2. Academic Validation
  3. Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease

Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease

  • Cell Rep Med. 2023 Feb 14;100953. doi: 10.1016/j.xcrm.2023.100953.
Rui Zhao 1,  Li Cao 2,  Wen-Jun Gu 2,  Lei Li 3,  Zhong-Zhong Chen 4,  Jie Xiang 2,  Ze-Yu Zhou 2,  Bo Xu 5,  Wei-Dong Zang 3,  Xiang-Yu Zhou 6,  Jing Cao 7,  Kun Sun 8,  Jian-Yuan Zhao 9
Affiliations

Affiliations

  • 1 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
  • 2 Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences, and Department of Materials Science, Fudan University, Shanghai 200438, China.
  • 3 Department of Anatomy and Neuroscience Research Institute, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 4 Urogenital Development Research Center, Department of Urology, Shanghai Children's Hospital School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China.
  • 5 Department of Anesthesiology, General Hospital of Southern Theatre Command of People's Liberation Army, Guangzhou 510030, China.
  • 6 Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences, and Department of Materials Science, Fudan University, Shanghai 200438, China. Electronic address: husq04@163.com.
  • 7 Department of Anatomy and Neuroscience Research Institute, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: caojing73@126.com.
  • 8 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Electronic address: sunkun@xinhuamed.com.cn.
  • 9 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Department of Anatomy and Neuroscience Research Institute, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; International Human Phenome Institutes (Shanghai), Shanghai 200433, China. Electronic address: zhaojy@vip.163.com.
PMID: 36809766 DOI: 10.1016/j.xcrm.2023.100953
Abstract

Dysregulated maternal fatty acid metabolism increases the risk of congenital heart disease (CHD) in offspring with an unknown mechanism, and the effect of folic acid fortification in preventing CHD is controversial. Using gas chromatography coupled to either a flame ionization detector or mass spectrometer (GC-FID/MS) analysis, we find that the palmitic acid (PA) concentration increases significantly in serum samples of pregnant women bearing children with CHD. Feeding pregnant mice with PA increased CHD risk in offspring and cannot be rescued by folic acid supplementation. We further find that PA promotes methionyl-tRNA synthetase (MARS) expression and protein lysine homocysteinylation (K-Hcy) of GATA4 and results in GATA4 inhibition and abnormal heart development. Targeting K-Hcy modification by either genetic ablation of Mars or using N-acetyl-L-cysteine (NAC) decreases CHD onset in high-PA-diet-fed mice. In summary, our work links maternal malnutrition and MARS/K-Hcy with the onset of CHD and provides a potential strategy in preventing CHD by targeting K-Hcy other than folic acid supplementation.

Keywords

GATA4; congenital heart disease; maternal fatty acids; methionyl-tRNA synthetase; palmitic acid; protein lysine homocysteinylation.

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