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  3. Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation

Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation

  • Sci Rep. 2016 Jul 22;6:30146. doi: 10.1038/srep30146.
Qi Zhang 1 2,  Yafei Deng 1 2,  Wenjing Lai 1 2,  Xiao Guan 1 2,  Xiongshan Sun 1 2,  Qi Han 1 2,  Fangjie Wang 1 2,  Xiaodong Pan 1 2,  Yan Ji 1 2,  Hongqin Luo 1 2,  Pei Huang 1 2,  Yuan Tang 1 2,  Liangqi Gu 3,  Guorong Dan 1 2,  Jianhua Yu 4,  Michael Namaka 5 6,  Jianxiang Zhang 1 2,  Youcai Deng 1 2,  Xiaohui Li 1 2
Affiliations

Affiliations

  • 1 Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
  • 2 Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
  • 3 The Center for Disease Control and Prevention of Chengdu Military Command, Chengdu 610021, China.
  • 4 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
  • 5 Colleges of Pharmacy and Medicine, University of Manitoba, Apotex Center 750, McDermot Avenue, Winnipeg, R3E 0T5, MB, Canada.
  • 6 Joint Laboratory of Biological Psychiatry between Shantou University Medical College and the College of Medicine University of Manitoba, Shantou 515063, China.
PMID: 27443826 DOI: 10.1038/srep30146
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.

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