The present study was to explore the impact of KN93 - a specific inhibitor of CaMKII - on cardiac function and cardiac reserve in HF mice.
We have generated pressure-overload HF mice using modified ...transverse aortic constriction (TAC) method. For acute inhibition (AI) experiment, HF mice were randomly divided into HF group, HF + KN93 AI group and HF + KN92 AI group, using sham mice as control. Mice in HF + KN93 AI group and HF + KN92 AI group were injected with CaMKII inhibitor KN93 or its inactive analogue KN92 on post-TAC day 15, while mice in HF group and Sham group were treated with saline. For chronic inhibition (CI) experiment, mice were injected daily with KN93, KN92 or saline for one week. At baseline and after isoproterenol (Iso) injection, in vivo cardiac function was assessed by echocardiography and left ventricular pressure-volume catheter.
Acute inhibition of CaMKII leads to decreased -dP/dtmin, increased EF, FS, longitudinal strain, longitudinal strain rate, ESPVR, dP/dtmax-EDV, PRSW, Tau and EDPVR, and unaltered reactivity to Iso in HF mice. Chronic inhibition results in increased EF, FS, longitudinal strain, longitudinal strain rate, ESPVR, dP/dtmax-EDV and PRSW, without alteration in -dP/dtmin, Tau and EDPVR. In addition, chronic inhibition reverses the effect of Iso on HF mice.
Although acute CaMKII inhibition can repair systolic function in HF mice, it also exacerbates the diastolic function, whereas chronic inhibition improves both systolic function and cardiac reserve to β-adrenergic stimulation without impairing diastolic function.
Objective: Oxidative stress causes excessive CaMKII activation in heart failure which exacerbates cardiac dysfunction. We determined whether restoration of down-regulated membrane Kv4.3 expression in ...ventricular myocytes can block oxidative CaMKII activation in heart failure. Design and method: Heart failure was induced in mice by severe thoracic aortic banding. Transjugular injection of AAV-Kv4.3 was performed in mice 1 week after banding. Fluorescence spectra were measured using F-4600 spectrophotometer (Hitachi). The slit width and excitation wavelength were set to 5 mm and 270 nm, respectively. Emission spectra were increased from 280 nm to 400 nm (step = 1nm). The spectra of purified proteins were examined, including CaMKII, CaMKII and Ca2+/CaM, CaMKII and Kv4.3, CaMKII, Kv4.3, and Ca2+/CaM. Results: Dissociation of Kv4.3 from Kv4.3-CaMKII molecular complex or down-regulation of Kv4.3 in mouse ventricular myocytes enhanced H2O2-induced CaMKII oxidation and autophosphorylation. Only non-oxidized and unphosphorylated forms of CaMKII have been detected from the Kv4.3 immunoprecipitates in ventricular myocytes with H2O2 Incubation. Fluorescence spectra assay showed that Kv4.3 prevented the transformational change of inactive CaMKII to its active conformation in the presence of Ca2+/CaM and H2O2. In vivo transfection with AAV9-Kv4.3 had no impact on reactive oxygen species in heart failure myocardium but effectively suppressed CaMKII oxidation and activation. Conclusions: Kv4.3 is a potent native suppressor for oxidative CaMKII activation by binding to the regulatory domain and preventing the opening of inhibitory domain in response to Ca2+/CaM and H2O2.
Aims:
The study aimed to compare and analyze the outcomes of high-flow nasal cannula (HFNC) and noninvasive positive-pressure ventilation (NPPV) in the treatment of patients with acute hypoxemic ...respiratory failure (AHRF) who had extubation after weaning from mechanical ventilation.
Methods:
A total 120 patients with AHRF were enrolled into this study. These patients underwent tracheal intubation and mechanical ventilation. They were organized into two groups according to the score of Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II); group A: APACHE II score <12; group B: 12⩽ APACHE II score <24. Group A had 72 patients and patients given HFNC were randomly assigned to subgroup I while patients given NPPV were assigned to subgroup II (36 patients in each subgroup). Group B had 48 patients and patients given HFNC were randomly assigned to subgroup I while patients given NPPV were assigned to subgroup II (24 patients in each subgroup). General information, respiratory parameters, endpoint event, and comorbidities of adverse effect were compared and analyzed between the two subgroups.
