Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis

eLife

Peter M Clark¹  Siavash K Kurdistani²  Atsushi Nakano²  Aldons J Lusis²  Heather Christofk³  James K Gimzewski⁴  Karen Reue⁴  Adam Z Stieg⁵  Matteo Pellegrini⁶  Christopher Dunham⁶  Xueqin Ding⁶  Laurent Vergnes⁷  Daniel Braas⁸  Norio Nakatsuji⁸  Bernard Ribalet⁹  Haruko Nakano⁹  Herman Pappoe⁹  Marco Morselli⁹  Addelynn Sagadevan⁹  Kai Fu⁹  Xiuju Wu^1,10  Itsunari Minami^1,11 

[1] California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States;Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, United States;Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States;WPI Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science, Meguro, Japan;California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States;Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States;Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States;Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States;Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States;Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, United States;Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan;

关键词: human pluripotent stem cell;    diabetes;    cardiac;   

DOI  :  10.7554/eLife.29330

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown