A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family.

Abstract

A B S T R A C T Significant hypertriglyceridemia with a very marked decrease of high density lipoproteins (HDL)-cholesterol levels (7)(8)(9)(10)(11)(12)(13)(14) proteins provided evidence for multiple isoproteins in the apoprotein(apo)-A-I range, with nine different bands being detected instead of the usual four bands observed in normal subjects. Two-dimensional immunoelectrophoresis against apo-A antiserum indicated a clear reduction of apo-A in the alpha electrophoretic region, with splitting of the protein "peak." The observation in otherwise clinically healthy subjects of hypertriglyceridemia, reduced HDL-cholesterol, and marked apoprotein abnormalities, without a significant incidence of atherosclerotic disease in the family suggests this is a new disease entity in the field of lipoprotein pathology, very probably related to an altered amino acid composition of the apo-A-I protein (see Weisgraber et al. 1980. J. Clin. Invest. 66: 901-907).

Lipoprotein-like Phospholipid Particles Inhibit the Smooth Muscle Cell Cytotoxicity of Lysophosphatidycholine and Platelet-Activating Factor

“…36 The carriers of this mutation have markedly reduced HDL cholesterol levels and a high prevalence of hypertriglyceridemia without an increased incidence of vascular disease. 24 The longer half-life of apoA-I Milano compared with the wild type may, at least in part, explain the former's possible favorable effect. 37 We have previously shown that apoA-I Milano inhibits the formation of intimal lesions after balloon injury of the aorta in hypercholesterolemic rabbits.…”

“…The effect of purified human apoA-I reconstituted in phospholipid liposomes was compared with that of liposomes containing recombinant apoA-I Milano , a mutant form of apoA-I believed to have increased antiatherogenic capacity. 24 …”

Cysteine Substitutions in Apolipoprotein A-I Primary Structure Modulate Paraoxonase Activity

“…Patients heterozygous for the Lys107 f 0 mutation (apoA-I Helsinki ) (20) have a 30% reduction in apoA-I and approximately 40% reduction in PON plasma concentration (19), and some subjects have documented coronary disease. Carriers of the apoA-I Milano trait characterized by the presence of a sulfhydryl group in apoA-I (Arg173 f Cys mutation) (21) have substantial reductions in apoA-I (approximately 50%) but have no predisposition for CAD. These patients have PON mass and activity similar to normal subjects (19).…”

HDL-C: Does it matter? An update on novel HDL-directed pharmaco-therapeutic strategies

“…Moreover, both genetic studies and clinical trials support the idea that, in some circumstances, HDL-C levels may behave opposite to what is predicted by the Framingham assessment model (9,10). For example, carriers of the apoAI Milano mutation present with low levels of HDL-C but are resistant to atherosclerosis (11,12), whereas subjects with cholesteryl ester transfer protein (CETP) deficiency have high HDL-C levels but are not patently protected against atherosclerosis (13)(14)(15)(16). In addition, common polymorphisms in the CETP and hepatic lipase genes linked to elevated HDL-C levels are associated with increased cardiovascular events (17,18).…”