Elevated CHCHD4 orchestrates mitochondrial oxidative phosphorylation to disturb hypoxic pulmonary hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a highly prevalent cardiopulmonary disorder characterized by vascular remodeling and increased resistance in pulmonary artery. Mitochondrial coiled-coil-helix-coiled-coil-helix domain (CHCHD)-containing proteins have various important pathophysiological roles. However, the functional roles of CHCHD proteins in hypoxic PAH is still ambiguous. Here, we aimed to investigate the role of CHCHD4 in hypoxic PAH and provide new insight into the mechanism driving the development of PAH. METHODS: Serotype 1 adeno-associated viral vector (AAV) carrying Chchd4 was intratracheally injected to overexpress CHCHD4 in Sprague Dawley (SD) rats. The Normoxia groups of animals were housed at 21% O2. Hypoxia groups were housed at 10% O2, for 8 h/day for 4 consecutive weeks. Hemodynamic and histological characteristics are investigated in PAH. Primary pulmonary artery smooth muscle cells of rats (PASMCs) are used to assess how CHCHD4 affects proliferation and migration. RESULTS: We found CHCHD4 was significantly downregulated among CHCHD proteins in hypoxic PASMCs and lung tissues from hypoxic PAH rats. AAV1-induced CHCHD4 elevation conspicuously alleviates vascular remodeling and pulmonary artery resistance, and orchestrates mitochondrial oxidative phosphorylation in PASMCs. Moreover, we found overexpression of CHCHD4 impeded proliferation and migration of PASMCs. Mechanistically, through lung tissues bulk RNA-sequencing (RNA-seq), we further identified CHCHD4 modulated mitochondrial dynamics by directly interacting with SAM50, a barrel protein on mitochondrial outer membrane surface. Furthermore, knockdown of SAM50 reversed the biological effects of CHCHD4 overexpression in isolated PASMCs. CONCLUSIONS: Collectively, our data demonstrated that CHCHD4 elevation orchestrates mitochondrial oxidative phosphorylation and antagonizes aberrant PASMC cell growth and migration, thereby disturbing hypoxic PAH, which could serve as a promising therapeutic target for PAH treatment.

Therapeutic overexpression of miR-92a-2-5p ameliorated cardiomyocyte oxidative stress injury in the development of diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) results from pathological changes in cardiac structure and function caused by diabetes. Excessive oxidative stress is an important feature of DCM pathogenesis. MicroRNAs (miRNAs) are key regulators of oxidative stress in the cardiovascular system. In the present study, we screened for the expression of oxidative stress-responsive miRNAs in the development of DCM. Furthermore, we aimed to explore the mechanism and therapeutic potential of miR-92a-2-5p in preventing diabetes-induced myocardial damage. METHODS: An experimental type 2 diabetic (T2DM) rat model was induced using a high-fat diet and low-dose streptozotocin (30 mg/kg). Oxidative stress injury in cardiomyocytes was induced by high glucose (33 mmol/L). Oxidative stress-responsive miRNAs were screened by quantitative real-time PCR. Intervention with miR-92a-2-5p was accomplished by tail vein injection of agomiR in vivo or adenovirus transfection in vitro. RESULTS: The expression of miR-92a-2-5p in the heart tissues was significantly decreased in the T2DM group. Decreased miR-92a-2-5p expression was also detected in high glucose-stimulated cardiomyocytes. Overexpression of miR-92a-2-5p attenuated cardiomyocyte oxidative stress injury, as demonstrated by increased glutathione level, and reduced reactive oxygen species accumulation, malondialdehyde and apoptosis levels. MAPK interacting serine/threonine kinase 2 (MKNK2) was verified as a novel target of miR-92a-2-5p. Overexpression of miR-92a-2-5p in cardiomyocytes significantly inhibited MKNK2 expression, leading to decreased phosphorylation of p38-MAPK signaling, which, in turn, ameliorated cardiomyocyte oxidative stress injury. Additionally, diabetes-induced myocardial damage was significantly alleviated by the injection of miR-92a-2-5p agomiR, which manifested as a significant improvement in myocardial remodeling and function. CONCLUSIONS: miR-92a-2-5p plays an important role in cardiac oxidative stress, and may serve as a therapeutic target in DCM.

