Obesity is approaching epidemic state in the western worid and is a known risk factor for acute myocardial infarction (AMI). AMI and the subsequent ischemic heart disease (IHD) are often complicated with high mortality and poor overall prognosis despite significant advances in medical therapy and revascularization strategies. Currently, short of heart transplantation with all of its inherit limitations, there are no available treatment strategies that replace the infracted myocardium and therapies are largely palliative. Paradoxically, obesity may also confer a protective effect against AMI-associated remodeling which leads to IHD. The molecular kiasis for this protection is poorly understood. AMI initiates poorly understood innate reparatory mechanisms through which BMSPCs are mobilized and home towards the ischemic myocardium contributing to myocardial regeneration and correlating with cardiac recovery. Our preliminary data indicates that bioactive lipids such as sphingosine-1 phosphate (SIP), but not traditional chemokines, play a quintessential role in this mobilization and homing. Interestingly, obesity and the associated metabolic syndrome are associated with alterations in bioactive lipids'metabolism. Our objective in this application, therefore, is to develop better understanding ofthe obesity-associated alterations in AMI-induced stem cell mobilization pathways, specially those involving bioactive lipids, and devise therapies that hamess this process for therapeutic myocardial regeneration strategies. Our central hypothesis has been formulated based upon the existing literature and our strong preliminary data demonstrating that BMSPCs express SIP receptors and will migrate towards plasma from AMI patients in an SI P dependent fashion. Our rationale for these studies is that understanding the protective role of bioactive lipids and stem cell mobilization during AMI in obesity would help establish a strong scientific framework for eventual generalizable human myocardial regenerative clinical trials utilizing the available and new pharmacological modulators of bioactive lipids and their receptors. In addition to clinical studies, our approach will exploit small molecule-strategies in mouse models through examining the obesity associated molecular and cellular pathways, specially those involving bioactive lipids, that are activated by myocardial infarction (Aim 1);and examine the modulation of bioactive lipids'metabolism and receptor expression to enhance cardiac recovery following AMI (Aim 2).
Obesity increases the risk for acute myocardial infarction but may paradoxically exert protective effect from the subsequent cardiac remodeling. Our objective is to develop better understanding of obesity-associated alterations in myocardial infarction-induced stem cell mobilization pathways, specially those involving bioactive lipids, and devise therapies that'harness this process for myocardial regeneration strategies.
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