The Role of Endoplasmic Reticulum Stress at the Rostral Ventrolateral Medulla in Neurogenic Hypertension

  • 趙 詠梅

Student thesis: Doctoral Thesis

Abstract

Regulation of the arterial blood pressure is a complex and delicate physiological process Vascular dysfunction alterations in the humeral factors including the circulatory metabolites angiotensin II (Ang II) superoxide anion nitric oxide and carbon monoxide are all engaged in pathophysiology of the high blood pressure At the same time perturbation of the central cardiovascular regulatory machineries also contributes to pathogenesis of hypertension It is well established that overexcitation of the premotor neurons in the rostral ventrolateral medulla (RVLM) results in sympathoexcitation and the increase in arterial blood pressure Previous studies have shown that oxidative stress of an enhanced production of the superoxide anion (O2 -) and/or hydrogen peroxide (H2O2) in the RVLM plays a pivotal role in manifestation of hypertension of the spontaneously hypertensive rats (SHR) The endoplasmic reticulum (ER) is the first compartment of the secretory pathways to rescue unfolded proteins in cells When misfolded or unfolded proteins accumulate in the ER the cells activate a self-protective mechanism termed the ER stress Prolonged ER stress has been proposed to be involved in the neurodegenerative diseases In this study we hypothesized that ER stress may underpin the cellular events leading to the manifestation of redox-associated neurogenic hypertension We found that in comparison with the normotensive Wistar-Kyoto (WKY) rats the expression of two major marker proteins of ER stress glucose-regulated protein 78 (GRP78) and the phosphorylated eukaryotic initiation factor 2? (eIF2?) at RVLM was significantly greater in the SHR Intraperitoneal or intracerebroventricular infusion of Ang II or direct microinjection of a ER stress inducer tunicamycin promoted ER stress and increased the systemic arterial pressure in the normotensive WKY rats Protection of the RVLM cells from undertaking ER stress by microinjection bilaterally into the RVLM of salubrinal on the other hand caused a significant decrease in systolic arterial pressure of SHR alongside a concomitant suppression of the increased GRP78 expression and downregulation of eIF2? phosphorylation We further found that ER stress induced activation of autophagy in RVLM leading to hypertension in the SHR Finally we identified that oxidative stress activated the ER stress through the activation of PI3K/Akt signaling and this redox-sensitive activation of PI3K/Akt signaling was engaged in the neurogenic hypertension Collectively these results suggest that exaggerated ER stress may be an important factor in the manifestation of neurogenic hypertension via redox-sensitive activation of PI3K/Akt pathway and autophagy in the RVLM
Date of Award2014 Jan 7
LanguageEnglish
SupervisorMing-Derg Lai (Supervisor)

Cite this

The Role of Endoplasmic Reticulum Stress at the Rostral Ventrolateral Medulla in Neurogenic Hypertension
詠梅, 趙. (Author). 2014 Jan 7

Student thesis: Doctoral Thesis