Maternal diabetes programs heart alterations in the offspring previous to metabolic impairments

ROBERTI S, HIGA R, STEDILE M, WHITE V, JAWERBAUM A

Budapest

Congreso; 46th Annual Meeting, Diabetes and Pregnancy Study Group (DPSG), EASD; 2014

DPSG

Maternal diabetes can program metabolic diseases and affect cardiovascular functions in the offspring. We previously found that metabolic and heart alterations are induced in the adult offspring of mild diabetic rats. As hyperglycemia is only evident in adult offspring of these diabetic animals and triglyceridemia observed from day 21 of age, we aimed to address whether heart alterations are induced in the offspring of diabetic animals at 2 days of age, when these metabolic parameters are normal. Therefore, we analysed markers of a pro-inflammatory state, the extracellular matrix (ECM) remodelling and protein expression of PPARalpha and PPARgamma coactivator-1alpha (a nuclear receptor and coactivator involved in the regulation of pro-inflammatory and matrix remodelling processes) in the heart of 2-day-old male and female offspring of mild diabetic rats. Methods: Diabetes was induced by neonatal streptozotocin administration (90 mg/kg), leading to adult diabetic animals with fasting glycemia values between 130 and 230 mg/dl. Control and diabetic adult females were mated. The heart was explanted in 2-day-old offspring for further evaluation of matrix metalloproteinase-9 (MMP-9, involved in ECM degradation), connective tissue growth factor (CTGF, involved pro-fibrotic and pro-inflammatory processes), nitrotyrosilation (indicating peroxynitrites formation), PPARalpha and PGC-1alpha through immunohistochemistry. Hearts from control rats were also incubated in the presence of reactive oxygen and nitrogen species (H2O2, xantine oxidase, sodium nitroprusside) for further evaluation of PGC-1 and PPARalpha expression (RT-PCR). Results: We found that MMP-9, CTGF and peroxynitrites were increased in the heart of 2-day old offspring from diabetic rats (p lower than 0.05). PPARalpha and PGC-1alpha were also increased in the heart of 2-day-old offspring of mild diabetic animals (p lower than 0.05). These changes were more marked in males than in female offspring (p lower than 0.05). Besides, no changes were detected in the expression of either PPARalpha or PGC-1alpha when the hearts were incubated in the presence of reactive oxygen/nitrogen species. Conclusion: Maternal mild diabetes induces intrauterine programming of heart alterations before inducing metabolic impairments. Markers of a pro-inflammation state and impaired ECM remodelling are evident in this early stage, being males more affected than female offspring. Offspring from diabetic rats show increased PPARalpha and PGC-1alpha, alterations that are probably intrauterine programmed as not reproduced with short term incubations, and that possibly constitute a compensatory mechanism aiming to regulate the energy balance and the pro-inflammatory state.