Atherosclerosis is the underlying cause of the majority of cardiovascular diseases including myocardial infarction, strokes, and heart failure leading to tremendous morbidity and mortality worldwide. Risk factor modification such as reductions in hyperlipidemia and hypertension constitute the only treatment strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Reports of the pro-atherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of processing both exogenous material such as excess atherogenic lipids and endogenous cargo that includes dysfunctional proteins and organelles. Indeed, this is a primary mechanism by which macrophages can degrade excess lipids and cytotoxic materials present in the atherosclerotic plaque. Various lines of evidence demonstrate a progressive dysfunction in the autophagy-lysosome system of plaque macrophages suggesting that attempts at reprogramming the degradative capacity of macrophages might be a fruitful therapeutic area. Our work with TFEB, the predominant transcription factor regulating autophagy-lysosomal biogenesis, shows that enhancing TFEB function in macrophages leads to reductions in atherosclerosis of mice. In an attempt to harness this pathway therapeutically, we have uncovered a safe and natural sugar called trehalose, able to induce TFEB and autophagy-lysosome biogenesis in macrophages and recapitulate the atheroprotective properties. This raises the prospect of this sugar as a novel and practical therapy.
In specific aim 1, we will dissect the mechanisms linking trehalose to macrophage autophagy- lysosomal biogenesis.
In specific aim 2, we will determine the predominant autophagic processes in macrophages that underlie trehalose?s ability to reduce atherosclerosis. A major impediment to the therapeutic use of trehalose is degradation by the enzyme trehalase, present in higher organisms including mammals.
In specific aim 3, genetic and pharmacological techniques of inhibiting trehalase will be used to determine if trehalose?s effects can be synergized. This proposal will test the hypothesis that trehalose can harness macrophage autophagy-lysosomal biogenesis to treat atherosclerosis.
Atherosclerotic vascular disease remains the leading cause of death in the United States with the majority of mortality due to coronary artery disease and myocardial infarction. Likewise, the Veteran population is not immune to this where a significant portion of VA medical care is focused on ischemic heart disease and its complications. Macrophages are primary cells that specialize in removing the excess lipids and other debris present in the atherosclerotic plaque. We have found that macrophages have the ability to augment their degradation machinery and when this response is stimulated genetically in mice, they have reduced atherosclerosis. Furthermore, we have discovered a safe and natural compound that can stimulate this macrophage degradation response with nearly identical results as the genetic models. Thus, we propose to dissect the links between this compound and the macrophage degradation machinery both in vitro and in vivo with the goal of developing a completely novel strategy of treating atherosclerosis.
| Zhang, Xiangyu; Evans, Trent D; Jeong, Se-Jin et al. (2018) Classical and alternative roles for autophagy in lipid metabolism. Curr Opin Lipidol 29:203-211 |
| Evans, Trent D; Jeong, Se-Jin; Zhang, Xiangyu et al. (2018) TFEB and trehalose drive the macrophage autophagy-lysosome system to protect against atherosclerosis. Autophagy 14:724-726 |
| Zhang, Yiming; Higgins, Cassandra B; Mayer, Allyson L et al. (2018) TFEB-dependent induction of thermogenesis by the hepatocyte SLC2A inhibitor trehalose. Autophagy 14:1959-1975 |
