Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis.
Haruko NakanoItsunari MinamiDaniel BraasHerman PappoeXiuju WuAddelynn SagadevanLaurent VergnesKai FuMarco MorselliChristopher DunhamXueqin DingAdam Z StiegJames K GimzewskiMatteo PellegriniPeter M ClarkKaren ReueAldons J LusisBernard RibaletSiavash K KurdistaniHeather ChristofkNorio NakatsujiAtsushi NakanoPublished in: eLife (2017)
The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy.
Keyphrases
- blood glucose
- high glucose
- endothelial cells
- pregnancy outcomes
- congenital heart disease
- glycemic control
- heart failure
- left ventricular
- preterm birth
- type diabetes
- pregnant women
- blood pressure
- fatty acid
- birth weight
- skeletal muscle
- gestational age
- weight gain
- signaling pathway
- adipose tissue
- cell cycle
- machine learning
- dna methylation
- big data
- oxidative stress
- angiotensin ii
- amino acid