Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig.

Abstract

Lipoprotein(a) [Lp(a)] is an extremely atherogenic lipoprotein. Lp(a) has been found in the plasma of humans and other primates, but until now only in a few other species. The mechanism by which it exerts its atherogenicity is still poorly understood. We observed that Lp(a) has been found in the plasma of several species unable to synthesize ascorbate and not in other species. We have now detected apoprotein(a) in the plasma of the guinea pig. We induced atherosclerosis in this animal by dietary ascorbate depletion and, using SDS/PAGE and subsequent immunoblotting, we identified Lp(a) as accumulating in the atherosclerotic plaque. Most importantly, adequate amounts of ascorbate (40 mg per kg of body weight per day) prevent the development of atherosclerotic lesions in this animal model and the accumulation of Lp(a) in the arterial wall. We suggest an analogous mechanism in humans because of the similarity between guinea pigs and humans with respect to both the lack of endogenous ascorbate production and the role of Lp(a) in human atherosclerosis.Lipoprotein(a) [Lp(a)] is a low density lipoprotein particle with an additional glycoprotein named apoprotein (a) [apo(a)]. The cDNA sequence of apo(a) shows a striking homology of apo(a) and plasminogen with multiple repeats of kringle 4, one kringle 5, and a protease domain (1). Lp(a) competitively inhibits the binding of plasminogen to immobilized fibrin, fibrinogen, and the plasminogen receptor on endothelial cells (2), and it attenuates clot lysis induced by tissue-type plasminogen activator (3). Therefore Lp(a) was assumed to be the missing link between atherosclerosis and thrombosis (4). Lp(a) has been shown in various epidemiological studies to be positively associated with coronary heart disease and other forms of atherosclerosis (5, 6). Furthermore, a significant positive correlation between Lp(a) concentrations in human plasma and arterial wall has been established (7) and the development of atherosclerotic lesions correlates with the degree of Lp(a) deposition in the arterial wall (8).We observed that Lp(a) had primarily been found in the plasma of species that have lost the ability to synthesize ascorbate and we have consequently formulated the hypothesis that Lp(a) is a surrogate for ascorbate (9). According to this hypothesis ascorbate and Lp(a) share common properties, such as the promotion of cell repair, and would be able to replace one another under physiological and pathophysiological conditions. In addition to humans and other primates, the guinea pig is known to have lost the ability to synthesize ascorbate. It was therefore of interest to look for Lp(a) in the plasma of the guinea pig. Earlier studies had shown that ascorbate deficiency induces atherosclerosis in the guinea pig (10,11). This is in contrast to most other species, where atherosclerosis must be induced by a high-fat diet or other atherogenic stimuli. It was therefore of particular interest to determine whether Lp(a) would also be found in the atherosclerotic lesion of ...

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