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Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine.
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Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Células Madre Pluripotentes Inducidas , Sirtuina 3 , Animales , Ratones , Cardiotoxicidad/metabolismo , Gemcitabina , Homeostasis , Células Madre Pluripotentes Inducidas/metabolismo , Mitocondrias/metabolismo , Miocitos Cardíacos , Oxidación-Reducción , Sirtuina 3/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismoRESUMEN
ABSTRACT: Colchicine has demonstrated promising effects in inhibiting local and systemic inflammation during acute coronary syndrome (ACS). However, the efficacy of colchicine in ACS is controversial. We performed a meta-analysis to assess the utility of colchicine in ACS by systematically searching randomized controlled trials. Recurrent myocardial infarction, coronary revascularization, and stroke were included as efficacy endpoint parameters whereas safety endpoints chosen were all-cause mortality, cardiovascular mortality, infectious events, and gastrointestinal (GI) adverse events. Nine identified studies were included (n = 7207 participants). Colchicine may reduce the risk of coronary revascularization by 54% [relative risk (RR) 0.46, 95% confidence interval (CI) 0.29-0.73; P < 0.01] and stroke by 61% (RR 0.39, 95%CI 0.18-0.81; P = 0.01). We observed no significant difference in all-cause mortality (RR 1.25, 95%CI 0.70-2.24; P = 0.46), cardiovascular mortality (RR 0.99, 95%CI 0.58-1.69; P = 0.98), recurrent myocardial infarction (RR 0.75, 95%CI 0.49-1.14; P = 0.18), and infectious events (RR 0.67, 95%CI 0.08-5.52; P = 0.71). Colchicine increased the risk of GI adverse reactions (RR 1.89, 95%CI 1.25-2.84; P < 0.01). Subgroup analysis of loading doses did not reveal significant differences in all endpoints (all P > 0.05), whereas subgroup analysis of follow-up periods showed a lower risk of GI adverse reactions with longer follow-up ( P < 0.01), which may be related to establishing tolerability. Trial sequential analysis suggested that further data are needed before definitive conclusions can be drawn. Colchicine may decrease the occurrence of stroke and revascularization in ACS, whereas slightly increasing the risk of GI reactions. The loading doses probably did not significantly improve the prognosis of patients.
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Síndrome Coronario Agudo , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/tratamiento farmacológico , Colchicina/efectos adversos , Causas de Muerte , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/prevención & controlRESUMEN
Background: Ventricular arrhythmias (VAs) mainly occur in the early post-myocardial infarction (MI) period. However, studies examining the association between total myocardial ischemia time interval and the risk of new-onset VAs during a long-term follow-up are scarce. Methods: This study (symptom-to-balloon time and VEntricular aRrhYthmias in patients with STEMI, VERY-STEMI study) was a multicenter, observational cohort and real-world study, which included patients with ST-segment elevation MI (STEMI) undergoing percutaneous coronary intervention (PCI). The primary endpoint was cumulative new-onset VAs during follow-up. The secondary endpoints were the major adverse cardiovascular events (MACE) and changes in left ventricular ejection fraction (ΔLVEF, %). Results: A total of 517 patients with STEMI were included and 236 primary endpoint events occurred. After multivariable adjustments, compared to patients with S2BT of 24 h-7d, those with S2BT ≤ 24 h and S2BT > 7d had a lower risk of primary endpoint. RCS showed an inverted U-shaped relationship between S2BT and the primary endpoint, with an S2BT of 68.4 h at the inflection point. Patients with S2BT ≤ 24 h were associated with a lower risk of MACE and a 4.44 increase in LVEF, while there was no significant difference in MACE and LVEF change between the S2BT > 7d group and S2BT of 24 h-7d group. Conclusions: S2BT of 24 h-7d in STEMI patients was associated with a higher risk of VAs during follow-up. There was an inverted U-shaped relationship between S2BT and VAs, with the highest risk at an S2BT of 68.4 h.
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BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.
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Proliferación Celular , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Modelos Animales de Enfermedad , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Humanos , Piruvato Quinasa/metabolismo , Piruvato Quinasa/genética , Células HEK293 , Porcinos , Reprogramación Celular , Proteínas de Unión a Hormona Tiroide , Regeneración , Unión Proteica , Sus scrofa , Remodelación Ventricular/fisiología , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Metabolismo Energético/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Reprogramación MetabólicaRESUMEN
The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.
