TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension.
Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-κB signaling pathway and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10μg/h), or losartan (LOS, 20μg/h), or the PPAR-γ antagonist GW9662 (GW, 100μg/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-γ, pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF-κB) activity and plasma norepinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-γ in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-κB levels and increased PPAR-γ level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-κB signaling and PPAR-γ within the PVN are involved in the beneficial effects of telmisartan in hypertension.
Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an 710061, China.
Hong-Bao
HB
Li
Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an 710061, China.
Xiang
X
Li
Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an 710061, China.
Chan-Juan
CJ
Huo
Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an 710061, China.
Qing
Q
Su
Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an 710061, China.
Jing
J
Guo
Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an 710061, China.
Zu-Yi
ZY
Yuan
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
Guo-Qing
GQ
Zhu
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. Electronic address: shxl@mail.xjtu.edu.cn.
Xiao-Lian
XL
Shi
Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. Electronic address: jupet@163.com.
Jin-Jun
JJ
Liu
Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an 710061, China. Electronic address: ykang@mail.xjtu.edu.cn.
Yu-Ming
YM
Kang
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D062186:Arterial Pressure / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D006332:Cardiomegaly / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000097:blood / Q000378:metabolism*; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D047495:PPAR gamma / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D016207:Cytokines; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D047495:PPAR gamma; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000077333:Telmisartan; D009638:Norepinephrine
AT1 receptor; Hypertension; PPAR-γ; Paraventricular nucleus; Toll-like receptor 4