Serum amyloid A-activating factor-1 and HOCl-HDL

Hypochlorite (HOCl)-modified (lipo)proteins are present in human and rabbit lesion material. Modification of high-density lipoprotein (HDL) by HOCl - generated in vivo by the myeloperoxidase-H2O2-halide system of activated phagocytes - transforms an antiatherogenic lipoprotein particle into a proatherogenic and proinflammatory lipoprotein particle. Preliminary studies have shown that HOCl-HDL can increase DNA-binding and transactivating potential of serum amyloid A[SAA]-activating factor-1 (SAF-1). The SAF family of transcription factors is implicated in the pathogenesis of atherosclerosis because of their involvement in the regulation of SAA. Persistent high levels of SAA is linked to various pathophysiological conditions, e.g. amyloidosis, rheumatoid arthritis, and atherosclerosis. The goal of this application is to elucidate potential cellular mechanisms involved in the pathogenesis of atherosclerosis mediated by proinflammatory HOCl-HDL. We hypothesize that HOCl-HDL- mediated tissue- and cell-specific activation of SAF-1 is a key step for induction of SAA under atherosclerotic conditions and that SAF-1 could be a potential target in developing a therapeutic measure against atherosclerosis. Analysis of its activation pathway will facilitate identification of critical and specific steps necessary for regulating transcriptional activity of SAF-1. Specific aims for testing the hypothesis are: 1) Understand the activation mechanism of SAF-1 by proatherogenic HOCl-HDL in vascular smooth muscle and endothelial cells, monocytes/macrophages and liver cells. 2) Identify the signaling pathways by which HOCl-HDL activates SAF-1. Establish the role of involved protein kinases. 3) Delineate the pathways of activation of SAF-1 in arterial wall co-culture by HOCl- HDL. 4) Immunohistochemical detection of SAF-1 in atherosclerotic lesions and colocalization with HOCl-modified (lipo)proteins. We believe that the outcome of this proposal will provide new and useful information to understand biological properties of cells during development of atherosclerosis and inflammation when exposed to a proatherogenic lipoprotein species occuring in vivo.

Hypochlorite (HOCl)-modified (lipo)proteins are present in human and rabbit lesion material. Modification of high-density lipoprotein (HDL) by HOCl - generated in vivo by the myeloperoxidase-H2O2-halide system of activated phagocytes - transforms an antiatherogenic lipoprotein particle into a proatherogenic and proinflammatory lipoprotein particle. Preliminary studies have shown that HOCl-HDL can increase DNA-binding and transactivating potential of serum amyloid A[SAA]-activating factor-1 (SAF-1). The SAF family of transcription factors is implicated in the pathogenesis of atherosclerosis because of their involvement in the regulation of SAA. Persistent high levels of SAA is linked to various pathophysiological conditions, e.g. amyloidosis, rheumatoid arthritis, and atherosclerosis. The goal of this application is to elucidate potential cellular mechanisms involved in the pathogenesis of atherosclerosis mediated by proinflammatory HOCl-HDL. We hypothesize that HOCl-HDL- mediated tissue- and cell-specific activation of SAF-1 is a key step for induction of SAA under atherosclerotic conditions and that SAF-1 could be a potential target in developing a therapeutic measure against atherosclerosis. Analysis of its activation pathway will facilitate identification of critical and specific steps necessary for regulating transcriptional activity of SAF-1. Specific aims for testing the hypothesis are: 1. Understand the activation mechanism of SAF-1 by proatherogenic HOCl-HDL in vascular smooth muscle and endothelial cells, monocytes/macrophages and liver cells. 2. Identify the signaling pathways by which HOCl-HDL activates SAF-1. Establish the role of involved protein kinases. 3. Delineate the pathways of activation of SAF-1 in arterial wall co-culture by HOCl- HDL. 4. Immunohistochemical detection of SAF-1 in atherosclerotic lesions and colocalization with HOCl-modified (lipo)proteins. We believe that the outcome of this proposal will provide new and useful information to understand biological properties of cells during development of atherosclerosis and inflammation when exposed to a proatherogenic lipoprotein species occuring in vivo.