Department of Psychiatry, Harvard Medical School, Laboratory of Molecular and Developmental Neurobiology, McLean Hospital, 115 Mill Street, MRC Rm 116, Mail Stop 144, Belmont, MA 02478, USA.
Cell Mol Neurobiol. 2010 Nov;30(8):1451-7. doi: 10.1007/s10571-010-9567-z. Epub 2010 Nov 3.
Stress elicits adrenal epinephrine and cortisol release into the bloodstream to initiate physiological and behavioral responses to counter and overcome stress, the classic "fight or flight" response (Cannon and De La Paz, Am J Physiol 28:64-70, 1911). Stress and the stress hormone epinephrine also contribute to the pathophysiology of illness, e.g., behavioral disorders, cardiovascular disease, and immune dysfunction. Epinephrine itself is regulated by stress through its biosynthesis by phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). Single and repeated immobilization (IMMO) stress in rats stimulates adrenal PNMT mRNA and protein expression via the transcription factors, Egr-1 and Sp1. Moderate hypoxic stress increases PNMT promoter-driven gene expression and endogenous PNMT mRNA and protein in PC12 cells. Induction is initiated through cAMP and PLC signaling, with PKA, PKC, PI3K, ERK1/2 MAPK, and p38 MAPK continuing downstream signal transduction, followed by activation of HIF1α, Egr-1, and Sp1. While functional Egr-1 and Sp1 binding sites exist within the proximal PNMT promoter, a putative hypoxia response element is a weak HIF binding site. Yet, HIF1α overexpression increases PNMT promoter-driven luciferase activity and endogenous PNMT. When the Egr-1 or Sp1 sites are mutated, HIF1α does not stimulate the PNMT promoter. siRNA knock down of Egr-1 or Sp1 prevents promoter activation while siRNA knock down of HIF1α inhibits Egr-1 and Sp1 induction. Findings suggest that hypoxia activates the PNMT gene indirectly via HIF1α stimulation of Egr-1 and Sp1. Thus, for stress-induced illnesses where adrenergic dysfunction is implicated, HIF1α may be an "on-off" switch regulating adrenergic responses to stress and a potential target for therapeutic intervention.
应激会导致肾上腺素和皮质醇释放到血液中，从而启动生理和行为反应，以对抗和克服应激，即经典的“战斗或逃跑”反应（Cannon 和 De La Paz，Am J Physiol 28：64-70，1911）。应激和应激激素肾上腺素也会导致疾病的病理生理学，例如行为障碍、心血管疾病和免疫功能障碍。肾上腺素本身通过苯乙醇胺 N-甲基转移酶（PNMT，EC 2.1.1.28）的生物合成受到应激的调节。在大鼠中，单次和重复束缚（IMMO）应激通过转录因子 Egr-1 和 Sp1 刺激肾上腺 PNMT mRNA 和蛋白表达。中度低氧应激会增加 PC12 细胞中 PNMT 启动子驱动的基因表达以及内源性 PNMT mRNA 和蛋白。诱导是通过 cAMP 和 PLC 信号转导启动的，PKA、PKC、PI3K、ERK1/2 MAPK 和 p38 MAPK 继续下游信号转导，随后激活 HIF1α、Egr-1 和 Sp1。虽然在近端 PNMT 启动子内存在功能性 Egr-1 和 Sp1 结合位点，但假定的低氧反应元件是一个弱 HIF 结合位点。然而，HIF1α 的过表达会增加 PNMT 启动子驱动的荧光素酶活性和内源性 PNMT。当 Egr-1 或 Sp1 位点发生突变时，HIF1α 不会刺激 PNMT 启动子。Egr-1 或 Sp1 的 siRNA 敲低会阻止启动子激活，而 HIF1α 的 siRNA 敲低会抑制 Egr-1 和 Sp1 的诱导。研究结果表明，低氧通过 HIF1α 刺激 Egr-1 和 Sp1 间接激活 PNMT 基因。因此，对于涉及肾上腺素能功能障碍的应激诱导疾病，HIF1α 可能是调节应激时肾上腺素反应的“开-关”开关，也是治疗干预的潜在靶点。
