Investigating the Mechanism of Hyperglycemia-Induced Fetal Cardiac Hypertrophy

Abstract

Hyperglycemia in diabetic mothers enhances the risk of fetal cardiac hypertrophy during gestation. However, the mechanism of high-glucose-induced cardiac hypertrophy is not largely understood. In this study, we first demonstrated that the incidence rate of cardiac hypertrophy dramatically increased in fetuses of diabetic mothers using color ultrasound examination. In addition, human fetal cardiac hypertrophy was successfully mimicked in a streptozotocin (STZ)-induced diabetes mouse model, in which mouse cardiac hypertrophy was diagnosed using type-M ultrasound and a histological assay. PH3 immunofluorescent staining of mouse fetal hearts and in vitro-cultured H9c2 cells indicated that cell proliferation decreased in E18.5, E15.5 and E13.5 mice, and cell apoptosis in H9c2 cells increased in the presence of high glucose in a dose-dependent manner. Next, we found that the individual cardiomyocyte size increased in pre-gestational diabetes mellitus mice and in response to high glucose exposure. Meanwhile, the expression of β-MHC and BMP-10 was up-regulated. Nkx2.5 immunofluorescent staining showed that the expression of Nkx2.5, a crucial cardiac transcription factor, was suppressed in the ventricular septum, left ventricular wall and right ventricular wall of E18.5, E15.5 and E13.5 mouse hearts. However, cardiac hypertrophy did not morphologically occur in E13.5 mouse hearts. In cultured H9c2 cells exposed to high glucose, Nkx2.5 expression decreased, as detected by both immunostaining and western blotting, and the expression of KCNE1 and Cx43 was also restricted. Taken together, alterations in cell size rather than cell proliferation or apoptosis are responsible for hyperglycemia-induced fetal cardiac hypertrophy. The aberrant expression of Nkx2.5 and its regulatory target genes in the presence of high glucose could be a principal component of pathogenesis in the development of fetal cardiac hypertrophy.

Resveratrol alleviates diabetic cardiomyopathy in rats by improving mitochondrial function through PGC-1α deacetylation

“…To determine whether diabetes mellitus altered the cardiac morphology, the hearts were harvested at the end of the study. These hearts were photographed and fixed in 4% para-formaldehyde [23] . Then, tissues were dehydrated, embedded in paraffin blocks, cut into 5-μm sections, and mounted on 3-aminopropyltriethoxysilane-coated slides.…”

Mitochondrial dysfunction and its impact on diabetic heart

“…Previous studies have shown that mitochondrial ROS activates multiple pathways related to cellular damage in the setting of hyperglycemia [88–91]. An increase in 3-nitrotyrosine in association with increased cell death has been noted in human myocardial samples [15, 92], as well as in a streptozotocin (STZ)-induced model of Type 1 diabetes [93]. Indeed, Cai et al demonstrated a reduction in nitrosative damage with overexpression of metallothionein, an antioxidant protein, in STZ-treated mice [94].…”

An audit of stillborn babies in mothers with diabetes mellitus at a tertiary South African Hospital

“…In animal studies it was found that the cardiac changes are ascribed to cardiomyocyte hypertrophy and the suppression of cardiac transcription factors in both ventricular walls, as well as the ventricular septum, and are not driven by cell proliferation or apoptosis. 16 Patients with known pre-gestational target-organ damage, especially nephropathy, are at particular risk of intra-uterine growth restriction; 17 however, none of the five mothers with small-forgestational-age babies had nephropathy.…”