BACKGROUND: Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart. METHODS AND RESULTS: In a mouse model, we demonstrated that haploinsufficient (Hif1a+/-) offspring from a diabetic pregnancy developed left ventricle dysfunction at 12 weeks of age, as manifested by decreased fractional shortening and structural remodeling of the myocardium. Transcriptional profiling by RNA-seq revealed significant transcriptome changes in the left ventricle of diabetes-exposed Hif1a+/- offspring associated with development, metabolism, apoptosis, and blood vessel physiology. In contrast, both wild type and Hif1a+/- offspring from diabetic pregnancies showed changes in immune system processes and inflammatory responses. Immunohistochemical analyses demonstrated that the combination of haploinsufficiency of Hif1a and exposure to maternal diabetes resulted in impaired macrophage infiltration, increased levels of advanced glycation end products, and changes in vascular homeostasis in the adult offspring heart. CONCLUSIONS: Together our findings provide evidence that a global reduction in Hif1a gene dosage increases predisposition of the offspring exposed to maternal diabetes to cardiac dysfunction, and also underscore Hif1a as a critical factor in the fetal programming of adult cardiovascular disease.

• MeSH
• experimentální diabetes mellitus komplikace   metabolismus   patologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• funkce levé komory srdeční MeSH
• gestační diabetes * metabolismus   patologie   MeSH
• haploinsuficience MeSH
• interakce genů a prostředí MeSH
• kardiovaskulární nemoci genetika   metabolismus   patologie   patofyziologie   MeSH
• mutace * MeSH
• myokard metabolismus   patologie   MeSH
• myši knockoutované MeSH
• remodelace komor MeSH
• rizikové faktory MeSH
• těhotenství MeSH
• vývojová regulace genové exprese MeSH
• zpožděný efekt prenatální expozice * MeSH
• zvířata MeSH
• Check Tag
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH