Abstract
Despite many recent breakthroughs to prevent or limit cardiovascular disease, heart attacks and congestive heart failure remain among the world's most prominent health challenges. In fact, despite successful approaches, the restoration of function to the damaged heart remains a formidable challenge. Oxidative stress results in excessive accumulation of reactive oxygen species (ROS) and contributes to the pathogenesis of cardiovascular diseases including hypertension, atherosclerosis, cardiac hypertrophy, heart failure and diabetes mellitus. In recent years, the incredible boost in stem cell research has kindled the expectations of researchers, patients and physicians. Mesenchymal stem cells (MSCs) have been utilized in potential therapeutic applications. MSCs contribute to tissue repair in vivo and form an attractive alternative to embryonic stem cells in tissue engineering and regenerative medicine. MSCs can easily be obtained from adult bone marrow and have no ethical issues as a source of multipotent stem cells capable of differentiating into multiple mesodermal cell lineages. The effects of MSCs on oxidative stress are still unknown. Recent data from the Hare Lab suggests that GSNOR (S-nitrosoglutathione reductase) deficiency protects cardiac proteins from ROS. Here, using the same mouse model, we will determine whether transendocardial administration of allogeneic MSCs will further reduce oxidative stress in GSNOR-/- mice compared with C57Bl6/J control mice during left ventricular remodeling (post-injury). Additionally, we will test if MSCs restore redox status in vitro, in cardiomyocytes, endothelial cells and reduce SO-damage. To test this hypothesis we propose the following specific aims: Aim 1. To test the hypothesis that allogeneic MSCs decrease myocardial oxidative stress in vivo during left ventricular remodeling by reducing ROS production. There is accumulating evidence that mesenchymal stem cells (MSCs) are a safe and efficacious approach to treating disorders characterized by left ventricular (LV) remodeling. We hypothesize that MSCs can restore redox balance lost during LV remodeling. Therefore, we will examine the molecular mechanisms by which MSCs controls superoxide and peroxide production as well biomarkers of oxidative stress damage. To access the role of MSCs on myocardium superoxide and hydrogen peroxide production we will use specific probes described in our methods section.Aim 2. To test the hypothesis that allogeneic MSCs restore redox status in vitro, in cardiomyocytes and endothelial cells and reduce ROS production/damage. MSCs represent a promising therapeutic candidate for cardiovascular repair. Our study will analyze their capacity to reduce oxidative stress on cardiomyocytes and endothelial cells. We will test if co-culture of MSCs with macrophage-exposed endothelial cells or macrophage-exposed cardiomyocytes results in the preservation and repair of cell-cell interaction, NO bioavailability, and cell survival. Together, these results will suggest the potential mechanisms involved in the disruption of oxidative/ nitrosative insult.
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