Abstract
Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches. However, the etiology of this rare disease remains unknown. Serum microRNA (miRNA) profiles have been screened to identify novel biomarkers of prognostic values. Here, we identified serum miRNAs that might play an important role in the pathogenesis of MMD. A genome-wide miRNA array analysis of two pooled serum samples from patients with MMD and controls revealed 94 differentially expressed serum miRNAs, including 50 upregulated and 44 downregulated miRNAs. In an independent MMD cohort, real-time PCR confirmed that miR-106b, miR-130a and miR-126 were significantly upregulated while miR-125a-3p was significantly downregulated in serum. GO analysis showed that the differentially expressed serum miRNAs were enriched in metabolic processes, transcription and signal transduction. Pathway analysis showed that the most enriched pathway was mTOR signaling pathway with 16 potential, functional targets. Finally, we found that 16 and 13 aberrant serum miRNAs coordinately inhibited RNF213 and BRCC3 protein expression at the posttranscriptional level, respectively, resulting in defective angiogenesis and MMD pathogenesis. To our knowledge, this is the first study to identify a serum miRNA signature in MMD. Modulation of the mechanism underlying the role of serum miRNAs in MMD is a potential therapeutic strategy and warrants further investigations.
Highlights
Moyamoya disease (MMD) is an idiopathic disorder manifesting stenosis or occlusion of a terminal portion of the internal carotid artery (ICA) or a proximal portion of the anterior cerebral arteries and the middle cerebral arteries (ACAs, MCAs) as well as abnormal vascular networks near the occlusive or stenotic lesions, as shown by cerebral angiography [1].Histopathology of the carotid arteries reveals fibrocellular thickening of the intima
High-resolution magnetic resonance imaging (HR-MRI) manifested smaller, concentric occlusive lesions, which are rarely enhanced in comparison with symptomatic intracranial atherosclerotic disease (ICAD) [8]
Extensive data indicate that serum miRNAs act as potential biomarkers for various diseases [54]
Summary
Moyamoya disease (MMD) is an idiopathic disorder manifesting stenosis or occlusion of a terminal portion of the internal carotid artery (ICA) or a proximal portion of the anterior cerebral arteries and the middle cerebral arteries (ACAs, MCAs) as well as abnormal vascular networks near the occlusive or stenotic lesions, as shown by cerebral angiography [1].Histopathology of the carotid arteries reveals fibrocellular thickening of the intima. Moyamoya vessels show dilated perforating arteries with fibrin deposits, fragmented elastic laminae, and microaneurysms [2, 3]. Radiological findings such as computed tomography (CT) perfusion [4] and magnetic resonance imaging (MRI), are necessary for accurate diagnosis, especially MRI, which assists easier detections of asymptomatic patients with familial MMD [2]. The ‘‘ivy sign’’ refers to the diffuse leptomeningeal enhancement that is found on post contrast MR images in patients with MMD or moyamoya syndrome [6]. High-resolution magnetic resonance imaging (HR-MRI) manifested smaller, concentric occlusive lesions, which are rarely enhanced in comparison with symptomatic intracranial atherosclerotic disease (ICAD) [8]. Essential to investigate the mechanisms underlying the development and progression of the disease
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