The Progression of Cardiac Damage in the Offspring of Mothers with Gestational Diabetes Is Regulated by the p53/miR-34/SIRT1/7 Pathway

Gestational diabetes mellitus (GDM) exposes the fetus to chronic hyperglycemia, promoting early cardiac remodeling and increasing the risk of diabetic cardiomyopathy later in life. Epigenetic regulators such as p53 tumor suppressor gene (p53), microRNA-34a (miR-34a), and the sirtuins 1 and 7 (SIRT1/SIRT7) may contribute to this programming process; however, their temporal dynamics during postnatal cardiac development remain unclear. This study aimed to characterize structural and molecular alterations in the hearts of offspring exposed to GDM and to determine the involvement of the p53–miR-34a–SIRT1/SIRT7 axis in early cardiac remodeling. Cardiac morphometry was assessed at birth (newborn NB) and at 8, 15, 25, and 35 days. Left ventricles were examined through hematoxylin/eosin staining. SIRT1, SIRT7, Bcl-2, and Bax were evaluated by immunofluorescence, while p53 and miR-34a were evaluated by RT-PCR. Molecular interactions were integrated using IPA software, version 159584291. Offspring exposed to GDM exhibited a reduced cardiac area and ventricular lumen, along with increased left ventricular wall thickness and fibrosis during early postnatal stages. The cardiomyocyte area was elevated at all ages. The level of miR-34a increased early, preceding p53 upregulation. SIRT1 presences decreased from NB to 35 days, whereas SIRT7 expression remained consistently elevated. These findings suggest that GDM induces early and sustained cardiac remodeling associated with dysregulation of the p53–miR-34a–SIRT1/SIRT7 axis, a pattern that could increase susceptibility to diabetic cardiomyopathy.