Vascular inflammation is a critical contributing factor to the development of atherosclerosis. Combined with the effects of lipid deposition, inflammation promotes endothelial dysfunction, smooth muscle proliferation, and matrix destabilization, adverse events that exacerbate developing atherosclerotic lesions and may ultimate lead to their rupture and to vessel thrombosis. The sources of inflammation are varied, but among the most important are the circulating substances that stimulate G protein-coupled receptors (GPCRs) present on the surface of endothelial cells. These include a diverse array of peptide ligands, amines, glycoproteins and enzymes. The activated receptors then relay intracellular signals by stimulating multiple pathways, including those for ERK, Akt, JNK, p38MAPK, and STAT, but activation of the NF-kB transcription factor has been deemed one of the most important and potent pro-inflammatory signals. We have uncovered a signal transduction pathway that mediates NF-kB activation in response to the GPCR agonists, Angiotensin II and thrombin. This pathway centers on the assembly of a multiprotein signaling module composed of the molecules CARMA3, Bcl10, and MALT1, which we now refer to as the CBM signalosome. In this signalosome, the MALT1 protein acts as the primary effector, coordinating downstream stimulation of the canonical NF-kB machinery. It appears that this CBM signalosome is also critical for NF-kB activation induced by GPCRs that recognize lsyophosphatidic acid (LPA), IL-8, endothelin-1, and SDF-1/CXCL12. Most of these substances have been clearly linked to vascular dysfunction, inflammation, and atherogenesis, and it is thought that their ability to activate NF-kB is central to these pathophysiologic responses. Thus, we believe the CBM signalosome is a mechanistic hub responsible for relaying proinflammatory signals in the vessel wall, since it is stimulated by such a diverse array of GPCR agonists. As such, targeting the actions of the signalosome may prove to be a highly effective strategy for managing atherogenesis. In this proposal, we will probe the mechanistic links between the CBM signalosome and specific aspects of vascular pathobiology. This will be accomplished through three specific aims that (1) investigate the effect of blocking CBM activity on NF-kB activation in endothelial cells and novel aspects of endothelial pathophysiology, (2) explore the mechanisms whereby the CBM signalosome is assembled following GPCR activation, and (3) test the effect of blocking CBM activity on the atherogenic process in vivo. We anticipate that the results will broadly inform development of pharmaceutical strategies for curtailing the contributions of inflammation to atherogenesis.
Vascular inflammation is a critical contributing factor to the development of atherosclerosis. This proposal will advance our knowledge of basic molecular mechanisms that are the root-cause of vascular inflammation, and will provide a framework for the rational design of pharmacologic agents to quench this important pathologic process. As such, these studies will facilitate the movement of basic discoveries in vascular cell biology and inflammation to clinical application in the treatment of cardiovascular disease.
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