Regulation of epinephrine biosynthesis by intermittent and continuous hypoxia

Abstract

Phenylethanolamine N-methyltransferase (PNMT) synthesizes the catecholamine (CA), epinephrine (Epi), and is increased in hypertensive patients. Patients with obstructive sleep apnea (OSA) experience oxidative stress, which is associated with elevated blood pressure (BP) and CAs, and consequently, hypertension (HTN). Studies have demonstrated PNMT regulation by continuous hypoxia (CH) and intermittent hypoxia (IH). In the present study, the role of Epi synthesis by both forms of hypoxia are compared in O2-sensitive PC12 cells. RT-PCR and Western analysis demonstrated a robust induction in CA biosynthesis enzymes by IH, compared to CH,

especially following the sustained duration of exposure. Further, mechanisms involved in this IH- mediated induction include a potent increase in transcription factors that regulate the PNMT gene.

This led to an enhanced activation of the PNMT promoter by IH, compared to that resulting from CH exposure, as shown by the luciferase reporter assay. Additionally, IH, but not CH, contributed to increased reactive oxygen species (ROS), which appeared to play a prominent role in the induction of CA biosynthesis enzymes. Prior treatment with a synthetic antioxidant and selected polyphenols were able to abolish these IH-mediated inductions. In summary, these findings demonstrate the role of IH-induced oxidative stress in PNMT gene regulation. This study furthers our understanding of how IH, associated with OSA, contributes to the development of secondary HTN.