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High-density lipoprotein (HDL)-associated protein (HAP) 1 is a novel phospholipid-binding protein. The HAP1 gene locus is a candidate gene for hyperlipidemia because of its lipid-binding property. HAP1 has also been reported to be highly expressed in the atherosclerotic plaque. The present study investigated the pathophysiological role of HAP1 and HAP1-Lp(a) (lipoprotein(a)) in vascular disease in rats and humans. HAP1 and HAP1-Lp(a) were purified from rat plasma by affinity chromatography. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining were performed. As animal models, we used HAP1-deficient rats and Apo-E-deficient (Apo-E(0))-rats. In atherosclerosis-prone rats, we compared plasma lipid profiles, histopathological changes, and the expression of HAP1 and HAP1-Lp(a) with those of control. We also investigated the changes of these proteins in carotid arteries of patients with atherosclerotic lesions. All rats and mice having the HAP1 deficiency died suddenly at the age of 4-8 months, but the Apo-E(0) rats survived for at least 18 months. In HAP1-deficient rats, both of plasma lipids, C-reactive protein, and leukocyte counts were normalized. In Apo-E(0) rats, only plasma lipid profiles were normalized. In HAP1-deficient rats, HAP1 and HAP1-Lp(a) were markedly decreased in plasma. In Apo-E(0) rats, both were moderately decreased. In human carotid arteries, strong HAP1-Lp(a) and HAP1 staining was observed in

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