RESUMO
OBJECTIVE: To compare the immediate, early, and delayed percutaneous coronary intervention (PCI) strategies in non-ST-segment-elevation myocardial infarction (NSTEMI) patients with high-risk. METHODS: Medical records of patients treated at the Daping Hospital, Third Military Medical University, Chongqing, China between 2011 and 2021 were retrospectively reviewed. Only patients with complete available information were included. All patients assigned into three groups based on the timing of PCI including immediate (< 2 h), early (2-24 h) and delayed (≥ 24 h) intervention. Multivariable Cox hazards regression and simpler nonlinear models were performed. RESULTS: A total of 657 patients were included in the study. The median follow-up length was 3.29 (interquartile range: 1.45-4.85) years. Early PCI strategy improved the major adverse cardiac event (MACE) outcome compared to the immediate or delayed PCI strategy. Early PCI, diabetes mellitus, and left main or/and left anterior descending or/and left circumflex stenosis or/and right coronary artery ≥ 99% were predictors for MACE outcome. The optimal timing range for PCI to reduce MACE risk is 3-14 h post-admission. For high-risk NSTEMI patients, early PCI reduced primary clinical outcomes compared to immediate or delayed PCI, and the optimal timing range was 3-14 h post-admission. Delayed PCI was superior for NSTEMI with chronic kidney injury. CONCLUSIONS: Delayed invasive strategy was helpful to reduce the incidence of MACE for high-risk NSTEMI with chronic kidney injury. An immediate PCI strategy might increase the rate of MACE.
RESUMO
The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction.
Assuntos
Proliferação de Células , Histona Desmetilases com o Domínio Jumonji , Ácidos Cetoglutáricos , Infarto do Miocárdio , Miócitos Cardíacos , Regeneração , Animais , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Animais Recém-Nascidos , Células Cultivadas , Histonas/metabolismo , Camundongos , Complexo Cetoglutarato Desidrogenase/metabolismo , Complexo Cetoglutarato Desidrogenase/genética , MasculinoRESUMO
Protein-encoding circular RNAs (circRNAs) are newly identified RNA molecules characterized by intense interaction with translating ribosome. Emerging evidence has implicated physiological and pathological significance of these non-canonical RNAs, yet a large body of them remains unidentified. Due to limited tools at hand, we developed CircProPlus, an automated computational pipeline for de novo detection of translated circRNAs. In comparison to previously established CircPro, CircProPlus adjusts the overall workflow and integrates more robust implements for achieving easier accessibility, higher flexibility and productivity. In present study, we tested the performance of CircProPlus when using different circRNA-detecting implements (i.e., CIRI2, CirComPara2) in the evaluation of coding ability of circRNAs. Results showed that CirComPara2, a state-of-the-art algorithm, consistently outperformed CIRI2 when coupled with CircProPlus in testing real data collected from different RNA libraries and species, which highlighted its potency in data mining of circRNAs with protein-coding potential.
Assuntos
Algoritmos , RNA Circular , RNA Circular/genética , Humanos , Biologia Computacional/métodos , SoftwareRESUMO
Acute kidney injury (AKI) is the sudden decrease in renal function that can be attributed to dysregulated reactive oxygen species (ROS) production and impaired mitochondrial function. Irisin, a type I membrane protein secreted by skeletal muscles in response to physical activity, has been reported to alleviate kidney damage through regulation of mitochondrial biogenesis and oxidative metabolism. In this study, a macrophage membrane-coated metal-organic framework (MCM@MOF) is developed as a nanocarrier for encapsulating irisin to overcome the inherent characteristics of irisin, including a short circulation time, limited kidney-targeting ability, and low membrane permeability. The engineered irisin-mediated biomimetic nanotherapeutics have extended circulation time and enhanced targeting capability toward injured kidneys due to the preservation of macrophage membrane proteins. The irisin-encapsulated biomimetic nanotherapeutics effectively mitigate acute ischemia-reperfusion injury by protecting mitochondrial function and modulating SOD2 levels in renal tubular epithelial cells. The present study provides novel insights to advance the development of irisin as a potential therapeutic approach for AKI.
