Impact of type 1 diabetes on cardiac fibroblast activation: enhanced cell cycle progression and reduced myofibroblast content in diabetic myocardium.

Shamhart PE, Luther DJ, Hodson BR, Koshy JC, Ohanyan V, Meszaros JG. Impact of type 1 diabetes on cardiac fibroblast activation: enhanced cell cycle progression and reduced myofibroblast content in diabetic myocardium. Am J Physiol Endocrinol Metab 297: E1147-E1153, 2009. First published August 25, 2009; doi: 10.1152/ajpendo.00327.2009.-Diabetic patients are prone to developing myocardial fibrosis and suffer from decreased wound healing capabilities. The purpose of this study was to determine whether diabetes alters cardiac fibroblast activity in the myocardium in a 6-wk streptozotocin-induced type 1 diabetic model. In vivo echocardiography indicated significant dilation of the left ventricle (LV) in the diabetic animals, while cardiac function was comparable to that in the normal group. We isolated cardiac fibroblasts from diabetic and control hearts and observed increased proliferation of the diabetic fibroblasts. Microarray analysis using mRNA collected from whole LVs revealed downregulation of known inhibitors of proliferation, p53 and p21, in the diabetic group, consistent with our proliferation data. Western blot analysis confirmed a reduction in p53 protein expression in the diabetic hearts compared with control. We explored the potential signaling underlying the downregulation of these cell cycle mediators and determined that activated Akt, a signal that inhibits p53, was elevated in the diabetic group. Surprisingly, the hearts from the diabetic group contained lower levels of the myofibroblast marker alpha-smooth muscle actin (alpha-SMA) and higher levels of desmin and platelet endothelial cell adhesion molecule (PECAM). The isolated fibroblasts from the diabetic group also contained significantly less alpha-SMA. These data suggest that early-stage diabetic hearts contain highly proliferative fibroblasts, which predisposes the diabetic myocardium to fibrosis, but have fewer myofibroblasts, which may compromise wound healing.