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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103527-07
Application #
8733727
Study Section
Special Emphasis Panel (ZGM1-TWD-Y)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
$255,066
Indirect Cost
$85,066
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Petriello, Michael C; Brandon, J Anthony; Hoffman, Jessie et al. (2018) Dioxin-like PCB 126 Increases Systemic Inflammation and Accelerates Atherosclerosis in Lean LDL Receptor-Deficient Mice. Toxicol Sci 162:548-558
Alsiraj, Yasir; Thatcher, Sean E; Blalock, Eric et al. (2018) Sex Chromosome Complement Defines Diffuse Versus Focal Angiotensin II-Induced Aortic Pathology. Arterioscler Thromb Vasc Biol 38:143-153
Thompson, Joel C; Wilson, Patricia G; Wyllie, Alex P et al. (2018) Elevated circulating TGF-? is not the cause of increased atherosclerosis development in biglycan deficient mice. Atherosclerosis 268:68-75
Thalman, Carine; Horta, Guilherme; Qiao, Lianyong et al. (2018) Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders. Mol Psychiatry 23:1699-1710
Lee, Scott J; Zea, Ryan; Kim, David H et al. (2018) CT texture features of liver parenchyma for predicting development of metastatic disease and overall survival in patients with colorectal cancer. Eur Radiol 28:1520-1528
Brandon, Jason A; Farmer, Brandon C; Williams, Holden C et al. (2018) APOE and Alzheimer's Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction. Front Aging Neurosci 10:180
Sui, Yipeng; Park, Se-Hyung; Wang, Fang et al. (2018) Perinatal Bisphenol A Exposure Increases Atherosclerosis in Adult Male PXR-Humanized Mice. Endocrinology 159:1595-1608
Sui, Yipeng; Liu, Zun; Park, Se-Hyung et al. (2018) IKK? is a ?-catenin kinase that regulates mesenchymal stem cell differentiation. JCI Insight 3:
Deng, Pan; Barney, Jazmyne; Petriello, Michael C et al. (2018) Hepatic metabolomics reveals that liver injury increases PCB 126-induced oxidative stress and metabolic dysfunction. Chemosphere 217:140-149
Al-Darraji, Ahmed; Haydar, Dalia; Chelvarajan, Lakshman et al. (2018) Azithromycin therapy reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction: Potential therapeutic targets in ischemic heart disease. PLoS One 13:e0200474

Showing the most recent 10 out of 235 publications