Results:
The incidence of abdominal distension was significantly higher in patients treated with NPPV than in those treated with HFNC in group A (19.44% versus 0, p = 0.005) and group B (25% versus 0, p = 0.009). There was no significant difference between the HFNC- and NPPV-treated patients in blood pH, oxygenation index, partial pressure of carbon dioxide, respiratory rate, and blood lactic acid concentration in either group (p > 0.05). Occurrence rate of re-intubation within 72 h of extubation was slightly, but not significantly, higher in NPPV-treated patients (p > 0.05).
Conclusion:
There was no significant difference between HFNC and NPPV in preventing respiratory failure in patients with AHRF with an APACHE II score <24 after extubation. However, HFNC was superior to NPPV with less incidence of abdominal distension.
The reviews of this paper are available via the supplemental material section.
Cardiac symptoms or signs as the first manifestations in acute lymphoblastic leukemia patients are sporadically reported which lead to misdiagnosis or delayed diagnosis due to lack of clinical ...experience and improper diagnosis procedures. Here, we documented the clinical features, procedures of diagnosis, treatments, and outcomes from the so-far reported 30 lymphoblastic leukemia cases that initially presented as cardiac problems and provided management recommendations based on the experiences and lessons learned from these patients to help physicians avoid misdiagnosis and improper treatment.
Doxorubicin (DOX) is an effective anticancer agent. Its clinical use is, however, limited due to its detrimental side effects, especially the cardiotoxicity caused by ROS, mitochondrial dysfunction ...and apoptosis. 3’,4’-dihydroxyflavonol (DiOHF) is a recently developed potent synthetic flavonoid which has been reported to exert anti-oxidative activity in myocardial ischemia–reperfusion injury and maintain the normal mitochondrial function. The aim of this study was to explore the protective effects of DiOHF on the DOX-induced cardiotoxicity. We established DOX-induced cardiotoxicity in H9C2 cells by incubation with 1 μM DOX and in BALB/c mice by DOX injection. DiOHF effectively prevented and reversed the DOX-induced cardiotoxicity, including ROS production, mitochondrial dysfunction, and apoptosis. The DOX-induced cardiotoxicity was accompanied by ERK1/2 activation and abolished by the silence of ERK1, rather than ERK2. Furthermore, DOX treatment in mice induced an increase in serum CK-MB level and myocardial fibrosis with a reduction in left ventricular (LV) function. These detrimental effects were blunted by DiOHF administration. Conclusion: DiOHF suppresses and reverses the DOX-induced cardiotoxicity by inhibiting ROS release, stabilizing mitochondrial function and reducing apoptosis through activation of the ERK1 signaling.
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•Bioinformatic analysis was performed to screen the key gene of PH-LHD.•FABP5 was identified as a potential target for PH-LHD treatment.•Inhibition of FABP5 improved cardiac function ...and mitigated pulmonary fibrosis in PH-LHD.•FABP5 upregulated TGF-β1-mediated expression of pro-fibrotic proteins in PAFs.•FABP5 regulated PAF activation partly via activating wnt/β-catenin pathway.
Pulmonary hypertension secondary to left heart disease (PH-LHD) is a common and fatal disease. However, no effective therapeutic targets have been identified.
Here, we set out to illustrate the functional role and underlying mechanisms of fatty acid-binding protein 5 (FABP5) in PH-LHD development.
We performed a systematic analysis of datasets GSE84704 and GSE16624 to identify differentially expressed genes and then constructed protein-protein interaction network for significant modules. Potential target genes in the modules were validated by RT-qPCR and western blot in a PH-LHD mouse model. PH-LHD or sham mice were treated with FABP5 antagonist SBFI-26 or DMSO for 28 days. The role of FABP5 on cardiac function was determined by echocardiography, its impact on pulmonary vascular remodelling were evaluated with right heart catheter, histological analysis and western blot. In vitro, primary pulmonary adventitial fibroblasts were used to investigate the pro-fibrotic mechanisms involving in FABP5.
FABP5 was the only one dramatically upregulated along with increased protein expression in the established PH-LHD mouse model. Inhibition of FABP5 by SBFI-26 injection abrogated pulmonary artery remodelling in PH-LHD and improved cardiac function. In vitro, SBFI-26 or FABP5 siRNA blunted the TGF-β1-induced fibrotic response in cultured pulmonary adventitial fibroblasts. Mechanistically, FABP5 knockdown inhibited GSK3β phosphorylation and increased β-catenin phosphorylation. The wnt/β-catenin agonist SKL2001 diminished the antifibrotic effect of FABP5 knockdown on pulmonary adventitial fibroblasts under TGF-β1 stimulation.
FABP5 is an important mediator of pulmonary artery remodelling and a potential therapeutic target for PH-LHD.
