Prostaglandin Synthesis in Atherosclerotic Human Carotid Artery
Atheromatous arterial plaques have been reported to differ from normal arterial tissue in that lower levels of prostacyclin (PGI2) are produced and thromboxane A2 (TxA2) is formed. Both PGI2 and prostaglandin E2 (PGE2) inhibit platelet adherence and aggregation, whereas TxA2 promotes these activities; thus, reported alterations in prostaglandin (PG) metabolism could contribute to arterial throm-bogenicity. It is unclear whether such changes in PG formation in patients with atherosclerosis are localized to atheromatous plaques or can also be found in adjacent arterial tissue. The biochemical basis of these alterations is not completely defined but has clinical relevance, because embolization of platelet aggregates and thrombi from carotid plaques is thought to be an important factor in the etiology of stroke.
We investigated PG synthesis in carotid plaques removed from symptomatic patients by carotid endarterectomy. Specimens were dissected into the following fractions: nonatheromatous intima adjacent to carotid plaque, subintimal plaque, intima overlying the point of carotid stenosis, and intimal ulceration. Fractions were homogenized and incubated with 10 μM [14C]PGH2 (prostaglandin endoperoxide, the percursor of PGI2. TxA2, and PGE2) and 2 mM GSH (an endogenous antioxidant and cofactor required for synthesis of PGE2 from PGH2). The stable breakdown products of PGI2 (6-keto-PGFlα) and TxA2 (TxB2), as well as PGE2 and other PG products of PGH2 metabolism, were isolated by thin-layer chromatography, identified by comigration with authentic PG standards, and quantified by computer analysis of radiochromatographic scans. PGI2 synthase activity (pmol 6-keto-PGFια/2 min per 100 μg homogenate protein) of intima proximal and distal to carotid plaque was comparable to normal carotid and bovine coronary artery and greater than subintimal plaque, intima at point of stenosis (P < 0.01), and intimal ulceration. There was no detectable TxA2 synthase or GSH-dependent PGE2 isomerase activity.
These data suggest that PGI2 synthesis is not diminished in arterial wall adjacent to carotid lesions in patients with atherosclerosis, but is clearly different from that measured in stenotic, ulcerative, and subintimal areas. Furthermore, these data indicate that PGI2 synthesis decreases according to the degree of arterial pathology. Thus, diminished production of PGI2 reported previously in association with atheromatous plaques is, in part, a result of decreased PGI2 synthase activity, which could contribute to increased platelet adherence and subsequent platelet or thrombus embolization and result in clinical cerebrovascular insufficiency. These data do not suggest that this clinical picture is the result of vascular TxA2 synthase activity. In addition, human carotid artery appears to differ from other vascular segments in that no fraction exhibited a GSH-dependent PGH2-to-PGE2 isomerase activity, the absence of which may also contribute to thrombogenicity.
KeywordsCarotid Plaque Atheromatous Plaque Atherosclerotic Carotid Plaque Carotid Artery Plaque Human Carotid Artery
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