Improved anti-apoptotic and anti-remodeling potency of bone marrow mesenchymal stem cells by anoxic pre-conditioning in diabetic cardiomyopathy

Abstract

Bone marrow mesenchymal stem cells (MSC) mediate their protection by paracrine mechanism under ischemic conditions and anoxic pre-conditioning (AP) of MSC strongly enhances their survival and regenerative capacity. However, there is no report about the therapeutic potency of MSC transplantation on diabetic cardiomyopathy (DCM), an important cause of heart failure. Four months after streptozotocin injection, diabetic rats were randomly given an intramyocardial injection of one of the following: DMEM, MSC, or AP-MSC (no.=10 for each group). Two weeks after transplantation, MSC, especially AP-MSC greatly increased the fractional shortening of diabetic heart (p<0.01, respectively). AP-MSC increased the capillary density of diabetic myocardium and attenuated myocardial fibrosis (p<0.01, respectively) by increasing the activity of matrix metalloproteinase-2 and inhibitiing transforming growth factor beta-1 (p<0.01, respectively). AP-MSC are anti-apoptotic in the rat DCM model, possibly mediated through cardiac upregulation of Bcl-2/Bax ratio (p<0.05) and inhibiting the expression and activation of caspase- 3 (p<0.01). Intramyocardial transplantation of MSC has a protective effect on diabetic myocardium and anoxic pre-conditioning can enhance this protective effect. AP-MSC transplantation improved cardiac function in the rat DCM model, possibly through an anti-apoptotic effect on diabetic myocarium and attenuation of cardiac remodeling.