RESUMO
G protein-coupled receptors (GPCRs) mediate cellular responses to a myriad of hormones and neurotransmitters that play vital roles in the regulation of physiological processes such as blood pressure. In organs such as the artery and kidney, hormones or neurotransmitters, such as angiotensin II (Ang II), dopamine, epinephrine, and norepinephrine exert their functions via their receptors, with the ultimate effect of keeping normal vascular reactivity, normal body sodium, and normal blood pressure. GPCR kinases (GRKs) exert their biological functions, by mediating the regulation of agonist-occupied GPCRs, non-GPCRs, or non-receptor substrates. In particular, increasing number of studies show that aberrant expression and activity of GRKs in the cardiovascular system and kidney inhibit or stimulate GPCRs (e.g., dopamine receptors, Ang II receptors, and α- and ß-adrenergic receptors), resulting in hypertension. Current studies focus on the effect of selective GRK inhibitors in cardiovascular diseases, including hypertension. Moreover, genetic studies show that GRK gene variants are associated with essential hypertension, blood pressure response to antihypertensive medicines, and adverse cardiovascular outcomes of antihypertensive treatment. In this review, we present a comprehensive overview of GRK-mediated regulation of blood pressure, role of GRKs in the pathogenesis of hypertension, and highlight potential strategies for the treatment of hypertension. Schematic representation of GPCR desensitization process. Activation of GPCRs begins with the binding of an agonist to its corresponding receptor. Then G proteins activate downstream effectors that are mediated by various signaling pathways. GPCR signaling is halted by GRK-mediated receptor phosphorylation, which causes receptor internalization through ß-arrestin.
Assuntos
Quinases de Receptores Acoplados a Proteína G , Hipertensão , Humanos , Quinases de Receptores Acoplados a Proteína G/metabolismo , Quinases de Receptores Acoplados a Proteína G/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Animais , Anti-Hipertensivos/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Pressão Sanguínea/fisiologia , Transdução de SinaisRESUMO
The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) are two major blood pressure-regulating systems. The link between the renal and cerebral RAS axes was provided by reflex activation of renal afferents and efferent sympathetic nerves. There is a self-sustaining enhancement of the brain and the intrarenal RAS. In this study, prenatal exposure to lipopolysaccharide (LPS) led to increased RAS activity in the paraventricular nucleus (PVN) and overactivation of sympathetic outflow, accompanied by increased production of reactive oxygen species (ROS) and disturbances between inhibitory and excitatory neurons in PVN. The AT1 receptor blocker losartan and α2 adrenergic receptor agonist clonidine in the PVN significantly decreased renal sympathetic nerve activity (RSNA) and synchronously reduced systolic blood pressure. Prenatal LPS stimulation caused H3 acetylation at H3K9 and H3K14 in the PVN, which suggested that epigenetic changes are involved in transmitting the prenatal adverse stimulative information to the next generation. Additionally, melatonin treatment during pregnancy reduced RAS activity and ROS levels in the PVN; balanced the activity of inhibitory and excitatory neurons in the PVN; increased urine sodium secretion; reduced RSNA and blood pressure. In conclusion, prenatal LPS leads to increased RAS expression within the PVN and overactivation of the sympathetic outflow, thereby contributing to hypertension in offspring rats. Melatonin is expected to be a promising agent for preventing prenatal LPS exposure-induced hypertension.
Assuntos
Pressão Sanguínea , Lipopolissacarídeos , Núcleo Hipotalâmico Paraventricular , Efeitos Tardios da Exposição Pré-Natal , Sistema Renina-Angiotensina , Sistema Nervoso Simpático , Animais , Gravidez , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Feminino , Ratos , Pressão Sanguínea/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , MasculinoRESUMO
Objective: Previous studies have shown that apolipoprotein E (ApoE) gene polymorphisms have an impact on coronary artery disease(CAD). However, many studies have small sample sizes and different conclusions. The purpose was to retrospectively study the influence of ApoE gene polymorphisms on CAD. Methods: This study assessed the influence of different ApoE genotypes on coronary heart disease in patients who received coronary angiography and used multivariate logistic regression to assess the influence of different ApoE genotypes on CAD. Results: Patients with different ApoE genotypes had no obvious differences in the incidence of hypertension, diabetes or obesityï¼P > 0.05). Patients with ε2/ε2 had higher incidence of hypertriglyceridemia than patients with other ApoE genotypes, while patients with ε3/ε3 had a lower incidence of hypertriglyceridemia than those with ε3/ε4,ε4/ε4, ε2/ε3 and ε2/ε2ï¼P < 0.05ï¼. Patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no significant differences in the severity or incidence of CAD ï¼P > 0.05). ε2/ε4 and ε2/ε3 reduced the risk of high LDL-C, and reduced the severity and incidence of coronary heartï¼P < 0.05). ε2/ε3 reduced risk of premature coronary artery diseaseï¼PCADï¼ï¼P < 0.05). ε2/ε3 reduced risk of CAD in patients age <45,age at 60-74 and age ≥74, while ε2/ε4 reduced risk of CAD in patients age ≥74ï¼P < 0.05). Conclusion: Patients with ε3/ε4, ε4/ε4,ε3/ε3 and ε2/ε2 had no significant differences in the severity and occurrence of CAD. Compared to the isoform ε3 (ε3/ε3), isoform ε4 did not increased the severity and occurrence of CAD. Compared with ApoE other genotypes, ε2/ε3 and ε2/ε4 reduced the risk of high LDL-C and the severity and occurrence of CAD.
RESUMO
The formation of new and functional cardiomyocytes requires a 3-step process: dedifferentiation, proliferation, and redifferentiation, but the critical genes required for efficient dedifferentiation, proliferation, and redifferentiation remain unknown. In our study, a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive (PCM1+) cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction (MI) on postnatal Day 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentiation, proliferation, and redifferentiation of cardiomyocytes after injury. We identified four top actin-remodeling regulators, namely Tmsb4x, Tmsb10, Dmd, and Ctnna3, which we collectively referred to as 2D2P. Transiently expressed changes of 2D2P, using a polycistronic non-integrating lentivirus driven by Tnnt2 (cardiac-specific troponin T) promoters (Tnnt2-2D2P-NIL), efficiently induced transiently proliferative activation and actin remodeling in postnatal Day 7 cardiomyocytes and adult hearts. Furthermore, the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sustained improvement in cardiac function without ventricular dilatation, thickened septum, or fatal arrhythmia for at least 4 months. In conclusion, this study highlights the importance of actin remodeling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.
RESUMO
OBJECTIVE: The study aimed to explore the predictors of vascular complications (VCs) associated with transradial access, as the occurrence and severity of these complications were found to be significantly lower compared to femoral access. However, it is important to note that the occurrence of these complications still has a negative impact on clinical outcomes. Nevertheless, there is limited available data on the predictors of complications specifically related to radial access. METHODS: A retrospective case-control study was conducted on individuals who underwent percutaneous coronary diagnostic or therapeutic procedures at Daping Hospital, following the inclusion and exclusion criteria. The study compared demographic characteristics, VC types, ankle brachial index (ABI), and severity of coronary artery stenosis between the two groups. RESULTS: We enrolled 300 subjects with VCs and 300 age- and sex-matched subjects without VCs as controls. There were no differences in the baseline characteristics or comorbidities between the groups. Compared to the control group, the VC group has a higher portion of left radial access (6.0%) and previous radial artery puncture history (29.7% vs. 18.3%, p<0.001). The ABI was significantly lower than the non-VC group (1.17 ± 0.17 vs. 1.23 ± 0.14, p<0.001). In the multivariate logistic regression analysis, several factors were found to be independently associated with the occurrence of VC. These factors include ABI (OR=0.060, 95% CI: 0.014-0.249, p<0.001), the procedure being performed by junior operators (OR=1.892, 95% CI: 1.314-2.745, p<0.001), and previous access on the same radial artery (OR=1.795, 95% CI: 1.190-2.707, p<0.01). CONCLUSIONS: Patients who exhibit a lower ABI and have a history of prior radial access procedures may be at an increased risk of developing radial access VC. Therefore, it is recommended to routinely measure ABI prior to these procedures, as it may serve as a predictive tool for assessing the risk of VC.
