Lipoprotein(a) in nonhuman primates Presence and characteristics of Lp(a) immunoreactive materials using anti-human Lp(a) serum

Makino, Kazuhiko; Abe, Akira; Maeda, Shin; Noma, Akio; Kawade, Masato; Takenaka, Osamu

doi:10.1016/0021-9150(89)90161-5

Cited by 27 publications

(11 citation statements)

References 20 publications

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“…High plasma levels of Lp(a) are associated with coronary as well as peripheral atherosclerosis (1). Apo(a) is present in the plasma of hedgehogs, old world monkeys, great apes, and humans, but not in other species (2,3). In humans, the level of plasma Lp(a) varies from Ͻ 0.1 mg/dl to over 100 mg/dl (4).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein(a) kringle 4-containing fragments in human urine. Relationship to plasma levels of lipoprotein(a).

Mooser¹,

Seabra²,

Abedin³

et al. 1996

J. Clin. Invest.

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Apo(a) is a large glycoprotein of unknown function that circulates in plasma as part of lipoprotein(a). Apo(a) is structurally related to plasminogen and contains at least 10 kringle (K)4 repeats (type 1-10), a K5 repeat and sequences similar to the protease domain of plasminogen. Plasminogen generates two biologically active peptides: plasmin and angiostatin, a kringle-containing peptide. As a first step in determining if apo(a) generates a similar kringle-containing peptide, human urine was immunologically examined. Fragments ranging in size from 85 to 215 kD were immunodetected using antibodies directed against epitopes in the K4-type 2 repeat, but not the K4-type 9 repeat or protease domain. NH 2 -terminal sequence analysis revealed sequences specific for the K4-type 1 repeat, confirming that the fragments are from the NH 2 terminus of the K4 array.

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Section: Introductionmentioning

confidence: 99%

Apolipoprotein(a) kringle 4-containing fragments in human urine. Relationship to plasma levels of lipoprotein(a).

Mooser¹,

Seabra²,

Abedin³

et al. 1996

J. Clin. Invest.

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“…4 Thus no readily accessible human tissue is available for the analysis of hepatic apo(a) synthesis, and apo(a) is not present in the blood of any nonhuman species other than great apes or hedgehogs. 5,6 Apo(a) transgenic mice have been available for 6 years but cannot be used to examine the regulation of apo(a) synthesis because the cDNA is under the control of the mouse metallothionein promoter. 7 In 1995 Frazer and colleagues developed an apo(a) transgenic mouse that expresses the human apo(a) gene within its own genomic context.…”

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Human Growth Hormone Increases Apo(a) Expression in Transgenic Mice

Tao

Acquati

Marcovina

et al. 1999

ATVB

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Abstract-Levels of Lp(a), an atherogenic lipoprotein that circulates in human plasma, are increased by the administration of growth hormone (GH). Many of the physiological effects of GH are mediated through insulin-like growth factor-1 (IGF-1), but ironically, IGF-1 treatment of humans is associated with a fall in plasma Lp(a) levels. To glean insight into the mechanism responsible for the GH-associated increase in plasma levels of Lp(a), we administered recombinant human GH (rhGH) to mice expressing a 370-kb human genomic fragment containing the apo(a) gene, 40 kb of 5Ј-, and 200 kb of 3Ј-flanking sequence [YAC-apo(a) transgenic mice]. The plasma levels of apo(a) and hepatic levels of apo(a) mRNA rose dramatically in the post-pubertal male mice in response to rhGH treatment. To determine whether the increase in plasma apo(a) was mediated by IGF-1, we treated castrated and noncastrated YAC-apo(a) transgenic mice with a continuous infusion of IGF-1 (100 g/d) for 2 weeks, and plasma levels of apo(a) fell by Ϸ50%. Thus the effects of rhGH and IGF-1 administration on plasma levels of apo(a) in the YAC-apo(a) transgenic mice simulate those seen in humans. The coordinate changes in apo(a) mRNA and plasma levels of apo(a) in response to rhGH and IGF-1 strongly suggest that these 2 hormones have independent effects on the transcription of the apo ( Key Words: apo(a) Ⅲ growth hormone Ⅲ insulin-like growth factor-1 L p(a) is an atherogenic plasma lipoprotein composed of a particle of LDL attached to a large glycoprotein, apo(a). 1 Plasma levels of Lp(a) vary over a 1000-fold range (from Ͻ0.1 mg/dL to Ͼ100 mg/dL), and most of the interindividual variation is due to inherited differences in the size and sequence of the apo(a) gene. 2 The rate of synthesis of Lp(a), rather than its degradation, correlates best with its plasma levels. 3 Our knowledge regarding the mechanism by which sequence variations in apo(a) affect plasma levels of Lp(a) is limited due to the relative paucity of appropriate model systems in which to study the synthesis and metabolism of apo(a). In humans, the apo(a) that circulates in plasma is synthesized in the liver, but cultured human hepatocytes synthesize only a trace amount of apo(a). 4 Thus no readily accessible human tissue is available for the analysis of hepatic apo(a) synthesis, and apo(a) is not present in the blood of any nonhuman species other than great apes or hedgehogs. 5,6 Apo(a) transgenic mice have been available for 6 years but cannot be used to examine the regulation of apo(a) synthesis because the cDNA is under the control of the mouse metallothionein promoter. 7 In 1995 Frazer and colleagues developed an apo(a) transgenic mouse that expresses the human apo(a) gene within its own genomic context. 8 The mice contain a 270 kb human genomic fragment that includes the entire coding sequence of the apo(a) gene and at least 60 kb of 5Ј-and 3Ј-flanking sequences. The male and female transgenic mice have similar plasma levels of apo(a) (Ϸ20 mg/dL) until puberty. 9 At puberty the concentrat...