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Membrana Celular , Integrina beta3 , Ratones Noqueados , Regeneración , Animales , Masculino , Ratones , Membrana Celular/metabolismo , Proliferación Celular , Lesiones Cardíacas/metabolismo , Lesiones Cardíacas/patología , Lesiones Cardíacas/genética , Integrina beta3/metabolismo , Integrina beta3/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Plasmalógenos/metabolismo , Transducción de SeñalRESUMEN
Cadmium (Cd) is a toxic heavy metal linked to an increased risk of cardiovascular disease (CVD). But the relationship between urinary Cd (U-Cd) and electrocardiographic subclinical myocardial injury (SC-MI) in older people is unclear. This study evaluated the connection between U-Cd and SC-MI in people who did not have CVD. The study involved 4269 participants from the National Health and Nutrition Examination Survey III(NHANES III) aged ≥ 50 years and had no history of CVD. The relationship between U-Cd and cardiac infarction/injury score (CIIS) was assessed by multivariable linear regression. Whether U-Cd and SC-MI were correlated was determined by multivariate logistic regression, restricted cubic spline, and subgroup analysis. There was a significant association between U-Cd and CIIS (ß, 1.04, 95% confidence interval (CI): 0.39-1.69; P = 0.003) in the highest quartile and fully adjusted model. After adjusting for relevant confounders, multivariable logistic regression showed that participants in the highest quartile of U-Cd had a greater chance of having SC-MI than those in the first ( OR (95% CI), 1.37(1.13,1.66), P for trend = 0.003), and this relationship was especially strong among hypertensive participants. And a positive linear correlation between U-Cd and the prevalence of SC-MI was shown by restricted cubic spline analysis. U-Cd may be a novel risk element for SC-MI because it is independently and linearly linked to CIIS and SC-MI.
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Enfermedades Cardiovasculares , Hipertensión , Infarto del Miocardio , Humanos , Anciano , Enfermedades Cardiovasculares/epidemiología , Cadmio , Encuestas Nutricionales , Infarto del Miocardio/epidemiología , Hipertensión/epidemiologíaRESUMEN
BACKGROUND: High D-dimer (DD) is associated with short-term adverse outcomes in patients with acute coronary syndrome (ACS). In ACS patients who underwent percutaneous coronary intervention (PCI), however, the value of DD (or combined with neutrophil to lymphocyte ratio [NLR]) to predict long-term major adverse cardiovascular events (MACEs) has not been fully evaluated. METHODS: Patients diagnosed with ACS and receiving PCI were included. The primary outcome was MACEs. Cox proportional hazards regression and logistic regression were used to illustrate the relationship between clinical risk factors, biomarkers and MACEs. Survival models were developed based on significant factors and evaluated by the Concordance-index (C-index). RESULTS: The final study cohort was comprised of 650 patients (median age, 64 years; 474 males), including 98 (15%) with MACEs during a median follow-up period of 40 months. According to the cut-off value of DD and NLR, the patients were separated into four groups: high DD or nonhigh DD with high or nonhigh NLR. After adjusting for confounding variables, DD (adjusted hazard ratio [aHR]: 2.39, 95% confidence interval [CI]: 1.52-3.76) and NLR (aHR: 2.71, 95% CI: 1.78-4.11) were independently associated with long-term MACEs. Moreover, patients with both high DD and NLR had a significantly higher risk in MACEs when considering patients with nonhigh DD and NLR as reference (aHR: 6.19, 95% CI: 3.30-11.61). The area under curve increased and reached 0.70 in differentiating long-term MACEs when DD and NLR were combined, and survival models incorporating the two exhibited a stronger predictive power (C-index: 0.75). CONCLUSIONS: D-dimer (or combined with NLR) can be used to predict long-term MACEs in ACS patients undergoing PCI.
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Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Masculino , Humanos , Persona de Mediana Edad , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/cirugía , Intervención Coronaria Percutánea/efectos adversos , Neutrófilos , Linfocitos , Factores de RiesgoRESUMEN
PURPOSE: This research aimed to investigate the correlation between androgenic alopecia (AGA) and coronary artery disease (CAD) and analyze its value in predicting the severity of coronary atherosclerosis in the Han Chinese male population. PATIENTS AND METHODS: A total of 402 Han Chinese male patients aged 28-75 years were enrolled and performed coronary angiography (CAG) after admission. According to the BASP classification, the participants were divided into mild, moderate and severe AGA. CAD was determined via CAG and defined as stenosis of ≥50% in at least one major coronary artery, and the Gensini score was calculated to evaluate the severity of coronary atherosclerosis. RESULTS: In this study, CAD status (P = 0.002), dyslipidemia status (P = 0.002), age (P = 0.003) and coronary atherosclerosis severity (P < 0.001) were different in patients with different levels of AGA. Multivariate logistic regression analysis revealed that severe AGA was independently correlated to CAD risk (OR, 2.111; 95% CI 1.152 to 3.870, P = 0.016), while the relative CAD risk of early-onset AGA was 2.292 (OR, 2.292; 95% CI 1.132 to 4.640, P = 0.021). AGA status (OR, 2.247; 95% CI 1.396 to 3.617, P = 0.001), severe AGA (OR, 2.360; 95% CI 1.506 to 3.699, P < 0.001) and early-onset AGA (OR, 3.474; 95% CI 2.069 to 5.832, P < 0.001) were all independently associated with the severity of coronary atherosclerosis. The area under the receiver operating characteristic (ROC) curve plotted using severe AGA was 0.601, which is predictive of severe coronary atherosclerosis. Moreover, the presence of severe AGA increases the risk of developing CAD associated with obesity (SI = 1.663, SIM = 1.222, AP = 0.289), diabetes (SI = 2.239, SIM = 1.149, AP = 0.503) and dyslipidemia (SI = 1.062, SIM = 0.646, AP = 0.045). CONCLUSION: This study suggested that AGA is independently associated with CAD in a Han Chinese male population. AGA may be a simple and feasible method for screening CAD and indicative of the severity of coronary atherosclerosis.
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Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3ß (glycogen synthase kinase-3ß) activity and upregulating ß-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.