title: Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation.
abstract: Maternal inflammation contributes to the increased incidence of adult cardiovascular disease. The current study investigated the susceptibility of cardiac damage responding to isoproterenol (ISO) in adult offspring that underwent maternal inflammation (modeled by pregnant Sprague-Dawley rats with lipopolysaccharides (LPS) challenge). We found that 2 weeks of ISO treatment in adult offspring of LPS-treated mothers led to augmented heart damage, characterized by left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis. Mechanistically, prenatal exposure to LPS led to up-regulated expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, antioxidant enzymes, and p38 MAPK activity in left ventricular of adult offspring at resting state. ISO treatment exaggerated ROS generation, p38 MAPK activation but down-regulated reactive oxygen species (ROS) elimination capacity in the left ventricular of offspring from LPS-treated mothers, while antioxidant N-acetyl-L-cysteine (NAC) reversed these changes together with improved cardiac functions. The p38 inhibitor SB202190 alleviated the heart damage only via inhibiting the expression of NADPH oxidases. Collectively, our data demonstrated that prenatal inflammation programs pre-existed ROS activation in the heart tissue, which switches on the early process of oxidative damages on heart rapidly through a ROS-p38 MAPK-NADPH oxidase-ROS positive feedback loop in response to a myocardial hypertrophic challenge in adulthood.
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Lai
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Guan
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiongshan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Han
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Fangjie
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Pan
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Luo
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Huang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: The Center for Disease Control and Prevention of Chengdu Military Command, Chengdu 610021, China.
authors.forename: Liangqi
authors.initials: L
authors.lastname: Gu
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Guorong
authors.initials: G
authors.lastname: Dan
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Colleges of Pharmacy and Medicine, University of Manitoba, Apotex Center 750, McDermot Avenue, Winnipeg, R3E 0T5, MB, Canada.|Joint Laboratory of Biological Psychiatry between Shantou University Medical College and the College of Medicine University of Manitoba, Shantou 515063, China.
authors.forename: Michael
authors.initials: M
authors.lastname: Namaka
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.|Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D007545:Isoproterenol; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole