Inhibition of prostaglandin I2 (PGI2) formation by LDL-cholesterol or LDL-peroxides?
A hypothesis of Gryglewski et al. explains the correlation between increased level of LDL and development of atherosclerosis by inhibition of PGI2 synthesis by increased peroxide content of LDL. The aim of the present paper was to examine this hypothesis. The major results are: 1) Preparation of LDL in the presence of .02% butylated hydroxytoluene did not reduce the lipid peroxide content of LDL from men and women and not change the inhibition or stimulation of the in vitro biosynthesis of PGI2 by LDL isolated from blood of men or women, respectively. 2) In the LDL and HDL, respectively, of healthy men we found nearly the same lipid peroxide levels (nmole malondialdehyde (MDA)/mg lipoprotein-cholesterol) as in the lipoproteins of male patients with hyperlipidemia type IIa or IV, but the peroxide concentration is three times higher in HDL as in LDL. 3) LDL isolated from healthy men inhibited in dose dependent fashion the generation of PGI2 from PGH2 by aortic microsomes whereas LDL from premenopausal women stimulated PGI2 formation even calculated as LDL lipid peroxides (in nM MDA/ml). The results call into question the hypothesis that diminished PGI2 formation by atherosclerotic vessels is related to inhibition of PGI2 synthetase by lipid peroxides present in LDL in the lesions. A new working hypothesis is presented that also the fatty acid pattern and the lipid class composition in the LDL are important for their influence on the PGI2 formation.
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D008078:Cholesterol, LDL / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood; D006953:Hyperlipoproteinemia Type IV / Q000097:blood; D019746:Intramolecular Oxidoreductases; D008054:Lipid Peroxides / Q000097:blood / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D012737:Sex Factors; D013552:Swine
D008078:Cholesterol, LDL; D008054:Lipid Peroxides; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase