Cardiomyopathy in offspring of diabetic rats is associated with activation of the MAPK and apoptotic pathways

Abstract

Background: Maternal diabetes affects the developing fetal cardiovascular system. Newborn offspring of diabetic mothers can have a transient cardiomyopathy. We hypothesized that cardiomyopathic remodeling is associated with activation of the mitogen activated protein kinase (MAPK) signaling and apoptotic pathways.

Methods: To evaluate the effects of moderate and severe maternal hyperglycemia, pregnant rats were made diabetic with an injection of 50 mg/kg of streptozotocin. Moderately well controlled maternal diabetes was achieved with twice daily glucose checks and insulin injections. No insulin was given to severely diabetic dams. Offspring of moderate and severe diabetic mothers (OMDM and MSDM, respectively) were studied on postnatal days 1 (NB1) and 21 (NB21). Echocardiograms were performed to evaluate left ventricular (LV) dimensions and function. Myocardial MAPK and apoptotic protein levels were measured by Western blot.

Results: OMDM had increased cardiac mass at NB1 compared to controls that normalized at NB21. OSDM demonstrated microsomia with relative sparing of cardiac mass and a dilated cardiomyopathy at NB1. In both models, there was a persistent increase in the HW:BW and significant activation of MAPK and apoptotic pathways at NB21.

Conclusion: The degree of maternal hyperglycemia determines the type of cardiomyopathy seen in the offspring, while resolution of both the hypertrophic and dilated cardiomyopathies is associated with activation of MAPK signaling and apoptotic pathways.

Figure 1

Total and active c-Jun NH2-terminal kinase (JNK, and pJNK, respectively) protein levels were measured by immunoblot in hearts from control (C) and offspring of either moderately or severely diabetic dams (D) at 1 and 21 days of life (NB1 and NB21, respectively). The immunoblots are shown at the top with the bar graphs indicating protein levels expressed in arbitrary units. Molecular weights: JNK – 48 kD, pJNK – 46 kD. *p < 0.05 versus control value by unpaired t-test.

Figure 2

Total and active extracellular signal-regulated kinase (ERK, and pERK, respectively) protein levels were measured by immunoblot in hearts from control (C) and offspring of either moderately or severely diabetic dams (D) at 1 and 21 days of life (NB1 and NB21, respectively). In NB1 myocardial samples, ERK1 and ERK2 were both seen and quantitated as a single band. The immunoblots are shown at the top with the bar graphs indicating protein levels expressed in arbitrary units. Molecular weights: ERK1 – 42 kD, ERK2 – 44 kD, pERK – 43 kD. *p < 0.05 versus control value by unpaired t-test.

Figure 3

Active Caspase 3 and active Caspase 8 protein levels were measured by immunoblot in hearts from control (C) and offspring of either moderately or severely diabetic dams (D) at 1 and 21 days of life (NB1 and NB21, respectively). The immunoblots are shown at the top with the bar graphs indicating protein levels expressed in arbitrary units. Molecular weights: caspase 3 – 35 kD, caspase 8 – 55 kD. *p < 0.01 versus control value by unpaired t-test.