Assuntos
Índice Tornozelo-Braço , Artéria Radial , Humanos , Artéria Radial/fisiopatologia , Masculino , Feminino , Estudos de Casos e Controles , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Intervenção Coronária Percutânea/efeitos adversos , Fatores de RiscoRESUMO
OBJECTIVE: Many previous studies reported the relationship between lipoprotein(a) and cardiovascular disease, but the conclusions were controversial. The aim of our study was to retrospectively investigate the association between lipoprotein(a) and cardiovascular disease in patients undergoing coronary angiography. METHODS: We collected and compared clinical information of patients hospitalized for coronary angiography. Multivariable hierarchical logistic regression was used to evaluate the association between lipoprotein(a) and cardiovascular disease in patients undergoing coronary angiography. RESULTS: There were no significant differences in gender, hypertension, APOA1, smoking, hyperuricemia, obesity, acute myocardial infarction (AMI), cardiac insufficiency, family history of diabetes, or family history of hyperlipidemia among the four groups of lipoprotein(a). Elevated lipoprotein(a) does not increase the risk of hypertriglyceridemia, while elevated lipoprotein(a) increases the risk of high total cholesterol and high low-density lipoprotein cholesterol (LDL-c). Elevated lipoprotein(a) increases the risk of diabetes and premature coronary artery disease (CAD). Elevated lipoprotein(a) increases the incidence of CAD, multivessel lesions, and percutaneous coronary intervention (PCI). Multivariate logistic regression analysis further showed that elevated lipoprotein(a) increases the incidence of high total cholesterol, high LDLc, diabetes, CAD, premature CAD, multivessel lesions, and PCI. CONCLUSION: The findings indicated that elevated lipoprotein(a) had no obvious relationship with hypertension and obesity. Elevated lipoprotein(a) increases the risk of high total cholesterol, high LDLc, and premature CAD, and increases the occurrence and severity of coronary heart disease.
Assuntos
Angiografia Coronária , Lipoproteína(a) , Humanos , Masculino , Lipoproteína(a)/sangue , Feminino , Pessoa de Meia-Idade , Comorbidade , Fatores de Risco , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Biomarcadores/sangue , Estudos Retrospectivos , Incidência , Idoso , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , China/epidemiologia , Medição de RiscoRESUMO
AIMS: Doxorubicin is a powerful chemotherapeutic agent for cancer, whose use is limited due to its potential cardiotoxicity. Semaglutide (SEMA), a novel analog of glucagon-like peptide-1 (GLP-1), has received widespread attention for the treatment of diabetes. However, increasing evidence has highlighted its potential therapeutic benefits on cardiac function. Therefore, the objective of this study was to examine the efficacy of semaglutide in ameliorating doxorubicin-induced cardiotoxicity. METHODS AND RESULTS: Doxorubicin-induced cardiotoxicity is an established model to study cardiac function. Cardiac function was studied by transthoracic echocardiography and invasive hemodynamic monitoring. The results showed that semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction. RNA sequencing suggested that Bnip3 is the candidate gene that impaired the protective effect of semaglutide in doxorubicin-induced cardiotoxicity. To determine the role of BNIP3 on the effect of semaglutide in doxorubicin-induced cardiotoxicity, BNIP3 with adeno-associated virus serotype 9 (AAV9) expressing cardiac troponin T (cTnT) promoter was injected into tail vein of C57/BL6J mice to overexpress BNIP3, specifically in the heart. Overexpression of BNIP3 prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide, via PI3K/AKT pathway, reduced BNIP3 expression in the mitochondria, improving mitochondrial function. CONCLUSION: Semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction via PI3K/AKT pathway, by reducing BNIP3 expression in mitochondria. The improvement in mitochondrial function reduces doxorubicin-mediated cardiac injury and improves cardiac function. Therefore, semaglutide is a potential therapy to reduce doxorubicin-induced acute cardiotoxicity.
Assuntos
Cardiotoxicidade , Doxorrubicina , Peptídeos Semelhantes ao Glucagon , Proteínas de Membrana , Animais , Camundongos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Peptídeos Semelhantes ao Glucagon/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , HumanosRESUMO
BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.
