Search

Inflammation triggers pulmonary vascular remodelling. Ferroptosis, a nonapoptotic form of cell death that is triggered by iron-dependent lipid peroxidation and contributes to the pathogenesis of several inflammation-related diseases, but its role in pulmonary hypertension (PH) has not been studied. We examined endothelial cell ferroptosis in PH and the potential mechanisms. Pulmonary artery endothelial cells (PAECs) and lung tissues from monocrotaline (MCT)-induced PH rats were analysed for ferroptosis markers, including lipid peroxidation, the labile iron pool (LIP) and the protein expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1) and NADPH oxidase-4 (NOX4). The effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on endothelial cell ferroptosis and pulmonary vascular remodelling in MCT-induced rats were studied in vitro and in vivo. Ferroptosis was observed in PAECs from MCT-induced PH rats in vitro and in vivo and was characterized by a decline in cell viability accompanied by increases in the LIP and lipid peroxidation, the downregulation of GPX4 and FTH1 expression and the upregulation of NOX4 expression. High-mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signalling was measured by western blotting. These changes were significantly blocked by Fer-1 administration in vitro and in vivo. These results suggest that Fer-1 plays a role in inhibiting ferroptosis-mediated PAEC loss during the progression of PH. The ferroptosis-induced inflammatory response depended on the activation of HMGB1/TLR4 signalling, which activated the NLRP3 inflammasome in vivo. We are the first to suggest that pulmonary artery endothelial ferroptosis triggers inflammatory responses via the HMGB1/TLR4/NLRP3 inflammasome signalling pathway in MCT-induced rats. Treating PH with a ferroptosis inhibitor and exploring new treatments based on ferroptosis regulation might be promising therapeutic strategies for PH.

Objective To assess the performance of conventional ultrasound (US) combined with strain elastography (SE) in the Breast Imaging Reporting and Data System (BI-RADS) category 4 lesions on mammography. Methods Women with breast lesions identified as having mammography BI-RADS 4 lesions and underwent US examination were included in China. US features and US BI-RADS assessment were recorded in real-time and prospectively reported. The pathological result was referred to as the gold standard. The performance of US in the mammographic BI-RADS category 4 lesions was evaluated. Diagnostic performances of US BI-RADS, SE and combined both were compared. Results 751 women with 751 breast lesions classified as mammographic BI-RADS category 4 were included. For mammographic findings, 530 (70.6%) were true-positive and 221 (29.4%) were false-positive. Conventional US achieved higher positive predictive value (PPV) than mammography (78.5% vs 70.6%, p=0.001). The specificity increased from 34.4% to 47.1% (p Conclusions Conventional US combined with SE is a helpful tool for the non-invasive examination of breast lesions classified as BI-RADS category 4 on mammography. It helped increase the PPV and had the potential to avoid unnecessary biopsies of BI-RADS category 4 lesions detected on mammography. Micro Abstract We assessed the performance of conventional ultrasound (US) combined with strain elastography (SE) in the Breast Imaging Reporting and Data System (BI-RADS) category 4 lesions on mammography. 751 women with 751 breast lesions classified as mammographic BI-RADS category 4 were included. Conventional US combined with SE helped increase the PPV and had the potential to avoid unnecessary biopsies of BI-RADS category 4 lesions detected on mammography.

Aims Although interferon regulatory factor 7 (IRF7) has known roles in regulating the inflammatory response, vascular smooth muscle cell proliferation, and apoptosis, its role in the pathogenesis of pulmonary hypertension (PH) is unclear. We hypothesized that IRF7 overexpression could inhibit pulmonary vascular remodeling and slow the progression of PH. Main methods IRF7 mRNA and protein levels in the lung samples and pulmonary artery smooth muscle cells (PASMCs) isolated from monocrotaline (MCT)-induced PH rats were assessed. We evaluated the effects of IRF7 on inflammation, proliferation, and apoptosis using an in vivo MCT-induced PH rat model and in vitro methods. Key findings We noted decreased IRF7 mRNA and protein levels in the pulmonary vasculature of MCT-induced PH rats. IRF7 upregulation attenuated pulmonary vascular remodeling, decreased the pulmonary artery systolic pressure, and improved the right ventricular (RV) structure and function. Our findings suggest that nuclear factor kappa-Bp65 (NF-κBp65) deactivation could confer pulmonary vasculature protection, reduce proinflammatory cytokine (tumor necrosis factor-α, interleukin 6) release, and decrease PASMC proliferation and resistance to apoptosis via deactivating transcription factor 3 (ATF3) signaling. ATF3 deactivation induced the downregulation of the proliferation-dependent genes proliferating cell nuclear antigen (PCNA), cyclin D1, and survivin, coupled with increased levels of B cell lymphoma-2-associated X protein (Bax)/B cell lymphoma-2 (Bcl2) ratio, and cleaved caspase-3 in PASMCs. Significance Our findings showed that IRF7 downregulation could initiate inflammation via NF-κBp65 signaling, causing PASMC proliferation via ATF3 signaling pathway activation. Therefore, IRF7 could be a potential molecular target for PH therapy.

