Nox4 and the Redox-Regulation of MKPs in Monocyte Recruitment and Atherosclerosis

  • Asmis, Reto H (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.
StatusFinished
Effective start/end date7/16/124/30/16

Funding

  • National Institutes of Health: $20,283.00
  • National Institutes of Health: $377,893.00
  • National Institutes of Health: $389,008.00
  • National Institutes of Health: $390,991.00
  • National Institutes of Health: $470,504.00

ASJC

  • Medicine(all)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.