose/sangue , Aterosclerose/diagnóstico , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/sangue , Neoplasias/diagnósticoRESUMO
Both N6-methyladenosine (m6A) RNA modification and microRNAs (miRNAs) are common regulatory mechanisms for gene post-transcription by modulating mRNA stability and translation. They also share the same 3'-untranslated regions (UTRs) regions for their target gene. However, little is known about their potential interaction in cell development and biology. Here, we aimed to investigate how m6A regulates the specific miRNA repression during cardiac development and hypertrophy. Our multiple lines of bioinformatic and molecular biological evidence have shown that m6A modification on cardiac miR-133a target sequence promotes miR-133a repressive effect via AGO2-IGF2BP2 (Argonaute 2-Insulin-like growth factor 2 mRNA binding protein 2) complex. Among 139 cardiac miRNAs, only the seed sequence of miR-133a was inversely complement to m6A consensus motif "GGACH" by sequence alignment analysis. Immunofluorescence staining, luciferase reporter, and m6A-RIP (RNA immunoprecipitation) assays revealed that m6A modification facilitated miR-133a binding to and repressing their targets. The inhibition of the miR-133a on cardiac proliferation and hypertrophy could be prevented by silencing of Fto (FTO alpha-ketoglutarate dependent dioxygenase) which induced m6A modification. IGF2BP2, an m6A binding protein, physically interacted with AGO2 and increased more miR-133a accumulation on its target site, which was modified by m6A. In conclusion, our study revealed a novel and precise regulatory mechanism that the m6A modification promoted the repression of specific miRNA during heart development and hypertrophy. Targeting m6A modification might provide a strategy to repair hypertrophic gene expression induced by miR-133a.
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BACKGROUND: Persistent myocardial ischemia post-myocardial infarction can lead to fatal ventricular arrhythmias such as ventricular tachycardia and fibrillation, both of which carry high mortality rates. Dexmedetomidine (Dex) is a highly selective α2-agonist used in surgery for congenital cardiac disease because of its antiarrhythmic properties. Dex has previously been reported to prevent or terminate various arrhythmias. The purpose of the present study was to determine the anti-arrhythmic properties of Dex in the context of ischemic cardiomyopathy (ICM) after myocardial infarction. METHODS AND RESULTS: We randomly allocated 48 rats with ICM, created by persistent ligation of the left anterior descending artery for 4 weeks, into six groups: Sham (n = 8), Sham + BML (n = 8), ICM (n = 8), ICM + BML (n = 8), ICM + Dex (n = 8), and ICM + Dex + BML (n = 8). Treatments started after ICM was confirmed (the day after echocardiographic measurement) and continued for 4 weeks (inject intraperitoneally, daily). Dex inhibited the generation of collagens, cytokines, and other inflammatory mediators in rats with ICM via the suppression of NF-κB activation and increased the distribution of connexin 43 (Cx43) via phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Dex reduced the occurrence of spontaneous ventricular arrhythmias (ventricular premature beat or ventricular tachycardia), decreased the inducibility quotient of ventricular arrhythmias induced by PES, and partly improved cardiac contraction. The AMPK antagonist BML-275 dihydrochloride (BML) partly weakened the cardioprotective effect of Dex. CONCLUSION: Dex conferred anti-arrhythmic effects in the context of ICM via upregulation of Cx43 and suppression of inflammation and fibrosis. The anti-arrhythmic and anti-inflammatory properties of Dex may be mediated by phosphorylation of AMPK and subsequent suppression of NF-κB activation.