Background Right ventricular structure and function is a major predictor of outcomes in pulmonary hypertension (PH), yet the underlying mechanisms remain poorly understood. Growing evidence suggests the importance of autophagy in cardiac remodeling; however, its dynamics in the process of right ventricle(RV) remodeling in PH has not been fully explored. We sought to study the time course of cardiomyocyte autophagy in the RV in PH and determine whether mammalian target of rapamycin (mTOR) and Beclin-1 hypoxia-related pro-autophagic pathways are underlying mechanisms. Methods Rats were studied at 2, 4, and 6 weeks after subcutaneous injection of 60 mg/kg monocrotaline (MCT) (MCT-2 W, 4 W, 6 W) or vehicle (CON-2 W, 4 W, 6 W). Cardiac hemodynamics and RV function were assessed in rats. Autophagy structures and markers were assessed using transmission electron microscope, RT-qPCR, immunohistochemistry staining, and western blot analyses. Western blot was also used to quantify the expression of mTOR and Beclin-1 mediated pro-autophagy signalings in the RV. Results Two weeks after MCT injection, pulmonary artery systolic pressure increased and mild RV hypertrophy without RV dilation was observed. RV enlargement presented at 4 weeks with moderately decreased function, whereas typical characteristics of RV decompensation and failure occurred at 6 weeks thus demonstrating the progression of RV remodeling in the MCT model. A higher LC3 (microtubule- associated protein light chain 3) II/I ratio, upregulated LC3 mRNA and protein levels, as well as accumulation of autophagosomes in RV of MCT rats indicated autophagy induction. Autophagy activation was coincident with increased pulmonary artery systolic pressure. Pro-autophagy signaling pathways were activated in a RV remodeling stage-dependent manner since phospho-AMPK (adenosine monophosphate-activated protein kinase)-α were primarily upregulated and phospho-mTOR suppressed in the RV at 2 and 4 weeks post-MCT injection, whearas, BNIP3 (Bcl2-interacting protein 3) and beclin-1 expression were relatively low during these stages, they were significantly upregulated after 6 weeks in this model. Conclusions Our findings provide evidence of sustained activation of autophagy in RV remodeling of MCT induced PH model, while pro-autophagic signaling pathways varied depending on the phase.

Objective This study evaluated the feasibility of assessing left atrium (LA) function and asynchrony in patients with rheumatic mitral stenosis (MS) before and immediately after percutaneous balloon mitral valvuloplasty (PBMV) by real time three-dimensional echocardiography (RT3DE). Methods Thirty patients with rheumatic MS who underwent PBMV and 30 controls were enrolled. RT3DE was used to measure LA volume and function, the standard deviation of time to the minimal systolic volume divided into 16 segments, 12 segments, or 6 segments (Tmsv 16-SD, Tmsv 12-SD, Tmsv 6-SD), and the maximum differences (Tmsv 16-Dif, 12-Dif, 6-Dif) in RT3DE derived values in MS patients before and 2 days after PBMV were obtained and compared with those of normal controls. The associations between the LA asynchrony and heart volume, function, mitral valve area (MVA), maximum mitral valve gradient (MVGmax), mean mitral valve gradient (MVGmean), and mean LA pressure (MLAP) were investigated. Results Left atrium asynchrony indexes were significantly larger, and LA function parameters were significantly lower in the MS group than in the controls (P

Background: The purpose of this study was to investigate the relationship between left atrial (LA) myocardial function and left ventricular (LV) diastolic dysfunction in subjects with preserved LV ejection fraction (LVEF). Methods: The study included a group of 118 hypertensive patients and normal subjects. LV diastolic dysfunction was classified into 4 groups: none, mild, moderate, and severe. Peak strain rates in systole (S-Sr), early diastole (E-Sr), and late diastole (A-Sr) were obtained from Doppler-derived strain rate imaging to evaluate LA myocardial deformation. Results: No significant difference in LA dimension was observed in subjects with different degrees of LV diastolic dysfunction, although LA myocardial strain rate parameters were all significantly different across the 4 groups (all with P < 0.001). Compared with patients of normal diastolic function, the mild diastolic dysfunction group had significantly lower E-Sr (0.62 ± 0.18 s−1 vs 1.20 ± 0.38 s−1, P < 0.001) and S-Sr (0.78 ± 0.16 s−1 vs 0.94 ± 0.22 s−1, P < 0.001) but increased A-Sr (1.14 ± 0.29 s−1 vs 1.00 ± 0.23 s−1, P = 0.05). Conclusions: By using strain rate imaging, significant changes of LA deformation in response to different stages of LV diastolic dysfunction were detected in subjects with preserved LVEF. Quantification of LA myocardial function rather than LA size may have the potential to predict early LV diastolic dysfunction in subjects with preserved LVEF. Copyright © 2010 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.

