Modulation of prostaglandin I2 production from bovine aortic endothelial cells by serum amyloid A and its N-terminal tetradecapeptide.

Abstract

The study was aimed to explore the possible involvement of the acute phase HDL apolipoprotein, serum amyloid A (SAA) in the regulation of PGI2 production by endothelial cells. This, in view of the recent detection of SAA mRNA in endothelial cells of human atherosclerotic lesions. Human SAA induces PGI2 formation in bovine aortic endothelial cells culture in a concentration relevant to moderate acute phase events. 50 micrograms/ml of purified human SAA increases PGI2 production from a mean basal level of 2,490 +/- 330 pg/ml by 1.80 +/- 0.1 fold (n = 10; p < 0.01). The PGI2 inducing activity resides apparently in the N-terminal, i.e. amino acid residues 1-14, of the SAA molecule, 50 micrograms/ml of the peptide induces 2.9 +/- 0.5 fold increase of PGI2 production (n = 4; p < 0.03). TNF and LPS each induce PGI2 production in a concentration and time dependent manner. TNF in concentration of 10 ng/ml induces, in the presence of calf serum, an increase of 24.9 +/- 2.3 fold (n = 4; p < 0.001) and LPS in concentration of 1 microgram/ml causes a 18.3 +/- 1.3 fold increase, (n = 4; p < 0.01). In serum-free cultures, only a 2.5 +/- 0.3 fold increase was detected by 10 ng/ml TNF (n = 4), and a 5.9 +/- 0.4 by 1 microgram/ml of LPS. Thus, serum has a strong effect on PGI2 induction. When 50 micrograms/ml SAA is coadministered with 1 ng/ml TNF it reduces the TNF-induction of PGI2 from 7.7 +/- 2.8 to 3.3 +/- 1.2 fold (n = 4; p < 0.01). SAA attenuates, as well, LPS-mediated activity, although in a less pronounced manner. Our finding suggest a potential physiological function for SAA in regulation of basal and cytokine-induced PGI2 production by vascular endothelium. The capacity of SAA to markedly moderate PGI2 induction by TNF and LPS suggest that it may play a role in defending against vessel damage, in cases of atherosclerosis, bacterial infection or septic shock. The induction of PGI2 by SAA through its N-terminal domain, which also exhibits an anti-platelet aggregation activity, suggests a potential therapeutical use for this peptide as an anti-hypertensive and an anti-aggregatory agent.