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GPCR-dependent NF-kB Signaling in Endothelial Dysfunction: A Critical Role for the CARMA3/BcI10/MALT1 Signaling Complex.

By Phillip Charles Delekta

Abstract

Atherosclerosis is a complex inflammatory disease. Atherosclerotic lesions are characterized by the accumulation of lipid particles and immune cells in the subendothelial space, resulting in the narrowing of the arterial lumen restricting blood flow. Endothelial cell activation, upon exposure to oxidized lipids and pro-inflammatory stimuli, plays an important role in the pathogenesis of atherosclerosis. This damage leads to endothelial dysfunction in the vessel wall, resulting in the expression of chemotactic factors and adhesion molecules, attracting monocytes to migrate into the subendothelial space. Here, they differentiate into macrophages and phagocytose the lipids, becoming lipid-laden foam cells. A significant factor in the pathogenesis of atherosclerosis is the chronic activation of G protein-coupled receptors (GPCR) such as Protease activated receptor-1 (PAR-1). GPCRs are the largest family of cell surface receptors and are expressed in all vascular cell types. In response to agonists, these receptors signal to induce pro-inflammatory genes important to atherogenesis via the NF-κB cell signaling pathway. The NF-κB pathway is a driving force in the formation and progression of atherosclerotic plaques. Activation of the NF-κB pathway leads to nuclear translocation of the NF-κB transcription factors (p50 and p65) that are kept inactive in the cytoplasm by association with the regulatory protein, IκBα. Activated GPCRs stimulate the IκB kinase which phosphorylates IκBα, leading to IκBα ubiquitination and proteasomal degradation. The transcription factors are then released from IκBα, allowing them to accumulate in the nucleus. NF-κB transcription factors activate the expression of genes for key steps in plaque initiation such as the recruitment of monocytes, stimulation of lymphocytes, and the proliferation and migration of underlying vascular smooth muscle cells. Utilizing the PAR-1, we establish a critical link in GPCR-dependent NF-κB signaling in endothelial dysfunction. This involves a three protein complex consisting of CARMA3, a scaffolding protein with several protein interaction domains, Bcl10, a linker protein, and MALT1, an effector protein that appears to be involved in ubiquitin-mediated activation of the IKK complex. The CARMA3/Bcl10/MALT1 complex is a pivotal point in PAR-1 induced endothelial dysfunction and the disruption of this complex blocks PAR-1 induced NF-κB signaling and preserves normal endothelial cell function

Topics: CARMA3 Bcl10 MALT1, Atherosclerosis Inflammatory Disease, Endothelial Dysfunction, NF-κB, Protease Activated Receptor-1 PAR-1 GPCR, Endothelial Cell
OAI identifier: oai:deepblue.lib.umich.edu:2027.42/89853

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