دورية أكاديمية
Transgenic Expression of Nrf2 Induces a Pro-Reductive Stress and Adaptive Cardiac Remodeling in the Mouse
| العنوان: | Transgenic Expression of Nrf2 Induces a Pro-Reductive Stress and Adaptive Cardiac Remodeling in the Mouse |
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| المؤلفون: | Arun Jyothidasan, Sini Sunny, Saravanakumar Murugesan, Justin M. Quiles, Anil Kumar Challa, Brian Dalley, Senthil Kumar Cinghu, Vivek Nanda, Namakkal-Soorappan Rajasekaran |
| المصدر: | Genes, Vol 13, Iss 9, p 1514 (2022) |
| بيانات النشر: | MDPI AG, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Genetics |
| مصطلحات موضوعية: | Nrf2 transgene, constitutively active Nrf2, RNAseq, echocardiography, reductive stress, Genetics, QH426-470 |
| الوصف: | Nuclear factor, erythroid 2 like 2 (Nfe2l2 or Nrf2), is a transcription factor that protects cells by maintaining a homeostatic redox state during stress. The constitutive expression of Nrf2 (CaNrf2-TG) was previously shown to be pathological to the heart over time. We tested a hypothesis that the cardiac-specific expression of full length Nrf2 (mNrf2-TG) would moderately increase the basal antioxidant defense, triggering a pro-reductive environment leading to adaptive cardiac remodeling. Transgenic and non-transgenic (NTG) mice at 7–8 months of age were used to analyze the myocardial transcriptome, structure, and function. Next generation sequencing (NGS) for RNA profiling and qPCR-based validation of the NGS data, myocardial redox levels, and imaging (echocardiography) were performed. Transcriptomic analysis revealed that out of 14,665 identified mRNAs, 680 were differently expressed (DEG) in TG hearts. Of 680 DEGs, 429 were upregulated and 251 were downregulated significantly (FC > 2.0, p < 0.05). Gene set enrichment analysis revealed that the top altered pathways were (a) Nrf2 signaling, (b) glutathione metabolism and (c) ROS scavenging. A comparative analysis of the glutathione redox state in the hearts demonstrated significant differences between pro-reductive vs. hyper-reductive conditions (233 ± 36.7 and 380 ± 68.7 vs. 139 ± 8.6 µM/mg protein in mNrf2-TG and CaNrf2-TG vs. NTG). Genes involved in fetal development, hypertrophy, cytoskeletal rearrangement, histone deacetylases (HDACs), and GATA transcription factors were moderately increased in mNrf2-TG compared to CaNrf2-TG. Non-invasive echocardiography analysis revealed an increase in systolic function (ejection fraction) in mNrf2-TG, suggesting an adaptation, as opposed to pathological remodeling in CaNrf2-TG mice experiencing a hyper-reductive stress, leading to reduced survival (40% at 60 weeks). The effects of excess Nrf2-driven antioxidant transcriptome revealed a pro-reductive condition in the myocardium leading to an adaptive cardiac remodeling. While pre-conditioning the myocardial redox with excess antioxidants (i.e., pro-reductive state) could be beneficial against oxidative stress, a chronic pro-reductive environment in the myocardium might transition the adaptation to pathological remodeling. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 13091514 2073-4425 |
| العلاقة: | https://www.mdpi.com/2073-4425/13/9/1514Test; https://doaj.org/toc/2073-4425Test |
| DOI: | 10.3390/genes13091514 |
| الوصول الحر: | https://doaj.org/article/8653995b5c7c4b4593f7a7c9ece6f7a1Test |
| رقم الانضمام: | edsdoj.8653995b5c7c4b4593f7a7c9ece6f7a1 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 13091514 20734425 |
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| DOI: | 10.3390/genes13091514 |