Khurana Sandhya, Peng Siyuan, McDonald Erika, Yates William, Venkataraman Krishnan, Tai T C
Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, ON, Canada.
Department of Chemistry & Biochemistry, Laurentian University, Sudbury, ON, Canada.
Neurosci Lett. 2018 Feb 14;666:169-174. doi: 10.1016/j.neulet.2017.12.056. Epub 2017 Dec 27.
Epidemiological studies show a strong correlation between Obstructive Sleep Apnea (OSA) and cardiovascular disorders. OSA patients experience intermittent hypoxia (IH), characterized by brief, but recurring episodes of cessation in breathing. These patients have higher levels of circulating catecholamines and an increased incidence of hypertension; however the mechanisms defining this association are not clearly established. Genetic linkage studies have associated the phenylethanolamine N-methyltransferase (PNMT) gene to the development of hypertension. PNMT, the terminal enzyme in the catecholamine biosynthetic pathway, directly responsible for adrenaline synthesis, is elevated in hypertensive animals. Recent studies utilizing PC12 cells show an increase in the expression of PNMT and its regulatory transcription factors when exposed to continuous hypoxia. The current study examined the regulation of PNMT under conditions of IH. The mRNA of PNMT was analyzed to assess if the regulation of PNMT expression entails alternative splicing. The mRNA and protein of transcription factors HIF1α, Egr-1, GR, and Sp1, were analyzed to assess the cellular pathways involved in regulating PNMT expression. A PNMT promoter-driven luciferase assay was performed to evaluate promoter activity under IH. Preliminary results lay an antecedent for the regulation of PNMT by IH conceivably via an altered regulation of its transcription factors and establish a possible role for PNMT in IH mediated hypertension in OSA patients.
流行病学研究表明，阻塞性睡眠呼吸暂停（OSA）与心血管疾病之间存在密切关联。OSA患者会经历间歇性缺氧（IH），其特征为呼吸短暂但反复停止。这些患者循环儿茶酚胺水平较高，高血压发病率增加；然而，确定这种关联的机制尚未明确。基因连锁研究已将苯乙醇胺N-甲基转移酶（PNMT）基因与高血压的发生联系起来。PNMT是儿茶酚胺生物合成途径中的末端酶，直接负责肾上腺素的合成，在高血压动物中升高。最近利用PC12细胞的研究表明，当暴露于持续缺氧时，PNMT及其调节转录因子的表达会增加。本研究检测了IH条件下PNMT的调节情况。分析PNMT的mRNA以评估PNMT表达的调节是否涉及可变剪接。分析转录因子HIF1α、Egr-1、GR和Sp1的mRNA和蛋白质，以评估参与调节PNMT表达的细胞途径。进行了PNMT启动子驱动的荧光素酶测定，以评估IH条件下的启动子活性。初步结果为IH可能通过改变其转录因子的调节来调节PNMT奠定了基础，并确定了PNMT在OSA患者IH介导的高血压中的可能作用。