Abstract
Background
The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic ...targets for DCM.
Methods
We downloaded four datasets from the Gene Expression Omnibus (GEO) database: GSE141910, GSE3585, GSE42955 and GSE79962. Weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed to identify gene panels related to DCM. Meanwhile, the CIBERSORT algorithm was used to estimate the immune cells in DCM tissues. Multiple machine learning approaches were used to screen the hub genes and immune cells. Finally, the diagnostic value of the hub genes was assessed by receiver operating characteristic (ROC) analysis. An experimental mouse model of dilated cardiomyopathy was used to validate the bioinformatics results.
Results
FRZB and EXT1 were identified as hub biomarkers, and the ROC curves suggested an excellent diagnostic ability of the above genes for DCM. In addition, naive B cells were upregulated in DCM tissues, while eosinophils, M2 macrophages, and memory CD4 T cells were downregulated in DCM tissues. The increase in two hub genes and naive B cells was validated in animal experiments.
Conclusion
These results indicated that FRZB and EXT1 could be used as promising biomarkers, and eosinophils, M2 macrophages, resting memory CD4 T cells and naive B cells may also affect the occurrence of DCM.
Background
In December 2019, the outbreak of coronavirus disease 2019 (COVID‐19) started in Wuhan, and is now causing a worldwide pandemic. However, the experience in very elderly patients is very ...limited, which has important implications for the investigation of hospital infection in medical and health institutions.
Methods
Seven patients with confirmed COVID‐19 infection in the Department of Geriatrics at Zhongnan Hospital of Wuhan University were included. Clinical data were retrospectively collected and analyzed. Laboratory tests and chest computed tomography (CT) images from the patients before and after the COVID‐19 infection were compared.
Results
The median age of patients was 91 years old (87–96). Six patients had pneumonia in the last 6 months. Dyspnea occurred in one patient 64 h after the onset of the disease. In the other six patients, minor fatigue with low fever were the only other manifestations of the disease. Lymphopenia and a significant reduction in plasma globulin level was observed compared with levels before the onset of the disease. None had typical chest CT phenotypes during the early stage, except the critically ill patient mentioned who had developed “white lung” and then died. One patient even showed absorption of inflammation compared with previous hypostatic pneumonia.
Conclusions
The ratio of fatal cases in very elderly patients with COVID‐19 is no higher than that reported in non‐elderly patients was, and probably due to a low immune response. However, the elderly patients manifested minor clinical symptoms and atypical changes in chest CT images, which usually lead to misdiagnosis or delayed diagnosis. Geriatr Gerontol Int 2020; 20: 709–714.
The transmural heterogeneity of the contractility in ventricular muscle has not been well‐studied. Here, we investigated the calcium transient and sarcomere contraction/relaxation in the endocardial ...(Endo) and epicardial (Epi) myocytes. Endo and Epi myocytes were isolated from C57/BL6 mice by Langendorff perfusion. Ca2+ transient and sarcomere contraction/relaxation were recorded simultaneously at different stimulation frequencies using a dual excitation fluorescence photomultiplier system. We found that the Endo myocytes have higher baseline diastolic calcium, significantly larger calcium transient and stronger sarcomere shortening than Epi myocytes. However, both the rising and decline phases for calcium transient and sarcomere shortening were slower in Endo than in Epi myocytes. When simulation frequency was increased from 1 to 3 Hz, a greater percent increase in the diastole calcium level, Ca2+ transient and sarcomere shortening amplitude has been observed in the Endo myocytes. Accordingly, the frequency‐dependent acceleration in the decay rate of calcium transient and sarcomere relaxation was more profound in the Endo than in Epi myocytes. Western blot analysis showed that CaMKII activity was significantly higher in Epi than in Endo myocardium before stimulation. However, this transmural heterogeneity was reversed by rapid pacing. CaMKII inhibition by KN93 diminished the frequency‐dependent alterations of Ca2+ transient and sarcomere contraction. Our results suggest that the contractility of ventricular myocytes is heterogeneous. The Endo‐myocardium is the major force generating layer in the heart, both at slow and fast heart rate, and the transmural heterogeneity of CaMKII activation plays an important role in the frequency‐dependent alterations.
Under resting condition, Epi myocytes have a greater calcium transient and sarcomere contraction than Endo myocytes. However, calcium transient and sarcomere contraction were more sensitive to rapid pacing in Endo than in Epi myocytes, which may be partly mediated by the transmural heterogeneity of CaMKII activity.
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