Research paperSex-dichotomous effects of NOS1AP promoter DNA methylation on intracranial aneurysm and brain arteriovenous malformation
Introduction
Cerebrovascular disease (CD) leading to sudden death is a major cause of mortality worldwide [37]. It is considered the number one killer of people in middle-income countries. CD is usually characterized by cerebral vascular lesions and stroke. The most common types of CD are intracranial aneurysm (IA) and brain arteriovenous malformation (BAVM). The pathogeneses and etiologies of these diseases are still unclear. A commonly accepted hypothesis is that CD is a complex disease resulting from the interaction of several genetic and environmental factors [46]. Aberrant epigenetic modifications may bridge the environmental and genetic factors and have pathological consequences [5], such as cerebrovascular events [50], brain tumor [3], and coronary heart disease [21]. Epigenetic regulation modulates gene expression via DNA methylation and histone modifications. DNA methylation is considered the most important regulatory modification in epigenetics and cytosine methylation often occurs at cytosine-phosphate-guanine (CpG) dinucleotides in humans [39]. Promoter DNA methylation is known to repress gene expression and plays an important role in the pathogenesis of many diseases [31].
Nitric oxide (NO) is regarded as a central element of the cerebral circulation [44] and a potent dilator of cerebral blood vessels [48]. The main source of NO is neuronal nitric oxide synthase (nNOS) from the central nervous system. nNOS and endothelial nitric oxide synthase (eNOS) are both highly expressed in the arterial walls, particularly in nerve and endothelial cells [47]. nNOS and eNOS coordinately function in relieving hemodynamic force, and thereby aid in protecting the arterial walls from vascular inflammation [1]. Evidence has shown that both eNOS and nNOS have significant protective effects against various arterial diseases, including cardiovascular disease [9] and cerebral vascular disease [22], [30]. Recent studies have suggested that an eNOS deficiency could be compensated by nNOS upregulation in cerebral arteries. eNOS and nNOS coordinate to prevent the formation of IA or BAVM [1], [4]. Nitric oxide synthase 1 adaptor protein (NOS1AP) is a cytosolic protein that binds to the signaling molecule nNOS. NOS1AP is involved in glutamate-induced neuronal apoptosis and harbors a modified O-linked N-acetylglucosamine [52]. The expression of NOSIAP is low in the hippocampus and maximal in the cerebral cortex and medulla oblongata [20]. NOS1AP has been implicated in many human brain diseases such as neurodegeneration [52], stroke [42], psychiatric disorders [13], and post-traumatic stress disorder [28].
We hypothesized that DNA methylation in the NOS1AP promoter contributes to the risk of IA and BAVM. Accordingly, the goal of this study was to verify the association between DNA methylation in the NOS1AP promoter and the occurrence of IA and BAVM.
Section snippets
Sample collection
Our study included 96 unrelated inpatients from the Department of Neurosurgery in the Ningbo First Hospital in Ningbo city of Zhejiang province, China. All individuals were Han Chinese, aged between 26 and 70, and from Ningbo in Eastern China. Of these participants, 70 (48 IA patients and 22 BAVM patients) were diagnosed with CD using magnetic resonance imaging and angiography according to standardized definitions [2]. The remaining 26 with traumatic brain injury were included as the no-CD
Results
A total of 48 IA patients, 22 BAVM patients, and 26 age- and gender-matched controls were enrolled in the study. The clinical characteristics for patients and controls are shown in Table 2. No significant differences in clinical characteristics were found among the three groups. A fragment harboring 5CpG dinucleotides was selected to determine the level of DNA methylation in the NOS1AP promoter (Fig. 1). Strong correlations in the levels of DNA methylation were detected between CpG1 and CpG3 (
Discussion
NOS1AP is a ligand of nNOS and contributes to the NMDAR/nNOS-dependent regulation of neuronal functions, such as glutamate-induced neuronal apoptosis [52]. nNOS is considered a key factor in vascular dysfunction [33]. Recent evidence has shown that the activation of nNOS may play an important role in the pathogenesis of systemic inflammatory responses in vascular dysfunction [33], [41]. As a mediator of nNOS signaling, NOS1AP has a competitive relationship with nNOS in different signaling
Conclusion
Our results suggest that gender modulates the effects of NOS1AP promoter DNA methylation in IA and BAVM patients. Our results also confirm that regular tobacco smoking is associated with increased NOS1AP methylation in humans. Additional studies with larger sample sizes are required to replicate and extend these findings.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This study was supported by grants from the Ningbo People of Science and Technology Projects (2015C50005), Ningbo Natural Science Foundation (2014A610260, 2015A610232), Zhejiang Traditional Chinese Medicine Science and Technology Projects (2015ZB100), Ningbo Youth and Doctor Foundation, and Ningbo High Level Innovative Talents Program.
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