Assuntos
Diabetes Mellitus Tipo 1 , Cardiomiopatias Diabéticas , Ferroptose , Humanos , Animais , Camundongos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/prevenção & controle , Sirtuína 1 , Fibronectinas , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Proteína Supressora de Tumor p53 , Miócitos CardíacosRESUMO
Aims: Smooth muscle cell (SMC) remodeling poses a critical feature in the development and progression of atherosclerosis. Although fate mapping and in silicon approaches have expanded SMC phenotypes in atherosclerosis, it still remains elusive about the contributions of individual SMC phenotypes and molecular dynamics to advanced atherosclerotic plaque. Methods: Using single-cell transcriptome, we investigated cellular compositions of human carotid plaque laden with atherosclerotic core, followed by in vivo experiments utilizing SMC-lineage tracing technology, bulk RNA sequencing (RNA-seq) and both in vivo and in vitro validation of the underlying molecular mechanism. Results: 5 functionally distinct SMC subtypes were uncovered based on transcriptional features (described as contractile, fibroblast-like, osteogenic, synthetic and macrophage-like) within the niche. A proinflammatory, macrophage-like SMC subtype displaying an intermediary phenotype between SMC and macrophage, exhibits prominent potential in destabilizing plaque. At the molecular level, we explored cluster-specific master regulons by algorithm, and identified interferon regulatory factor-8 (IRF8) as a potential stimulator of SMC-to-macrophage transdifferentiation via activating nuclear factor-κB (NF-κB) signaling. Conclusions: Our study illustrates a comprehensive cell atlas and molecular landscape of advanced atherosclerotic lesion, which might renovate current understanding of SMC biology in atherosclerosis.
Assuntos
Aterosclerose , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Aterosclerose/genética , Aterosclerose/patologia , Perfilação da Expressão Gênica , Miócitos de Músculo Liso/patologia , Macrófagos/patologiaRESUMO
BACKGROUND: Pulmonary arteriovenous fistula (PAVF) is a rare disease, which can lead to the direct return of unoxidized venous blood to pulmonary veins and left heart, resulting in right-to-left shunt leading to hypoxia. Long term, the right-to-left shunt will cause severe pathophysiological changes in the patient's body and pulmonary circulation, and the prognosis will be poor if PAVF is not treated timely. CASE PRESENTATION: Here, we report the case of a 71-year-old man who presented with chest tightness and shortness of breath. After a series of examinations, PAVF and giant hemangioma were diagnosed, which are difficult to operate.Transcatheter interventional therapy was initiated. The patient recovered on the third day after operation and was discharged smoothly. During the long-term follow-up of nearly 4 years after discharge, the general condition and quality of life of the patient basically returned to normal. CONCLUSIONS: PAVF is rare but very important clinical problem. When the clinical manifestations of persistent unexplained hypoxia appear, it is necessary to fully consider the possibility of PAVF. Once the diagnosis of PAVF is clear, timely treatment is recommended to avoid deterioration of the disease and affecting the prognosis.
Assuntos
Fístula Arteriovenosa , Hemangioma , Artéria Pulmonar/anormalidades , Veias Pulmonares , Veias Pulmonares/anormalidades , Masculino , Humanos , Idoso , Veias Pulmonares/cirurgia , Qualidade de Vida , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgia , Hipóxia/etiologia , Hemangioma/complicações , Hemangioma/diagnóstico , Hemangioma/cirurgiaRESUMO
BACKGROUND: Ischemic heart disease (IHD) is the leading cause of death among noncommunicable diseases worldwide, but data on current epidemiological patterns and associated risk factors are lacking. OBJECTIVE: This study assessed the global, regional, and national trends in IHD mortality and attributable risks since 1990. METHODS: Mortality data were obtained from the Global Burden of Disease 2019 Study. We used an age-period-cohort model to calculate longitudinal age curves (expected longitudinal age-specific rate), net drift (overall annual percentage change), and local drift (annual percentage change in each age group) from 15 to >95 years of age and estimate cohort and period effects between 1990 and 2019. Deaths from IHD attributable to each risk factor were estimated on the basis of risk exposure, relative risks, and theoretical minimum risk exposure level. RESULTS: IHD is the leading cause of death in noncommunicable disease-related mortality (118.1/598.8, 19.7%). However, the age-standardized mortality rate for IHD decreased by 30.8% (95% CI -34.83% to -27.17%) over the past 30 years, and its net drift ranged from -2.89% (95% CI -3.07% to -2.71%) in high sociodemographic index (SDI) region to -0.24% (95% CI -0.32% to -0.16%) in low-middle-SDI region. The greatest