Lectin-like oxidized low-density lipoprotein receptor-1 regulates autophagy and Toll-like receptor 4 in the brain of hypertensive mice.
BACKGROUND
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) regulates blood pressure and is important for the development of inflammation, oxidative stress and autophagy. We posited that LOX-1 via NADPH oxidase activation may affect autophagy and Toll-like receptor (TLR)4 expression in the brains of hypertensive mice.


METHODS
To examine this postulate, wild-type mice were given continuous infusion of angiotensin II (50 ng/min) for 28 days. As expected, these mice developed significant increase in blood pressure.


RESULTS
Corpus callosum in the brains of these hypertensive mice revealed intense expression of NADPH oxidase (subunits P22phox and P47phox), activation of P38 MAPK and nuclear factor-kappaB (P65), autophagy-related proteins (beclin-1 and conversion of LC3-I to LC3-II), and TLR4 (and associated signaling molecules myeloid differentiation primary response gene (88) and TIR-domain-containing adapter-inducing interferon-β). These observations suggested activation of redox signals, autophagy and immune system. In parallel experiments, mice with LOX-1 deletion given similar infusion of angiotensin II showed much less expression of NADPH oxidase, activation of P38 MAPK and nuclear factor-kappaB, autophagy-related proteins and TLR4 [and myeloid differentiation primary response gene (88) and TIR-domain-containing adapter-inducing interferon-β]. Mice with LOX-1 deletion also showed a smaller rise in blood pressure than wild-type mice, both groups given similar infusion of angiotensin II.


CONCLUSIONS
These studies suggest immune activation in the brains of mice with angiotensin II-induced hypertension. Further, these observations imply the existence of a link between LOX-1, NADPH oxidase expression, development of autophagy and immune activation in hypertension.
aCentral Arkansas Veterans Healthcare System and the Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA bKey Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing cSchool of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou, PR China.
Zufeng
Z
Ding
Shijie
S
Liu
Xianwei
X
Wang
Magomed
M
Khaidakov
Yubo
Y
Fan
Xiaoyan
X
Deng
David
D
Xiang
Jawahar L
JL
Mehta
D000804:Angiotensin II; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071186:Beclin-1; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016328:NF-kappa B; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000804:Angiotensin II; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases