Correspondence to: Marco Rabinovitz, Ph.D., 4504 Traymore St., Bethesda, MD 20814-3965.
Major interest in factors that control angiogenesis has resulted in
the evaluation of many biologic entities whose biochemical mechanism of
action is not completely understood. Such understanding was derived
from earlier studies [(1) and references cited therein]
showing that copper deficiency in immature members of avian and
mammalian species produced fragility and rupture of the
microcirculation. A similar observation was made in the human genetic
disorder known as Menkes' syndrome, whose principal defect is a
failure in copper absorption (2). The cause of the lesion was
traced to disruption of the maturation of cardiovascular tropoelastin
to elastin. This maturation encompasses the oxidation of three
-amino groups of tropoelastin's lysines to aldehydes and their
condensation with a fourth to form desmosine (3). The
resulting protein cross-link provides the reticular network necessary
for the tubular construction of the microcirculation. The enzyme that
catalyzes the oxidation of the lysines of tropoelastin, lysyl oxidase,
has copper as an integral part of its structure (4);
therefore, copper deficiency prevents formation of elastin and
construction of the tubular network of the microcirculation.
The level of copper in cells and tissues, both in vitro and in vivo, can be altered with chelating agents that can either promote or block uptake. An example of the latter is the administration of D-penicillamine in Wilson's disease to increase excretion of copper and prevent the toxic accumulation that occurs in this syndrome (5). However, most such agents are not specific for copper. Bathocuproine sulphonate is specific for copper and can counteract the activity of other chelates that promote copper uptake in cell culture (6). Finally, it should be noted that ascorbic acid, when administered to species with copper deficiency, potentiates vascular damage and lysis [(7) and references cited therein].
It is hoped that this correspondence will stimulate studies on the role of copper status in angiogenesis and its inhibition in cancer.
REFERENCES
1 Coulson WF, Carnes WH. Cardiovascular studies on copper-deficient swine. IX. Repair of vascular defects in deficient swine treated with copper. Am J Pathol 1967;50:861-8.[Medline]
2 Oakes BW, Danks DM, Campbell PE. Human copper deficiency: ultrastructural studies of the aorta and skin in a child with Menkes' syndrome. Exp Mol Pathol 1976;25:82-98.[Medline]
3 Narayanan AS, Page RC, Kuzan F, Cooper CG. Elastin cross-linking in vitro. Studies on factors influencing the formation of desmosines by lysyl oxidase action on tropoelastin. Biochem J 1978;173:857-62.[Medline]
4 Harris ED, Gonnerman WA, Savage JE, O'Dell BL. Connective tissue amine oxidase. II. Purification and partial characterization of lysyl oxidase from chick aorta. Biochim Biophys Acta 1974;341:332-44.[Medline]
5 Walshe JM. Endogenous copper clearance in Wilson's disease: a study of the mode of action of penicillamine. Clin Sci 1964;26:461-9.[Medline]
6 Mohindru A, Fisher JM, Rabinovitz M. Bathocuproine sulphonate: a tissue culture-compatible indicator of copper-mediated toxicity. Nature 1983;303:64-5.[Medline]
7 Simpson CF, Robbins RC, Harms RH. Microscopic and biochemical observations of aortae of turkeys fed copper-deficient diets with and without ascorbic acid. J Nutr 1971;101:1359-66.[Medline]
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