Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a
| العنوان: | Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a |
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| المؤلفون: | Michele Geoffrion, Nadiya Khyzha, Katey J. Rayner, Angela Li, Chantal M. Boulanger, My-Anh Nguyen, Myron I. Cybulsky, Andreas Schober, Lei Cai, Mansoor Husain, Eric A. Shikatani, Tong Li, Rickvinder Besla, Ryan E. Temel, Maliheh Nazari-Jahantigh, Henry S. Cheng, Clinton S. Robbins, Jason E. Fish, Zhiqi Chen, Adel Hammoutene, Sonya A. MacParland |
| المصدر: | Circulation Research. 121:354-367 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.medical_specialty, Endothelium, Physiology, medicine.medical_treatment, Cholesterol, VLDL, Bone Marrow Cells, Inflammation, Biology, Article, Mice, 03 medical and health sciences, Internal medicine, medicine, Animals, Mice, Knockout, Bone marrow failure, Endothelial Cells, Hematopoietic stem cell, Atherosclerosis, medicine.disease, 3. Good health, Mice, Inbred C57BL, Endothelial stem cell, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Cytokine, Receptors, LDL, LDL receptor, Diet, Atherogenic, Cattle, Bone marrow, medicine.symptom, Cardiology and Cardiovascular Medicine |
| الوصف: | Rationale: Inflammation is a key contributor to atherosclerosis. MicroRNA-146a (miR-146a) has been identified as a critical brake on proinflammatory nuclear factor κ light chain enhancer of activated B cells signaling in several cell types, including endothelial cells and bone marrow (BM)–derived cells. Importantly, miR-146a expression is elevated in human atherosclerotic plaques, and polymorphisms in the miR-146a precursor have been associated with risk of coronary artery disease. Objective: To define the role of endogenous miR-146a during atherogenesis. Methods and Results: Paradoxically, Ldlr −/− (low-density lipoprotein receptor null) mice deficient in miR-146a develop less atherosclerosis, despite having highly elevated levels of circulating proinflammatory cytokines. In contrast, cytokine levels are normalized in Ldlr −/− ;miR-146a −/− mice receiving wild-type BM transplantation, and these mice have enhanced endothelial cell activation and elevated atherosclerotic plaque burden compared with Ldlr −/− mice receiving wild-type BM, demonstrating the atheroprotective role of miR-146a in the endothelium. We find that deficiency of miR-146a in BM-derived cells precipitates defects in hematopoietic stem cell function, contributing to extramedullary hematopoiesis, splenomegaly, BM failure, and decreased levels of circulating proatherogenic cells in mice fed an atherogenic diet. These hematopoietic phenotypes seem to be driven by unrestrained inflammatory signaling that leads to the expansion and eventual exhaustion of hematopoietic cells, and this occurs in the face of lower levels of circulating low-density lipoprotein cholesterol in mice lacking miR-146a in BM-derived cells. Furthermore, we identify sortilin-1( Sort1 ), a known regulator of circulating low-density lipoprotein levels in humans, as a novel target of miR-146a. Conclusions: Our study reveals that miR-146a regulates cholesterol metabolism and tempers chronic inflammatory responses to atherogenic diet by restraining proinflammatory signaling in endothelial cells and BM-derived cells. |
| تدمد: | 1524-4571 0009-7330 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8be7030121afd7044933204a0124939dTest https://doi.org/10.1161/circresaha.116.310529Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8be7030121afd7044933204a0124939d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244571 00097330 |
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