S100B regulates left ventricular (LV) remodelling following myocardial infarction (MI) by interaction with the receptor for advanced glycation end products (RAGE). Since S100B and RAGE are induced in diabetic vasculature, we hypothesized that i) hyperglycemia will augment expression or functional impact of S100B and RAGE post-MI and ii) abrogated or forced expression of S100B will alter post-MI structure and remodeling specifically in diabetes. Also, as S100B Knockout (BKO) mice appear resistant to streptozotocin (STZ)–induced diabetes, we postulated a role for S100B in development of diabetes.
In mouse, post-MI remodeling in diabetes exhibited an attenuation of LV dilation, myocyte hypertrophy, S100B expression and matrix metalloproteinase-2 (MMP-2) activity, increased apoptosis and fibrosis. Despite reduced LV dilation, impairment of cardiac function was similar to non-diabetic controls. Following MI, diabetic BKO demonstrated increased LV dilation compared to S100B transgenic (BTG) and WT with greater impairment of cardiac function, decreased glucose transporter type 4 (GLUT4) mRNA expression and increased AGE levels. These data suggest that S100B expression may serve to limit adverse diabetic post-MI remodeling and regulate associated metabolic changes in the heart.
In addition, we have defined a novel role of S100B in the development of diabetes. As BKO mice were resistant to STZ induced-diabetes with lower value for food and water intake and urine volume and increased body weight compared to WT mice, we hypothesized that S100B played a role in islet cell damage and/or insulin sensitivity. BKO exhibited enhanced glucose tolerance and insulin sensitivity with increased insulin in serum. S100B deficiency prevented β-cell disruption and functional impairment in response to STZ. Expression of S100B was increased in the WT islet after induction of diabetes and S100B induced apoptosis in β cells. These findings indicate that S100B expression is involved in islet dysfunction and in peripheral insulin resistance, at least in an STZ model.
In conclusion, our findings support a differential, paradoxical effect of S100B signalling in post-MI diabetic hearts, serving to limit dilation and functional impairment. Moreover, S100B may play a role in diabetes itself contributing to β-cell loss in pancreas and peripheral insulin resistance.Ph