Previous studies have demonstrated that polydatin, a crystal component extracted from the root stem of the perennial herbage Polygonum Cuspidatum Sieb.et Zucc, exerts a neuroprotective effect on cerebral injury induced by ischemia/reperfusion. To investigate the possible mechanism of this action, we determined the effects of polydatin on the expression of cell adhesion molecules (CAMs) after ischemia-induced cerebral injury. Rats were treated with polydatin (i.v.) immediately after the operation of middle cerebral artery occlusion (MCAO) for 1 h. It was found that polydatin improved neurological deficits and reduced the volume of brain infarction. In addition, polydatin decreased the levels of CAMs relative to the control (MCAO alone); these included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, L-selectin and Integrins. These results suggest that polydatin exerts protective effects likely via inhibition of the expression of various CAMs; polydatin may be a potential agent for treatment of brain injury associated with stroke.

Objectives The purpose of this study was to investigate the changes in the morphologic characteristics and performance of the right atrium (RA) that occur secondary to structural remodeling of the right ventricle (RV) in patients with pulmonary hypertension by real-time 3-dimensional echocardiography (3DE). Methods Comprehensive 2-dimensional echocardiography and real-time 3DE were performed in 112 patients and 30 healthy control participants. Patients with pulmonary hypertension were divided into 3 subgroups: 1, normal RV dimension (n = 34); 2, RV enlargement and preserved systolic function (n = 36); and 3, RV enlargement and systolic dysfunction (n = 42). Results Patients had larger RA volume parameters and lower RA passive emptying fractions than controls (P< .01). The RA active emptying fraction was higher in patient groups 1 (mean ± SD, 45.5% ± 10.7%) and 2 (40.1% ± 4.0%) and lower in group 3 (19.3% ± 4.3%) compared to controls (35.4% ± 3.5%). The RA total emptying fraction was similar between groups 1 and 2 (59.3% ± 9.7% and 52.6% ± 3.4%, respectively) but was significantly lower in group 3 compared to controls (26.8% ± 5.1% versus 55.2% ± 5.1%). Right atrial volume and phasic function were substantially affected by RV structure and function. Conclusions Real-time 3DE is a feasible, repeatable, and noninvasive method for accessing cyclic RA volume and function changes, such as those that occur with varying RV status in patients with pulmonary hypertension.

To investigate the effects of timosaponins, one group of the two major components of Anemarrhean asphodeloides Bge, on the learning and memory capacities of rats with dementia induced by amyloid beta-peptide (25-35) [Abeta (25-35)].Sixty SD rats were randomized into 6 groups (n=10) and except for those in the control group, all other rats were subjected to lateral cerebral ventriclar injection of aggregated Abeta (25-35) to prepare rat models of dementia. Twenty- four hours after the injection, the rats received intragastric administration of timosaponins at 3 different doses (treatment group) or Ginkgo biloba extract EGB761 on a daily basis for 14 consecutive days. From postoperative days 8 to 14 after Abeta (25-35) injection, Morris water maze test was performed to evaluate the effects of Abeta (25-35) and the therapeutic agents timosaponins on the learning and memory capacity of the rats. On day 14, the level of malonaldehyde (MDA), superoxide dismutase (SOD) activity and total antioxidation capacity in the brain tissue of the rats were measured.Abeta (25-35) induced significant learning and memory impairment in the rats, which had lowered SOD activity and total antioxidation capacity (P0.01) with elevated MDA level (P0.05). Compared with the rats in dementia model group, those receiving timosaponin treatment at different doses all manifested alleviation of learning and memory impairment (P0.05), with enhanced SOD activity (P0.05) and total antioxidation capacity (P0.01) and reduced MDA level (P0.05) in the brain tissue.Timosaponins can remarkably enhance the learning and memory capacities in rats with Abeta (25-35)-induced dementia, presumably in relation to their actions to promote the scavenging of the free radicals.