Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis

Abstract

Background Cardiac hypertrophy is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Experimental evidence has implied that pregnant women with T2DM and their children are at an increased risk of cardiovascular diseases. Our previous mouse model study has revealed that maternal T2DM induces structural heart defects in their offspring. Objective The present study aims to determine whether maternal T2DM induces embryonic heart hypertrophy in a murine model of diabetic embryopathy. Study design The T2DM embryopathy model was established by feeding 4-week-old female C57BL/6J mice with a high-fat diet (HFD) for 15 weeks. Cardiac hypertrophy in embryos at embryonic day 17.5 was characterized by measuring heart size and thickness of the right and left ventricle walls and the interventricular septum, as well as the expression of β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), insulin-like growth factor 1 (IGF1), desmin (DES), and adrenomedullin (ADM). Cardiac remodeling was determined by collagen synthesis and fibronectin synthesis. Fibrosis was evaluated by Masson staining and determining the expression of connective tissue growth factor (CTGF), osteopontin (OPN), and Galectin 3 (GAL3) genes. Cell apoptosis also was measured in the developing heart. Results The thicknesses of the left ventricle walls and the interventricular septum of embryonic hearts exposed to maternal diabetes were significantly thicker than those in the nondiabetic (ND) group. Maternal diabetes significantly increased β-MHC, ANP, IGF1 and DES expression, but decreased expression of ADM. Moreover, collagen synthesis was significantly elevated, whereas fibronectin synthesis was suppressed, in embryonic hearts from diabetic dams, suggesting that cardiac remodeling is a contributing factor to cardiac hypertrophy. The cardiac fibrosis marker, GAL3, was induced by maternal diabetes. Furthermore, maternal T2DM activated the pro-apoptotic c-Jun-N-terminal kinase (JNK1/2) stress signaling and triggered cell apoptosis by increasing the number of TUNEL positive cells (10.4 ± 2.2% of the T2DM group vs. 3.8 ± 0.7% of the ND group, P < 0.05). Conclusions Maternal T2DM induces cardiac hypertrophy in embryonic hearts. Adverse cardiac remodeling, including elevated collagen synthesis, suppressed fibronectin synthesis, profibrosis and apoptosis, is implicated as the etiology of cardiac hypertrophy.

Perinatal changes in fetal cardiac geometry and function in diabetic pregnancy at term

“…Increased thickness of ventricular walls and ventricular hypertrophy has been reported previously in fetuses of pregnancies with maternal diabetes and attributed to the altered metabolic environment and fetal hyperinsulinemia 3,17 . Recent animal studies have implicated adverse cardiac remodeling, including dysregulation of the insulin-like growth factors 1 and 2, elevated collagen synthesis, profibrosis and apoptosis as the etiology of fetal cardiac hypertrophy, ventricular chamber dilatation and myocardial dysfunction in gestational diabetes 18,19 . Previous studies reported that increased contractility in fetuses of diabetic women is a compensatory reaction to fetal hypoxemia which, after a finite period of time, could lead to increased ventricular-wall stress resulting in myocardial-cell damage, myocyte death and local fibrosis 20,21 .…”

Na+/H+exchanger isoform 1-induced osteopontin expression facilitates cardiac hypertrophy through p90 ribosomal S6 kinase

“…It was reported that activated NHE1 protein resulted in an increased activation of osteopontin (OPN) (44), a multifunctional protein that acts as a mediator in various cardiovascular diseases (41) and whose expression is found to be increased in conditions that promote cardiac hypertrophy (10,43). Furthermore, an increase in OPN expression is seen in a Type 2 diabetes mellitus embryopathy model inducing cardiac fibrosis and hypertrophy (16). Moreover, serum-and glucocorticoidinducible kinase (sgk1)-mediated cardiac hypertrophy and el-evated NHE1 expression induced by dexamethasone are accompanied by increased OPN expression (40).…”

Effect of Gestational Diabetes on Interventricular Septum Thickness in Newborns in the Golestan Province, Iran

“…Many studies have reported a significant relationship between gestational diabetes mellitus and septal hypertrophy (1,4,18,19,22). For example, in a study by Russell et al, ventricular septum was significantly thicker in fetus of mothers with gestational diabetes in the last trimester of pregnancy (18).…”

“…Although the effect of gestational diabetes on interventricular septum thickness have been investigated in different populations (1,4,(18)(19)(20)(21), a limited number of studies have been performed on this issue in Iran (22,23). Therefore, we aimed to study interventricular septum thickness in neonates of diabetic and non-diabetic mothers in an Iranian population.…”