COBRE Pilot Project for Ahmed Abdel-Latif: Center of Research in Obesity and Cardiovascular Disease

Obesity is approaching epidemic levels in the western world1 and increases the risk for acute myocardial infarction (AMI). AMI and associated complications from ischemic heart disease (IHD) carry a high mortality and overall poor prognosis, despite significant advances in medical therapy and revascularization strategies.2, 3 Currently, short of heart transplantation with all of its inherit limitations, replacing damaged myocardium is not possible. Paradoxically, while obesity is a risk factor for AMI, it appears to confer protection from complications of IHD.4, 5 The molecular mechanisms underlying the protective effects of obesity are not known. Cardiomyocyte renewal following ischemic injury is a dynamic process, maintained at least in part by bone marrow (BM)-derived stem/progenitor cells (SPCs),6-8 and capable of renewing up to half of the heart’s population of cardiomyocytes during the normal life span.9 In response to AMI BMSPC are mobilized and home to the ischemic myocardium, where they contribute to myocardial regeneration as we and others have demonstrated.10-12 The magnitude of BMSPC mobilization following AMI correlates with cardiac recovery.13 While the mechanisms underlying BMSPC mobilization are incompletely understood, the bioactive lipid mediator sphingosine-1 phosphate (S1P) has recently been demonstrated to exhibit potent chemotactic effects on hematopoietic stem cells (HSCs) and our data indicate that S1P is positioned to contribute to BMSPC mobilization in the setting of AMI. Obesity and the associated metabolic syndrome cause alterations in bioactive lipid metabolism.14, 15 Thus, alterations in S1P levels, BMSPC mobilization, or both may contribute to the protective effect of obesity on development and complications of IHD. Our long-term research goal is to discover and develop effective pharmaceuticals to enhance the mobilization and homing of BMSPC to the damaged myocardium as a basis for successful BMSPC-based myocardial regenerative therapies. Our preliminary data suggest that obese and overweight individuals have a heightened capability to mobilize BMSPC in the early stages following AMI and that this mobilization correlates with higher plasma S1P levels. Our objective in this application, therefore, is to develop better understanding of the obesity-associated alterations in AMI-induced stem cell mobilization pathways specially those involving bioactive lipids and to devise therapies that harness this process for therapeutic myocardial regeneration strategies. Our central hypothesis has been formulated, in large part, based upon the existing literature and our strong preliminary data demonstrating that BMSPC express S1P receptors and will migrate towards plasma from AMI patients in an S1P-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 available and new pharmacological modulators of bioactive lipid levels and signaling pathway. Significance. The proposed research will provide necessary preliminary data and shed more light on some of the potential protective mechanisms endowed by obesity in patients with ischemic heart disease. We will also explore the chemokine-independent mechanisms regulating stem cell mobilization and homing in myocardial ischemia in relation with obesity and metabolic syndrome. Ischemic heart disease represents a common and growing problem for which there are no definitive therapies. Evidence of cardiomyocyte renewal exist and suggest potential therapeutic targets for regenerative therapies. Bioactive lipids are convincingly implicated in a wide range of cardiovascular functions and their role in hematopoietic stem cell mobilization and homing has been well documented. The data gleaned from these experiments will serve as bases for future human studies examining the therapeutic role of S1P agonists in the mobilization and homing to myocardium of BMSPC in ischemic heart disease.