Chemokine-driven transmigration of monocytes into the subendothelial space is a fundamental and rate- limiting process in atherogenesis. Our preliminary data show that this process is dysregulated by metabolic stress and that increased monocyte responsiveness to chemokines appears to accelerate atherosclerotic plaque development. We have now uncovered a novel thiol redox-sensitive mechanism in monocytes that upon dysregulation by metabolic disorders, "primes" and transforms monocytes into a hyper-chemotactic pro- atherogenic phenotype. In addition, we have found that the recently discovered monocytic NADPH oxidase 4 is a mediator of monocyte priming. We propose that metabolic stress-induced Nox4 and the subsequent increase in H2O2 formation in monocytes promote the S-glutathionylation and inactivation of mitogen-activated protein kinase phosphatases (MPKs);MKPs are the enzymes responsible for the deactivation of both phospho-ERK and phospho-p38MAPK, the two principal MAPK pathways mediating MCP-1-induced monocyte adhesions and migration. We hypothesize that monocyte MPKs represent a novel, critical mechanistic link between oxidative stress induced by metabolic disorders and the formation of atherosclerotic lesions. Our studies support a new paradigm implicating monocyte priming and dysfunction as an early primary contributor to atherogenesis. The studies we propose here aim to test this paradigm and elucidate the underlying molecular mechanisms.
Specific Aim 1 : Determine the roles of mitogen-activated protein kinase phosphatases (MKP) in the redox regulation of monocyte adhesion, chemotaxis, and recruitment into atherosclerotic lesions.
Specific Aim 2 : Determine the roles of protein-S-glutathionylation in monocyte recruitment and the development of atherosclerotic lesions.
Specific Aim 3 : Determine the roles of monocytic Nox4 in monocyte priming and atherogenesis.
Monocyte recruitment into the vessel wall is an essential step in the development of atherosclerotic lesions - a process initiated by the injured vasculature releasing chemokines in response to inflammatory processes. With our discovery that chronic metabolic stress dramatically enhances the responsiveness of blood monocytes to chemoattractants and increases monocyte migration, we have uncovered a completely novel mechanism by which metabolic disorders promote atherosclerosis. Our data support a new paradigm that implicates monocyte priming and dysfunction induced by metabolic disorders as an early primary contributor to atherogenesis. The studies we propose here aim to test this paradigm and elucidate the underlying molecular mechanisms. Should our paradigm prove correct, our studies may have identified the molecular basis for a causal relationship that explains the well-established associations between metabolic disorders, oxidative stress, and cardiovascular diseases.
|Zamora, D A; Downs, K P; Ullevig, S L et al. (2015) Glutaredoxin 2a overexpression in macrophages promotes mitochondrial dysfunction but has little or no effect on atherogenesis in LDL-receptor null mice. Atherosclerosis 241:69-78|
|Ullevig, Sarah L; Kim, Hong Seok; Nguyen, Huynh Nga et al. (2014) Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4. Redox Biol 2:259-66|
|Kim, Hong Seok; Ullevig, Sarah L; Nguyen, Huynh Nga et al. (2014) Redox regulation of 14-3-3Î¶ controls monocyte migration. Arterioscler Thromb Vasc Biol 34:1514-21|
|Tavakoli, Sina; Zamora, Debora; Ullevig, Sarah et al. (2013) Bioenergetic profiles diverge during macrophage polarization: implications for the interpretation of 18F-FDG PET imaging of atherosclerosis. J Nucl Med 54:1661-7|
|Ullevig, Sarah; Kim, Hong Seok; Asmis, Reto (2013) S-glutathionylation in monocyte and macrophage (dys)function. Int J Mol Sci 14:15212-32|
|Lee, Chi Fung; Ullevig, Sarah; Kim, Hong Seok et al. (2013) Regulation of Monocyte Adhesion and Migration by Nox4. PLoS One 8:e66964|
|Kim, Hong Seok; Ullevig, Sarah L; Zamora, Debora et al. (2012) Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment. Proc Natl Acad Sci U S A 109:E2803-12|