decrease in IHD mortality occurred in the Republic of Korea (high SDI) with net drift -6.06% (95% CI -6.23% to -5.88%), followed by 5 high-SDI nations (Denmark, Norway, Estonia, the Netherlands, and Ireland) and 2 high-middle-SDI nations (Israel and Bahrain) with net drift less than -5.00%. Globally, age groups of >60 years continued to have the largest proportion of IHD-related mortality, with slightly higher mortality in male than female group. For period and birth cohort effects, the trend of rate ratios for IHD mortality declined across successive period groups from 2000 to 2004 and birth cohort groups from 1985 to 2000, with noticeable improvements in high-SDI regions. In low-SDI regions, IHD mortality significantly declined in female group but fluctuated in male group across successive periods; sex differences were greater in those born after 1945 in middle- and low-middle-SDI regions and after 1970 in low-SDI regions. Metabolic risks were the leading cause of mortality from IHD worldwide in 2019. Moreover, smoking, particulate matter pollution, and dietary risks were also important risk factors, increasingly occurring at a younger age. Diets low in whole grains and legumes were prominent dietary risks in both male and female groups, and smoking and high-sodium diet mainly affect male group. CONCLUSIONS: IHD, a major concern, needs focused health care attention, especially for older male individuals and those in low-SDI regions. Metabolic risks should be prioritized for prevention, and behavioral and environmental risks should attract more attention to decrease IHD mortality.
Assuntos
Carga Global da Doença , Fumar , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Instalações de Saúde , Pesquisa , Fatores de Risco , Adolescente , Adulto Jovem , IdosoRESUMO
Vascular disease is one of the major causes of death worldwide. Endothelial cells are important components of the vascular structure. A better understanding of the endothelial cell changes in the development of vascular disease may provide new targets for clinical treatment strategies. Single-cell RNA sequencing can serve as a powerful tool to explore transcription patterns, as well as cell type identity. Our current study is based on comprehensive scRNA-seq data of several types of human vascular disease datasets with deep-learning-based algorithm. A gene set scoring system, created based on cell clustering, may help to identify the relative stage of the development of vascular disease. Metabolic preference patterns were estimated using a graphic neural network model. Overall, our study may provide potential treatment targets for retaining normal endothelial function under pathological situations.
Assuntos
Perfilação da Expressão Gênica , Doenças Vasculares , Humanos , Células Endoteliais , Análise de Sequência de RNA , Análise da Expressão Gênica de Célula Única , Algoritmos , Artérias , Análise por ConglomeradosRESUMO
Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 µg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 µM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 µM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.
Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Camundongos , Animais , Ratos , Quimiocina CCL2/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos , Insuficiência Cardíaca/metabolismo , Regeneração , Camundongos Endogâmicos C57BL , Apoptose , Fator de Transcrição STAT3/metabolismoRESUMO
Stimulating cardiomyocyte proliferation in the adult heart has emerged as a promising strategy for cardiac regeneration following myocardial infarction (MI). The NRG1-ERBB4 signaling pathway has been implicated in the regulation of cardiomyocyte proliferation. However, the therapeutic potential of recombinant human NRG1 (rhNRG1) has been limited due to the low expression of ERBB4 in adult cardiomyocytes. Here, we investigated whether a fusion protein of rhNRG1 and an ERBB3 inhibitor (rhNRG1-HER3i) could enhance the affinity of NRG1 for ERBB4 and promote adult cardiomyocyte proliferation. In vitro and in vivo experiments were conducted using postnatal day 1 (P1), P7, and adult cardiomyocytes. Western blot analysis was performed to assess the expression and activity of ERBB4. Cardiomyocyte proliferation was evaluated using Ki67 and pH 3 immunostaining, while fibrosis was assessed using Masson staining. Our results indicate that rhNRG1-HER3i, but not rhNRG1, promoted P7 and adult cardiomyocyte proliferation. Furthermore, rhNRG1-HER3i improved cardiac function and reduced cardiac fibrosis in post-MI hearts. Administration of rhNRG1-HER3i inhibited ERBB3 phosphorylation while increasing ERBB4 phosphorylation in adult mouse hearts. Additionally, rhNRG1-HER3i enhanced angiogenesis following MI compared to rhNRG1. In conclusion, our findings suggest that rhNRG1-HER3i is a viable therapeutic approach for promoting adult cardiomyocyte proliferation and treating MI by enhancing NRG1-ERBB4 signaling pathway.
