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.
|Song, Eun Suk; Jang, HyeIn; Guo, Hou-Fu et al. (2017) Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes. Proc Natl Acad Sci U S A 114:E2826-E2835|
|Bradford, Emily M; Ryu, Stacy H; Singh, Ajay Pal et al. (2017) Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease. J Immunol 199:1886-1897|
|Pumphrey, Ashley L; Ye, Shaojing; Yang, Zhengshi et al. (2017) Cardiac Chemical Exchange Saturation Transfer MR Imaging Tracking of Cell Survival or Rejection in Mouse Models of Cell Therapy. Radiology 282:131-138|
|Muniappan, Latha; Javidan, Aida; Jiang, Weihua et al. (2017) Calpain Inhibition Attenuates Adipose Tissue Inflammation and Fibrosis in Diet-induced Obese Mice. Sci Rep 7:14398|
|Adamiak, M; Abdelbaset-Ismail, A; Suszynska, M et al. (2017) Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades. Leukemia 31:262-265|
|Adamiak, Mateusz; Chelvarajan, Lakshman; Lynch, Kevin R et al. (2017) Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells. Oncotarget 8:65588-65600|
|Wysoczynski, Marcin; Adamiak, Mateusz; Suszynska, Malwina et al. (2017) Poor Mobilization in T-Cell-Deficient Nude Mice Is Explained by Defective Activation of Granulocytes and Monocytes. Cell Transplant 26:83-93|
|Brown, J Mark; Temel, Ryan E; Graf, Gregory A (2017) Para-bile-osis Establishes a Role for Nonbiliary Macrophage to Feces Reverse Cholesterol Transport. Arterioscler Thromb Vasc Biol 37:738-739|
|Akenhead, Michael L; Fukuda, Shunichi; Schmid-Schönbein, Geert W et al. (2017) Fluid shear-induced cathepsin B release in the control of Mac1-dependent neutrophil adhesion. J Leukoc Biol 102:117-126|
|Wang, Yu; Shoemaker, Robin; Powell, David et al. (2017) Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice. Am J Physiol Heart Circ Physiol 312:H459-H468|
Showing the most recent 10 out of 197 publications