Upregulation of neuregulin-1 in the ventricle of diabetic cardiomyopathy model mice and its functional significance

Diabetic cardiomyopathy (DMCM) is myocardium disorder in diabetic patients independent of diabetic vascular dysfunction. It is characterized by an early diastolic dysfunction and subsequent progression to systolic dysfunction. The underlying mechanism of the DMCM development has not yet been fully understood. We aimed to elucidate the molecular mechanism of DMCM progression. In the streptozotocin (STZ)-induced DM model mice 4 weeks after STZ injection (STZ-4W), diastolic function was impaired without systolic dysfunction. In the ventricles of STZ-4W mice, the mRNA and protein expression levels of neuregulin1 (NRG-1) turned out to be significantly higher than that of control mice. Chronic insulin administration restored the blood glucose, left ventricular diastolic function, and NRG-1 expression to the control levels. NRG-1 was localized in the epicardium, endocardium, and endothelial cells of blood vessels in the ventricle. To clarify the role of up-regulated NRG-1 in the early stage of DMCM, we examined the effects of trastuzumab (TRZ), antibody against NRG-1 receptor ErbB2. Not only diastolic function but also systolic function was significantly impaired in the TRZ-injected STZ-4W mice. These results suggest that a compensatory increase in NRG-1 prevents the progression to systolic dysfunction during the early stage of DMCM.