Chronic hypoxic stress induces epigenetic modifications mainly DNA methylation in cardiac fibroblasts, inactivating tumor suppressor genes (RASSF1A) and activating kinases (ERK1/2) leading to fibroblast proliferation and cardiac fibrosis. The Ras/ERK signaling pathway is an intracellular signal transduction critically involved in fibroblast proliferation. RASSF1A functions through its effect on downstream ERK1/2. The antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), decreases oxidative stress from chronic hypoxia, but its effects on these epigenetic changes have not been fully explored. To test our hypothesis, we used an in-vitro model: wild-type C57B6 male mice (WT) and transgenic males with an extra copy of human hEC-SOD (TG). The studied animals were housed in hypoxia (10% O2) for 21 days. The right ventricular tissue was studied for cardiac fibrosis markers using RT-PCR and Western blot analyses. Primary C57BL6 mouse cardiac fibroblast tissue culture was used to study the in-vitro model, the downstream effects of RASSF-1 expression and methylation, and its relation to ERK1/2. Our findings showed a significant increase in cardiac fibrosis markers: Collagen 1, alpha smooth muscle actin (ASMA), and SNAIL, in the WT hypoxic animals as compared to the TG hypoxic group (p < 0.05). The expression of DNA methylation enzymes (DNMT 1&3b) was significantly increased in the WT hypoxic mice as compared to the hypoxic TG mice (p < 0.001). RASSF1A expression was significantly lower and ERK1/2 was significantly higher in hypoxia WT compared to the hypoxic TG group (p < 0.05). Use of SiRNA to block RASSF1A gene expression in murine cardiac fibroblast tissue culture led to increased fibroblast proliferation (p < 0.05). Methylation of the RASSF1A promoter region was significantly reduced in the TG hypoxic group compared to the WT hypoxic group (0.59 vs. 0.75, respectively). Based on our findings, we can speculate that EC-SOD significantly attenuates RASSF1A gene methylation and can alleviate cardiac fibrosis induced by hypoxia.
Pulmonary arterial hypertension (PAH) is characterized by vascular cell growth and proliferation leading to increased pulmonary vascular resistance, increased pulmonary arterial pressure, right ventricular failure, and death. The main objective of the study was to investigate the prophylactic and therapeutic benefits of over expression of EC-SOD in an animal model with chronic PAH. Chronic PAH was induced by exposing adult male C57BL6 mice to hypoxia (FiO 2 10%) for 3 weeks and Sugen administration, once per week (3 doses). Hemodynamic, histologic, immunohistochemistry, NO Pathway, angiogenesis markers and inflammatory marker studies were performed at 3, 7, 11-and 14-weeks post-exposure. Transgenic mice which overexpress EC-SOD showed less evidence of PAH, associated with mild inflammation which was resolved by 11-14 weeks post exposure compared with wildtype mice under the same conditions. Overexpression of EC-SOD postestablishment of chronic progressive PAH showed significant therapeutic benefits. There was a significant decrease in pulmonary pressures associated with resolution of the chronic changes at the level of the parenchyma in transfected hypoxic wild type animals compared to wild type hypoxic non-transfected. The data suggest that EC-SOD has a marked and a significant role in ameliorating and reversing the chronic, progressive form of PAH. in murine mo del.
We describe an uncommon presentation of a rare disease in a 15-day-old term infant with a sudden increase in head circumference, wide sutures, and open fontanels. Magnetic resonance imaging/magnetic resonance venography showed cerebral venous sinus thrombosis (CVST). The infant had multiple maternal-fetal risk factors for CSVT, with screening coagulation studies within normal limits. Unfractionated heparin was the treatment of choice with a suitable response and no further thrombosis or hemorrhages. Neurologic examination findings on discharge and at 2 months were within normal limits.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.