Mechanism of maternal gestational diabetes mellitus exacerbating myocardial injury in male offspring by upregulating growth differentiation factor 15 to promote mitochondrial dysfunction.

Gestational diabetes mellitus (GDM) is a prevalent metabolic disturbance in pregnancy. This study analyzed the mechanism of maternal GDM inducing myocardial injury in male offspring through growth differentiation factor-15 (GDF-15). Pregnant rats were randomly assigned to the GDM-mother (streptozotocin [STZ] induction) and the Control-mother (normal saline injection) groups. Here, 32 male offspring from the Control-mother group and 92 from the GDM-mother group were used for experiments. The myocardial ischemia model was established by left anterior descending (LAD) coronary artery ligation in 6-week-old male offspring. Male offspring in the GDM-mother group were treated with sh-Gdf15, pyrroloquinoline quinone, or rotenone. Cardiac function, oxidative stress-associated indicators, myocardial infarct size and necrosis, inflammatory infiltration, cardiomyocyte apoptosis, mitochondrial damage, and Gdf15 mRNA and protein expression were examined using echocardiography, kits, TTC/H&E/TUNEL staining, flow cytometry, RT-qPCR, and western blot. GDM maternal rats had elevated blood glucose and a reduced body weight, representing successful modeling. Prenatal STZ exposure did not affect blood glucose but decreased the body weight in male offspring. The baseline cardiac function was not affected by prenatal STZ exposure, whereas LAD ligation-induced ischemia caused severe cardiac dysfunction in GDM male offspring versus controls. GDF-15 was upregulated in GDM rat male offspring, and its knockdown alleviated myocardial injury. Adult male offspring of GDM rats exhibited pronounced mitochondrial damage, and mitochondrial homeostasis restoration improved ischemia-caused cardiac dysfunction. Suppressing mitochondrial function partly abrogated cardioprotective effects of Gdf15 knockdown. Maternal GDM promoted myocardial injury in male offspring by upregulating GDF-15 to aggravate mitochondrial damage.