FUNCTION OF SERUM AMYLOID A PROTEIN (SAA)

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During the acute phase response, serum amyloid A protein apolipoprotein, increases 1,000 fold, and becomes a major component of HDL. In spite of intense modern interest in the HDL particle, the teleological role of this alteration of HDL by SAA in acute inflammation is unknown. We propose that a major role may be facilitation of delivery by HDL of needed phospholipid in peripheral sites of inflammation, where consumption of phospholipid in cell membrane destruction, prostonoid synthesis and the phosphatidyl inositol cell activation pathway is considerable. Chronic persistence of A-SAA render HDL less capable of mediating reverse cholesterol transport and provides a molecular explanation for the increased mortality of patients with chronic active rheumatoid arthritis from particularly cardiovascular disease. In addition to acute phase SAA (A-SAA), we have characterized a new SAA subfamily constitutive on normal HDL (C-SAA). This establishes the existence of a SAA superfamily with two distinct subfamilies. We propose that the C-SAA subfamily play a role in the normal biological function of HDL in that it promotes reverse cholesterol transport by causing the degradation of apo-AII. We will investigate whether during inflammation, aberrant induction of C-SAA might cause pathological neutral protease release with destructive potential. The studies proposed will extend our understanding of the physiologic role of the SAA's in inflammation and may help explain the propensity to advanced atherosclerosis in patients with chronic inflammatory rheumatic diseases.