Análise das células-tronco cardíacas residentes em modelo experimental de obesidade

Abstract

The nutritional transition process has contributed to growing obesity rates. Cardiac complications constitute the main mortality cause in obese or type 2 diabetic patients, in which an increased fatty acid offer is related to the increased heart adiposity and dysfunction. Obesity promotes cardiac hypertrophy, left ventricle (LV) dysfunction, cardiac fibrosis and ultrastructural damage. For a long time, the heart has been known as a post-mitotic organ; however, it was recently discovery a resident cardiac stem cells (CSC) population distributed throughout the myocardium, suggesting a possible mechanism of cardiac regeneration. The aim of this work was to evaluate the effects of western diet induced obesity over CSC. For this purpose, 21d old - male Swiss mice were divided into control group (CG, N = 8), fed standard chow AIN93G and obese group (OG, N = 8), fed Western diet rich in simple carbohydrates and saturated fat. All groups were followed up for 12 weeks, with food and water ad libitum. To verify if western diet was able to induce obese mice, it was measured: body weight, naso-anal length, tibia length, fasting glucose, epididymal and retroperitoneal fat weight, and heart weight. After euthanasia, the hearts were collected and processed for the following techniques: confocal microscopy, western blotting, flow cytometry, high-resolution respirometry and immunohistochemistry. Cardiac hypertrophy was analyzed by left ventricle weight/tibia length ratio. OG presented a progressive weight gain (P<0.05) and glucose intolerance (P<0.05) compared to CG. Left ventricle weight/tibia length ratio indicated cardiac hypertrophy (131.82%, OG). High-resolution respirometry revealed mitochondrial dysfunction, with a significant reduction in carbohydrate and fatty acid oxidation capacity and increased mitochondrial uncoupling (P<0.001). The analysis of collagen deposition showed a higher percentage of area stained by Sirius red in GO (P<0.0001), and also increased contents of collagen I (P< 0.01), collagen III (P< 0.05), MMP-9 (P<0.02) and MMP-13 (P<0.01), indicating fibrosis. In addition, OG presented decreased contents of CD133 (P<0.037), c-Kit (P<0.006) and conexin 43 (P< 0.02), compared to CG. Moreover, OG demonstrated increased proapoptotic proteins, with a higher BAX/Bcl-2 ratio than CG (P< 0.0075). Taking all these results, we can conclude that obesity leads to structural heart modifications, with extracellular matrix adverse remodeling, decreased cardiomyocytes ionic coupling, energetic metabolism dysfunction and increased apoptosis. These changes are related to an impairment and reduction of CSC (c-Kit+) and endothelial progenitor cells (CD133+), suggesting a reduced regenerative capacity of the heart against injuries.