The heart reduces fatty acid (FAs) oxidation and switches to greater glucose utilization with ischemia. While this process allows more ATP production with less oxygen use, it occurs at the expense of limiting the use of FAs, the major substrates for cardiac energy. We hypothesize that this leads to fuel deprivation, especially as blood flow reduction decreases energetic substrate availability. If this hypothesis is correct, then storage of more triglyceride in the heart would lead to reduced ischemic damage; this we speculate is the reason for the ?obesity paradox? in which obese humans who have more ischemic disease also have increased post myocardial infarction survival. This proposal includes experiments to study basic and clinically relevant relationships between heart FA metabolism and heart function. Specifically, we will use mice created by the PI to study how changes in triglyceride stores and lipid uptake alter cardiac response to ischemia/reperfusion. In addition, we will test whether deletion of genes required for normal uptake of FAs by myeloid cells affects their conversion to an alternatively activated and reparative phenotype. These studies will include assessment of cardiac gene changes and lipidomics and will utilize tracer kinetics to assess uptake and oxidation of glucose and lipids, and to determine their downstream products. The experiments will require the collaboration of two laboratories: one with expertise in heart lipid metabolism and the second with expertise in ischemic/reperfusion models and analysis of substrate metabolism. The three aims of this application are the following:
Aim 1. To determine whether increased cardiomyocyte storage of triglyceride improves response to ischemia.
Aim 2. To assess whether mice with reduced heart lipid uptake have altered response to ischemia.
Aim 3. To assess ischemic injury and repair in mice with macrophage-specific deletions of lipoprotein lipase and cluster of differentiation (CD)36. The experiments will use several lines greater cardiac triglyceride stores due to transgenic expression of diacylglycerol acyl transferase 1 and peroxisomal proliferator activated receptor ?, and mice with reduced uptake of FAs due to tissue specific deletions of lipoprotein lipase and CD36. These studies will illustrate possible metabolic approaches to reducing ischemic injury and improving repair of damaged myocardium.
This application proposes experiments to assess how lipid metabolism in cardiomyocytes and white blood cells affects heart injury and repair after ischemia/reperfusion. We will use a number of genetically modified mice and will assess metabolic changes by radioactive uptake in vivo and substrate metabolism in perfused heart. Cardiac white blood cells will be analyzed by FACS and laser capture microscopy.
|Lee, Gloria; Plaksin, Joseph; Ramasamy, Ravichandran et al. (2018) Targeted drug discovery and development, from molecular signaling to the global market: an educational program at New York University, 5-year metrics. J Transl Sci 4:1-9|
|Lee, Gloria; Kranzler, Jay D; Ramasamy, Ravichandran et al. (2018) Training scientists as future industry leaders: teaching translational science from an industry executive's perspective. J Transl Sci 4:|