Intrauterine Programming of Cardiovascular Diseases in Maternal Diabetes

Abstract

Maternal diabetes is a prevalent pathology that increases the risk of cardiovascular diseases in the offspring, the heart being one of the main target organs affected from the fetal stage until the adult life. Metabolic, pro-oxidant, and proinflammatory alterations in the fetal heart constitute the first steps in the adverse fetal programming of cardiovascular disease in the context of maternal diabetes. This review discusses both human and experimental studies addressing putative mechanisms involved in this fetal programming of heart damage in maternal diabetes. These include cardiac epigenetic changes, alterations in cardiac carbohydrate and lipid metabolism, damaging effects caused by a pro-oxidant and proinflammatory environment, alterations in the cardiac extracellular matrix remodeling, and specific signaling pathways. Putative actions to prevent cardiovascular impairments in the offspring of mothers with diabetes are also discussed.

Keywords: animal model; diabetes mellitus; heart; humans; intrauterine programming; offspring; pathways.

Figure 1

Mechanisms involved in the programming of cardiovascular alterations in offspring by maternal diabetes. Main players that regulate cellular metabolism in the heart of offspring exposed to diabetes in utero are mTOR, PPAR, PANK1, PGC1α, GDK3β, NPR1, SCAND1, and the FGF/PI3K/AKT pathway. Maternal treatments with probiotics or a diet enriched in olive or fish oil or N-acetyl-cysteine have been shown to ameliorate cardiac cell metabolism of offspring from diabetic dams. TGFβ-1, CTGF, FoxO1, matrix metalloproteinases (MMPs), and connexin 37 (CX37) and 43 (CX43) have been shown to play important roles in the process of ECM remodeling and intercellular communication. A maternal treatment with N-acetyl-cysteine (NAC) or with an olive oil-supplemented diet was able to prevent alterations in the ECM remodeling process observed in the offspring’s heart of animal models of diabetes. An increased pro-oxidant/proinflammatory process and related molecules (VCAM-1, E-selectin, and NOX) have been shown to be involved in the cardiovascular alterations programmed by maternal diabetes. Maternal treatments with an olive oil-supplemented diet or with antioxidants, as idebenone or N-acetyl-cysteine have beneficial effects on this process. All these pathways are interconnected and the underlying mechanism affecting them may be epigenetic phenomena.