title: Redox-sensitive endoplasmic reticulum stress and autophagy at rostral ventrolateral medulla contribute to hypertension in spontaneously hypertensive rats.
abstract: Perturbations of proper functions of the endoplasmic reticulum (ER) cause accumulation of misfolded or unfolded proteins in the cell, creating a condition known as ER stress. Prolonged ER stress has been implicated in hypertension. Oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside, plays a pivotal role in neurogenic hypertension. This study aimed to evaluate the contribution of ER stress in RVLM to oxidative stress-associated hypertension and delineate the underlying molecular mechanisms. The expression of glucose-regulated protein 78 kDa and the phosphorylation of protein kinase RNA-like ER kinase-translation initiation factor α, 2 major protein markers of ER stress, were augmented in RVLM and preceded the development of hypertensive phenotype in spontaneously hypertensive rats. In RVLM of spontaneously hypertensive rats, stabilizing ER stress by salubrinal promoted antihypertension, and scavenging the reactive oxygen species by tempol reduced the augmented ER stress. Furthermore, induction of oxidative stress by angiotensin II induced ER stress in RVLM, and induction of ER stress by tunicamycin in RVLM induced pressor response in normotensive Wistar-Kyoto rats. Autophagy, as reflected by the expression of lysosome-associated membrane protein-2 and microtubule-associated protein 1 light chain 3-II (LC3-II), was significantly increased in RVLM of spontaneously hypertensive rats and was abrogated by salubrinal. In addition, inhibition of autophagy or silencing LC3-II gene in RVLM resulted in antihypertension in spontaneously hypertensive rats. These results suggest that redox-sensitive induction of ER stress and activation of autophagy in RVLM contribute to oxidative stress-associated neurogenic hypertension.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Yung-Mei
authors.initials: YM
authors.lastname: Chao
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.forename: Julie Y H
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000818:Animals; D001343:Autophagy; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase
chemical_list: D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase
keywords: angiotensin II; autophagy; endoplasmic reticulum stress; neurogenic hypertension; oxidative stress