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Cited by 63Birth, Development, and HealthGestational Diabetes Research and ManagementEpigenetics and DNA Methylation

Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life

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Chen, Zewen, Gong, Lei, Zhang, Peng, Li, Yong, Liu, Bailin, Zhang, Lubo, Zhuang, Jian, Xiao, Daliao·2019·International Journal of Biological Sciences
DOI 10.7150/ijbs.33044PMC PMC6567811
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Abstract

Rationale: The incidence of gestational diabetes mellitus (GDM) is increasing worldwide.However, whether and how GDM exposure induces fetal programming of adult cardiac dysfunctional phenotype, especially the underlying epigenetic molecular mechanisms and theranostics remain unclear.To address this problem, we developed a late GDM rat model. Methods: Pregnant rats were made diabetic on day 12 of gestation by streptozotocin (STZ). Experiments were conducted in 6 weeks old offspring.Results: There were significant increases in ischemia-induced cardiac infarction and gender-dependent left ventricular (LV) dysfunction in male offspring in GDM group as compared to controls.Exposure to GDM enhanced ROS level and caused a global DNA methylation in offspring cardiomyocytes.GDM attenuated cardiac Sirt 1 protein and p-Akt/Akt levels, but enhanced autophagy-related proteins expression (Atg 5 and LC3 II/LC3 I) as compared to controls.Ex-vivo treatment of DNA methylation inhibitor, 5-Aza directly inhibited Dnmt3A and enhanced Sirt 1 protein expression in fetal hearts.Furthermore, treatment with antioxidant, N-acetyl-cysteine (NAC) in offspring reversed GDM-mediated DNA hypermethylation, Sirt1 repression and autophagy-related gene protein overexpression in the hearts, and rescued GDM-induced deterioration in heart ischemic injury and LV dysfunction.Conclusion: Our data indicated that exposure to GDM induced offspring cardiac oxidative stress and DNA hypermethylation, resulting in an epigenetic down-regulation of Sirt1 gene and aberrant development of heart ischemia-sensitive phenotype, which suggests that Sirt 1-mediated signaling is the potential therapeutic target for the heart ischemic disease in offspring.

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  • Significant increases in ischemia-induced cardiac infarction have been reported in adult male and female offspring of STZ-induced diabetes dams.

    “Significant increases in ischemia-induced cardiac infarction have also been reported in adult male and female offspring of STZ-induced diabetes dams [120,121].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [120]

    The Results report larger ischemia-induced cardiac infarcts in both male and female offspring of STZ-treated dams, and the Discussion describes the increase as significant. However, the Methods say the rats were tested at 6 weeks of age and describe them as young offspring; the paper does not establish the claim's 'adult' age qualifier. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Some of the observed mitochondrial and autophagy changes in offspring of STZ-induced diabetes dams could be a consequence of reduced SIRT1 expression in the heart.

    “Some of these observations could be a consequence of reduced SIRT1 expression in the hearts from offspring of STZ-induced diabetes dams that is associated with hypermethylation of the Sirt1 gene [120].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [120]

    The Results and Discussion (pages unavailable) report reduced cardiac Sirt1 expression and increased autophagy markers in male offspring of STZ-treated dams; the Discussion also links Sirt1 signaling to mitochondrial integrity and autophagy. The paper suggests that DNA hypermethylation regulates Sirt1 repression, but says it is unknown whether that regulation is direct. It therefore does not establish hypermethylation of the Sirt1 gene itself. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Reduced SIRT1 expression in hearts from offspring of STZ-induced diabetes dams is associated with hypermethylation of the Sirt1 gene.

    “Some of these observations could be a consequence of reduced SIRT1 expression in the hearts from offspring of STZ-induced diabetes dams that is associated with hypermethylation of the Sirt1 gene [120].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [120]

    The Results report reduced cardiac Sirt1 protein expression in offspring of STZ-treated dams, and the Discussion links Sirt1 repression to increased global DNA methylation in offspring hearts. The paper does not establish hypermethylation of the Sirt1 gene specifically; the Discussion says direct versus indirect regulation remains unknown. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Enhanced expression of autophagy-related proteins Atg5 and LC3 II/LC3 I has been reported in offspring of STZ-induced diabetes dams.

    “Notably, enhanced expression of autophagy-related proteins Atg5, LC3 II/LC3 I have also been reported [120].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [120]

  • SIRT1 expression is reduced in the hearts from offspring of STZ-induced diabetes dams.

    “Some of these observations could be a consequence of reduced SIRT1 expression in the hearts from offspring of STZ-induced diabetes dams that is associated with hypermethylation of the Sirt1 gene [120].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [120]

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Cited by

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Authors
Chen, Z., Gong, L., Zhang, P., Li, Y., Liu, B., Zhang, L., Zhuang, J., & Xiao, D.
Affiliations
  • Loma Linda University Medical Center (US)
  • Guangdong Academy of Medical Sciences (CN)
Corresponding author
Xiao, Daliao
ORCID
Venue
International Journal of Biological Sciences
Publisher
Ivyspring International Publisher
Published
2019
Volume
15
Issue
6
Pages
1240-1251
ISSN
1449-2288 (ISSN-L)
DOI
10.7150/ijbs.33044
PMC
PMC6567811
OpenAlex
W2947355008
Cited by
63
References
4
Citations by year
2026: 5 · 2025: 8 · 2024: 10 · 2023: 9 · 2022: 13 · 2021: 13 · 2020: 3 · 2019: 1 · 2017: 1
FWCI
7.80
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • International Journal of Biological Sciences (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Loma Linda University
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL135623, R01HL118861)
  • National Institute on Drug Abuse (R03DA041492)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD088039, P01HD083132)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
gestational diabetes mellitus, fetal programming, SIRT1, DNA methylation, oxidative stress, heart ischemia, left ventricular dysfunction, cardiomyocytes, autophagy, DNMT3A, decitabine, N-acetylcysteine, streptozotocin-induced diabetes, myocardial infarction, epigenetic regulation
MeSH terms
Animals, Diabetes Mellitus, Experimental, Female, Pregnancy, Prenatal Exposure Delayed Effects, Signal Transduction, Down-Regulation, Diabetes, Gestational, Myocardial Ischemia, Rats, Sprague-Dawley, Reactive Oxygen Species, Oxidative Stress, DNA Methylation, Genetic Predisposition to Disease, Fetal Development, Rats, Sirtuin 1, Epigenomics

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