Análise das células-tronco cardíacas residentes e do potencial terapêutico de IGF-1 no coração em modelo experimental de obesidade

Abstract

Cardiovascular diseases are the leading cause of mortality in obesity. Progenitor cells presence in myocardium, including cardiac residents stem cells (CSC; c-kit+ Lin-) and endothelial progenitor cells (EPC; CD133+), has been suggested as a possible cardiac regeneration mechanism. However, despite the advance in understanding these cells, the mechanisms that regulate its survival in pathological conditions are not yet clear. Our group recently demonstrated that obesity is related to bone marrow stem cells damage. In addition, diabetic cardiomyopathy is associated with decreased CSC number and proliferative capacity. IGF-1 and HGF administration in myocardial infarction a model stimulated regenerative response of CSC, without the need for cell transplantation by inducing migration, proliferation and differentiation of CSC into cardiac and microvasculature cells. Therefore, this work aimed to study the therapeutic potential of IGF-1 on CSC in a Western diet-induced obesity model. 21 days old Swiss male mice were divided into control group (CG, N = 8), fed with standard diet, and obese group (OG, N = 16), fed with Western diet, high in saturated fat and simple carbohydrates, for 12 weeks. Part of the obese group animal (N = 8) received a daily subcutaneous injection of IGF-1 for seven consecutive days (OG + IGF-1). Control obese animals (N = 8) received saline. Our data demonstrated that IGF-1 treatment in obese mice (OG + IGF1) contributed to decrease of analyzed biometric parameters, reduced hepatic steatosis and cardiac hypertrophy when compared to OG. Treatment was also able to restore extracellular matrix and reduce apoptosis, reducing cardiac fibrosis area, which was corroborated by the lower content of collagens I and III, as well as the reduction of Bax / Bcl2 ratio. Treatment with IGF-1 reduced MMP-9 and TIMP-1 content and increased MMP-13 content, contributing to the favorable remodeling of cardiac parenchyma. OG + IGF-1 also showed improvement of calcium influx and cardiac coupling, evidenced by increased SERCA-2 and Connexin 43 contents. We also observed cardiac energetic metabolism improvement in OG + IGF-1 and a significant increase in the number of CSC, EPC and new cardiomyocytes formation compared to OG. These results suggest that IGF-1 has cardioprotective effect related to AKT pathway upregulation, providing tissue environment improvement and, thus, ensuring CSC and EPC survival, as well new cardiomyocytes formation. In parallel, AKT pathway activation has direct action on CSC, activating the survival and proliferation of these cells. Activated CSC, in turn, secrete several factors that act in a paracrine way in the cardiac tissue, contributing to morphofunctional recovery of the organ and cardiac failure rescue.