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“…Lp(a) is found only in a relatively small group of mammals that synthesize apo(a), notably humans, old-world monkeys, and the hedgehog (3)(4)(5). Most mammals cannot synthesize apo(a) and therefore cannot produce Lp(a).…”

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An Analysis of the Interaction between Mouse Apolipoprotein B100 and Apolipoprotein(a)

Cheesman¹,

Sharp²,

Zlot³

et al. 2000

Journal of Biological Chemistry

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SUMMARY The assembly of lipoprotein(a) [Lp(a)] involves an initial noncovalent interactionbetween apolipoprotein (apo) B100 and apo(a), followed by the formation of a disulfide bond between apoB100 cysteine-4326 and apo(a) cysteine-4057. The structural features of apoB100 that are required for its noncovalent interaction with apo(a) have not been fully defined. To analyze that initial interaction, we tested whether apo(a) could bind noncovalently to two apoB proteins that lack cysteine-4326-mouse apoB100 and human apoB100-Cys4326Gly. Our experiments demonstrated that both mouse apoB and the human apoB100-Cys4326Gly bind noncovalently to apo(a). We next sought to gain insights into the apoB amino acid sequences required for the interaction between apoB100 and apo(a). Previous studies of truncated human apoB proteins indicated that the carboxyl terminus of human apoB100 (amino acids 4330-4397) is important for Lp(a) assembly. To determine if the carboxyl terminus of mouse apoB100 can interact with apo(a), transgenic mice were produced with a mutant human apoB gene construct in which human apoB100 amino acids 4279-4536 were replaced with the corresponding mouse apoB100 sequences, and tyrosine-4326 was changed to a cysteine. The mutant apoB100 bound to apo(a) and formed bona fide disulfide-linked Lp(a), but Lp(a) assembly was less efficient than with wild-type human apoB100. The fact that Lp(a) assembly was less efficient with the mouse apoB sequences provides additional support for the notion that sequences in the carboxyl-terminus of apoB100 are important for Lp(a) assembly. (1) is formed by the disulfide linkage of apoB100 on a low density lipoprotein (LDL) particle to apo(a), a plasminogen-like glycoprotein (2). Lp(a) is found only in a relatively small group of mammals that synthesize apo(a), notably humans, old-world monkeys, and the hedgehog (3-5). Most mammals cannot synthesize apo(a) and therefore cannot produce Lp(a).In addition, many mammals (e.g., mouse, rat, and pig) synthesize an apoB100 molecule that cannot form a disulfide linkage with human apo(a) (6). The development and analysis of human apo(a) transgenic mice illustrated the latter point (7). The mouse apoB100 in the plasma of apo(a) transgenic mice did not form a covalent linkage with apo(a), and biochemical assays suggested that the apo(a) circulated free of the apoB-containing lipoproteins in the plasma (7).During the past five years, we have sought to define the structural features of apoB100 that are important for Lp(a) assembly. In 1995, we produced human apoB transgenic mice expressing a mutant form of human apoB in which cysteine-4326 was replaced by a glycine (human apoB100-Cys4326Gly) (8). The mutant human apoB could not form Lp(a) in in vitro assays of Lp(a) assembly or in vivo in the plasma of transgenic mice, establishing that cysteine-4326 was crucial for the disulfide linkage with apo(a). Callow and collaborators (9) made similar observations. Of note, cysteine-4326 is not present in the apoB100 of mouse, rat, or pig (8), likely e...

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Lipoprotein(a) in nonhuman primates Presence and characteristics of Lp(a) immunoreactive materials using anti-human Lp(a) serum

Cited by 27 publications

References 20 publications

Apolipoprotein(a) kringle 4-containing fragments in human urine. Relationship to plasma levels of lipoprotein(a).

Apolipoprotein(a) kringle 4-containing fragments in human urine. Relationship to plasma levels of lipoprotein(a).

Human Growth Hormone Increases Apo(a) Expression in Transgenic Mice

An Analysis of the Interaction between Mouse Apolipoprotein B100 and Apolipoprotein(a)

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