Sustained elevation of NF-κB activity sensitizes offspring of maternal inflammation to hypertension via impairing PGC-1α recovery.
Growing evidence has demonstrated that maternal detrimental factors, including inflammation, contribute to the development of hypertension in the offspring. The current study found that offspring subjected to prenatal exposure of inflammation by lipopolysaccharide (LPS) challenge during the second semester showed significantly increased systolic blood pressure. In addition, these offspring also displayed augmented vascular damage and reactive oxygen species (ROS) levels in thoracic aortas when challenged with deoxycorticosterone acetate and high-salt diet (DOCA-salt). Interestingly, the antioxidant N-acetyl-L-cysteine markedly reversed these changes. Mechanistically, prenatal LPS exposure led to pre-existing elevated peroxisome proliferators-activated receptor-γ co-activator (PGC)-1α, a critical master of ROS metabolism, which up-regulated the ROS defense capacity and maintained the balance of ROS generation and elimination under resting state. However, continued elevation of NF-κB activity significantly suppressed the rapid recovery of PGC-1α expression response to DOCA-salt challenge in offspring that underwent prenatal inflammatory stimulation. This was further confirmed by using a NF-κB inhibitor (N-p-Tosyl-L-phenylalanine chloromethyl ketone) that restored PGC-1α recovery and prevented blood pressure elevation induced by DOCA-salt. Our results suggest that maternal inflammation programmed proneness to NF-κB over-activation which impaired PGC-1α-mediated anti-oxidant capacity resulting in the increased sensitivity of offspring to hypertensive damage.
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Yafei
Y
Deng
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Qi
Q
Zhang
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Hongqin
H
Luo
Diagosis and Treatment Center for Servicemen, Southwest Hospital, Third Military Medical University, Chongqing, China.
Xianhua
X
Chen
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Qi
Q
Han
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Fangjie
F
Wang
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Pei
P
Huang
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Wenjing
W
Lai
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Xiao
X
Guan
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Xiaodong
X
Pan
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Yan
Y
Ji
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Wei
W
Guo
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Ling
L
Che
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Yuan
Y
Tang
The Center for Disease Control and Prevention of Chengdu Military Command, Chengdu, China.
Liangqi
L
Gu
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Jianhua
J
Yu
Colleges of Pharmacy and Medicine, University of Manitoba, Winnipeg, MB, Canada.|Joint Laboratory of Biological Psychiatry Between Shantou University Medical College and the College of Medicine University of Manitoba, Shantou, China.
Michael
M
Namaka
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Youcai
Y
Deng
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China.
Xiaohui
X
Li
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000235:genetics; D003900:Desoxycorticosterone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D018811:Maternal Exposure; D016328:NF-kappa B / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D000975:Antioxidants; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D017382:Reactive Oxygen Species; D003900:Desoxycorticosterone