title: Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring.
abstract: Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring's aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention.
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Jiangjin District Central Hospital, Chongqing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: He
authors.affiliation: Suzhou Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Chu
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Jianzhi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Huang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Guan
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Shanyu
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Department of Pharmacy, Hospital 159 of PLA, Zhumadian, Henan, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Chongqing Center for Biomedicine and Medical Equipment, Chongqing Academy of Science and Technology, Chongqing, China.
authors.forename: Chiming
authors.initials: C
authors.lastname: Wei
authors.affiliation: Colleges of Pharmacy and Medicine, University of Manitoba, Apotex Center 750, McDermot Avenue, Winnipeg, MB, Canada.|Joint Laboratory of Biological Psychiatry Between Shantou University Medical College and the College of Medicine University of Manitoba, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Namaka
authors.affiliation: Department of Obstetrics and Gynecology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yi
authors.affiliation: Department of Obstetrics and Gynecology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000075222:Essential Hypertension; D005260:Female; D006973:Hypertension / Q000503:physiopathology*; D007249:Inflammation / Q000150:complications*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B