RNA-Seq analysis and functional characterization revealed lncRNA NONRATT007560.2 regulated cardiomyocytes oxidative stress and apoptosis induced by high glucose.

Hyperglycemia in diabetic patients would cause cardiomyocytes oxidative stress and apoptosis due to the excessive reactive oxygen species (ROS) accumulation, leading to progressive deterioration of cardiac structure and function. Long noncoding RNAs (lncRNAs) play essential roles on controlling oxidative stress and apoptotic activity. In the present study, RNA sequencing was used to detect the differentially expressed lncRNAs during high glucose-induced cardiomyocytes oxidative stress and apoptosis. A total of 306/400 lncRNAs were identified as differentially expressed, including 156/198 lncRNAs with increased expression and 150/202 lncRNAs with decreased expression at 24 hours/48 hours after high-glucose stimulation respectively. Among these dysregulated lncRNAs, 45 lncRNAs were consistently differentially expressed in cardiomyocytes at both two time points after high-glucose stimulation. Twenty lncRNAs were upregulated and 25 lncRNAs were downregulated at both 24 hours and 48 hours, respectively. The top three upregulated lncRNAs, NONRATT029805.2, NONRATT007560.2, and NONRATT002486.2 were selected for functional studies to determine the role in oxidative stress-related apoptosis. The results showed that inhibition of non-ratt007560.2 could abate the formation of ROS and reduce apoptosis, suggesting NONRATT007560.2 might play critical roles in the development of cardiomyopathy. The dysregulated lncRNAs might participate in regulating cardiomyocytes oxidative stress and apoptosis. These findings would be important theoretical and experimental basis for investigation on diabetic cardiomyopathy pathogenesis.

Circuity analyses of HSR network and high-speed train paths in China.

Circuity, defined as the ratio of the shortest network distance to the Euclidean distance between one origin-destination (O-D) pair, can be adopted as a helpful evaluation method of indirect degrees of train paths. In this paper, the maximum circuity of the paths of operated trains is set to be the threshold value of the circuity of high-speed train paths. For the shortest paths of any node pairs, if their circuity is not higher than the threshold value, the paths can be regarded as the reasonable paths. With the consideration of a certain relative or absolute error, we cluster the reasonable paths on the basis of their inclusion relationship and the center path of each class represents a passenger transit corridor. We take the high-speed rail (HSR) network in China at the end of 2014 as an example, and obtain 51 passenger transit corridors, which are alternative sets of train paths. Furthermore, we analyze the circuity distribution of paths of all node pairs in the network. We find that the high circuity of train paths can be decreased with the construction of a high-speed railway line, which indicates that the structure of the HSR network in China tends to be more complete and the HSR network can make the Chinese railway network more efficient.

[IgG4-related lung disease:a clinical analysis and literature review].

OBJECTIVE: To summarize the clinical features, diagnosis and treatment experience of IgG4-related lung disease for the sake of improving clinical understanding of this disease and reducing the misdiagnosis and mistreatment rates. METHODS: To analyze the general situation, clinical manifestation, laboratory examination, histopathology, therapy and prognosis of 2 patients with IgG4-related lung disease, who were admitted in the department of respiratory diseases at Changhai Hospital. Publications related to IgG4 lung disease were reviewed. RESULTS: Both patients were male with elevated serum IgG4 level (2.25 g/L and 10 g/L respectively). In one patient, radiologic finding showed solid nodules in the lung with ileocecal involvement. He responded well to glucocorticoid. The other patient's computed tomography of lung demonstrated bronchovascular type. Glucocorticoid therapy was effective to both patients. A total of 69 cases with IgG4-related lung disease were reported worldwide, among whom 39 cases were admitted with chief complaints of respiratory symptoms. However, there were 41 cases suffering extra-pulmonary involvement. Serum IgG4 levels detected in 48 cases were significantly elevated (307-52 500 mg/L). The radiographic pattern of solid nodule type was the most frequent, accounting for 50.7% (35 cases). A total of 31 (44.9%) patients received glucocorticoid therapy with good response and prognosis. CONCLUSION: IgG4-related lung disease is a rare immunological disease lack of specific symptoms. Serum immunological examination, radiographic characteristics and histopathology should be comprehensively considered for diagnosis. Glucocorticoid is so far the most acceptable therapy with good response rate.

RETRACTED: Effect of thioredoxin-interacting protein on Wnt/ß-catenin signaling pathway and diabetic myocardial infarction.

OBJECTIVE: To explore the regulatory role of thioredoxin-interacting protein (TXNIP) in Wnt/ß-catenin signaling pathway and therefore to elucidate its function in diabetic myocardial infarction. METHODS: Diabetic myocardial infarction models were generated in mice. The expression levels of TXNIP and ß-catenin and level of reactive oxygen species (ROS) were determined and compared with those in control group. Human umbilical vein endothelial cells were treated with high-concentration glucose and/or silencing TXNIP and/or H2O2. After 24 h, expression levels of TXNIP, ß-catenin and its downstream protein Cyclin D1, and C-myc gene were determined by real-time PCR, Western blot and immunofluorescence method. The cell proliferation and ROS production capability in different groups were determined by methyl thiazolyl tetrazolium assay. RESULTS: Compared with control group, hyperglycemia significantly up-regulated TXNIP expression and ROS level in the myocardium and endothelial cells of myocardial infarction area, whereas the ß-catenin expression was down-regulated, and the difference was statistically significant (P < 0.05). In comparison with Human umbilical vein endothelial cells in the control group, high glucose level increased the levels of TXNIP expression and ROS level in cells, but reduced cell proliferation as well as migration capability and expression levels of ß-catenin, Cyclin D1 and C-myc; the difference was statistically significant (P < 0.05). However, this trend can be partially reversed by silencing TXNIP. CONCLUSIONS: Diabetic myocardial ischemia could up-regulate levels of TXNIP expression and ROS production in endothelial cells of myocardial infarction area. The regulation effect of TXNIP on ß-catenin was partially achieved by changing ROS levels.

Transcatheter closure of atrial septal defects improves cardiac remodeling and function of adult patients with permanent atrial fibrillation.

BACKGROUND: Permanent atrial fibrillation (AF) is the most common form of dysrhythmia associated with atrial septal defects (ASDs) in patients older than 40 years. However, little is known about cardiac remodeling after transcatheter closure in patients with permanent AF. This study was designed to compare cardiac events and remodeling effects after transcatheter closure in such patients. METHODS: Clinical data of 289 adult patients older than 40 years who underwent ASD closure at our center were analyzed retrospectively. Of them, 63 patients with permanent AF were assigned to the case group, and the other 226 patients without permanent AF were assigned to the control group. Cardiac events and changes in left and right cardiac cavity dimensions before the procedure and 6 months after the procedure were compared between the two groups. RESULTS: Patients in the case group were significantly older than those in the control group. The right ventricular (RV) volume and right atrial (RA) volume were decreased significantly in both the groups during a median follow-up period of 6 months after closure (P < 0.001). The left atrial dimensions, left ventricular end-systolic dimensions, left ventricular end-diastolic dimensions and left ventricular ejection fraction showed no significant change before and after the procedure in both the groups. Changes of the RV volume and RA volume in the case group were significantly smaller than those in the control group (P = 0.005 and P < 0.001). The New York Heart Association cardiac function was improved in both the groups during the 6 months follow-up period. CONCLUSIONS: The transcatheter closure of ASD can improve the cardiac remodeling and cardiac function in patients with or without AF.