Widiapradja Alexander, Connery Heather, Bullock Martyn, Kasparian Ainsley O, Clifton-Bligh Roderick, Levick Scott P
Department of Physiology, Pharmacology, and Toxicology, West Virginia University Health Sciences Center, Morgantown, WV, USA.
Kolling Institute, St Leonards, NSW, Australia.
Cell Mol Life Sci. 2024 Dec 7;81(1):484. doi: 10.1007/s00018-024-05513-8.
The orphan nuclear receptor Nr4a1 has complex biological functions and has been implicated in numerous diseases, including cardiovascular disease. While protective in atherosclerosis and myocardial ischemia, Nr4a1 has been shown to cause cardiac fibrosis in non-ischemic adverse remodeling of the heart. However, mechanisms underlying these actions are still poorly understood. Accordingly, we sought to: (1) understand the contribution of Nr4a1 to the inflammatory environment including macrophage phenotype; and (2) determine the contribution of Nr4a1 to cardiac fibroblast phenotype in the fibrotic heart. Wild type and Nr4a1 mice were infused with angiotensin II (1500 ng/kg/min) to induce cardiac fibrosis and diastolic dysfunction. Nr4a1 deletion prevented cardiac fibrosis and maintained normal diastolic function. We determined that macrophages lacking Nr4a1 had distinctly different phenotypes to wild type macrophages, with Nr4a1 deletion preventing the induction of a pro-inflammatory macrophage phenotype, instead promoting an anti-inflammatory phenotype. This had functional consequences in that macrophages lacking Nr4a1 showed a reduced ability to induce cardiac fibroblast migration. Interestingly, deletion of Nr4a1 in isolated cardiac fibroblasts also had profound effects on their phenotype and function, with these cells not able to produce excess extracellular matrix proteins, convert to a myofibroblast phenotype, or respond to macrophage stimuli. Nr4a1 causes cardiac fibrosis and subsequent diastolic dysfunction by inducing a pro-inflammatory phenotype in macrophages and by pushing cardiac fibroblasts towards a pro-fibrotic phenotype in response to pro-fibrotic stimuli. Nr4a1 is also critical for macrophage/fibroblast interactions.
孤儿核受体Nr4a1具有复杂的生物学功能，并且与包括心血管疾病在内的多种疾病有关。虽然Nr4a1在动脉粥样硬化和心肌缺血中具有保护作用，但已表明它在心脏的非缺血性不良重塑中会导致心脏纤维化。然而，这些作用背后的机制仍知之甚少。因此，我们试图：（1）了解Nr4a1对包括巨噬细胞表型在内的炎症环境的作用；（2）确定Nr4a1对纤维化心脏中心肌成纤维细胞表型的作用。对野生型和Nr4a1基因敲除小鼠输注血管紧张素II（1500 ng/kg/min）以诱导心脏纤维化和舒张功能障碍。Nr4a1基因缺失可预防心脏纤维化并维持正常的舒张功能。我们确定，缺乏Nr4a1的巨噬细胞与野生型巨噬细胞具有明显不同的表型，Nr4a1基因缺失可阻止促炎巨噬细胞表型的诱导，反而促进抗炎表型。这产生了功能性后果，即缺乏Nr4a1的巨噬细胞诱导心肌成纤维细胞迁移的能力降低。有趣的是，在分离的心肌成纤维细胞中删除Nr4a1也对其表型和功能产生了深远影响，这些细胞无法产生过量的细胞外基质蛋白、转变为肌成纤维细胞表型或对巨噬细胞刺激作出反应。Nr4a1通过在巨噬细胞中诱导促炎表型以及在促纤维化刺激下将心肌成纤维细胞推向促纤维化表型而导致心脏纤维化和随后的舒张功能障碍。Nr4a1对巨噬细胞/成纤维细胞相互作用也至关重要。
