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.

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 (CF) activity, myofibroblast content, and overall function of the myocardium in a 6 week streptozotocin‐induced (STZ) type 1 diabetic model. The initial stages of dilated cardiomyopathy were evident: echocardiography revealed a 58.6% increase in corrected LV chamber volume despite no obvious hypertrophy in the STZ rats. We observed increased proliferation of CFs isolated from the diabetic heart vs. those from control hearts. Microarray analysis of mRNA from whole left ventricles revealed down‐regulation of known inhibitors of proliferation, p53 and p21, in the STZ group (p<0.05), consistent with our proliferation data. We explored the potential signaling underlying the down‐regulation of these genes, utilizing whole heart protein lysates and Western analysis. Activated AKT, a signal that inhibits p53, was elevated in the stz group. Surprisingly, the STZ group contained lower levels of the myofibroblast marker α‐SMA (34.6% control, p<0.05) and higher levels of desmin (192% control, P<0.05). These data suggest that early stage diabetic hearts have fewer myofibroblasts which may compromise wound healing, but contain more proliferative CFs which predisposes the diabetic myocardium to fibrosis.