Assuntos
Cardiomiopatias , Infarto do Miocárdio , Camundongos , Animais , Humanos , Transdução de Sinais , Miócitos Cardíacos/metabolismo , Neuregulina-1/uso terapêutico , Cardiomiopatias/metabolismo , Receptor ErbB-4/metabolismoRESUMO
BACKGROUND: Lung ischemia-reperfusion (I/R) injury is a serious clinical problem without effective treatment. Enhancing branched-chain amino acids (BCAA) metabolism can protect against cardiac I/R injury, which may be related to bioactive molecules generated by BCAA metabolites. L-ß-aminoisobutyric acid (L-BAIBA), a metabolite of BCAA, has multi-organ protective effects, but whether it protects against lung I/R injury is unclear. METHODS: To assess the protective effect of L-BAIBA against lung I/R injury, an animal model was generated by clamping the hilum of the left lung, followed by releasing the clamp in C57BL/6 mice. Mice with lung I/R injury were pre-treated or post-treated with L-BAIBA (150 mg/kg/day), given by gavage or intraperitoneal injection. Lung injury was assessed by measuring lung edema and analyzing blood gases. Inflammation was assessed by measuring proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), and neutrophil infiltration of the lung was measured by myeloperoxidase activity. Molecular biological methods, including western blot and immunofluorescence, were used to detect potential signaling mechanisms in A549 and BEAS-2B cells. RESULTS: We found that L-BAIBA can protect the lung from I/R injury by inhibiting ferroptosis, which depends on the up-regulation of the expressions of GPX4 and SLC7A11 in C57BL/6 mice. Additionally, we demonstrated that the Nrf-2 signaling pathway is key to the inhibitory effect of L-BAIBA on ferroptosis in A549 and BEAS-2B cells. L-BAIBA can induce the nuclear translocation of Nrf-2. Interfering with the expression of Nrf-2 eliminated the protective effect of L-BAIBA on ferroptosis. A screening of potential signaling pathways revealed that L-BAIBA can increase the phosphorylation of AMPK, and compound C can block the Nrf-2 nuclear translocation induced by L-BAIBA. The presence of compound C also blocked the protective effects of L-BAIBA on lung I/R injury in C57BL/6 mice. CONCLUSIONS: Our study showed that L-BAIBA protects against lung I/R injury via the AMPK/Nrf-2 signaling pathway, which could be a therapeutic target.
L-BAIBA upregulates the expression of GPX4 and SLC7A11 by activating the AMPK/Nrf-2/GPX4/SLC7A11 signaling pathway, thereby protecting against I/R-induced increase in ROS and ferroptosis in the lung.
Assuntos
Ferroptose , Traumatismo por Reperfusão , Camundongos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Camundongos Endogâmicos C57BL , Pulmão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismoRESUMO
Better understanding of the mechanisms regulating the proliferation of pre-existing cardiomyocyte (CM) should lead to better options for regenerating injured myocardium. The absence of a perfect research model to definitively identify newly formed mammalian CMs is lacking. However, methodologies are being developed to identify and enrich proliferative CMs. These methods take advantages of the different proliferative states of CMs during postnatal development, before and after injury in the neonatal heart. New approaches use CMs labeled in lineage tracing animals or single cell technique-based CM clusters. This review aims to provide a timely update on the characteristics of the proliferative CMs, including their structural, functional, genetic, epigenetic and metabolic characteristics versus non-proliferative CMs. A better understanding of the characteristics of proliferative CMs should lead to the mechanisms for inducing endogenous CMs to self-renew, which is a promising therapeutic strategy to treat cardiac diseases that cause CM death in humans.