Molecular basis for a link between complement and the vascular complications of diabetes

Citation
J. Acosta et al., Molecular basis for a link between complement and the vascular complications of diabetes, P NAS US, 97(10), 2000, pp. 5450-5455
Citations number
46
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
00278424 → ACNP
Volume
97
Issue
10
Year of publication
2000
Pages
5450 - 5455
Database
ISI
SICI code
0027-8424(20000509)97:10<5450:MBFALB>2.0.ZU;2-V
Abstract
Activated terminal complement proteins C5b to C9 form the membrane attack c omplex (MAC) pore. Insertion of the MAC into endothelial cell membranes cau ses the release of growth factors that stimulate tissue growth and prolifer ation. The complement regulatory membrane protein CD59 restricts MAC format ion. Because increased cell proliferation characterizes the major chronic v ascular complications of human diabetes and because increased glucose level s in diabetes cause protein glycation and impairment of protein function, w e investigated whether glycation could inhibit CD59. Glycation-inactivation of CD59 would cause increased MAC deposition and MAC-stimulated cell proli feration. Here, we report that (i) human CD59 is glycated in vivo, (ii) gly cated human CD59 loses its MAC-inhibitory function, and (iii) inactivation of CD59 increases MAC-induced growth factor release from endothelial cells. We demonstrate by site-directed mutagenesis that residues K41 and H44 form a preferential glycation motif in human CD59. The presence of this glycati on motif in human CD59, but not in CD59 of other species, may help explain the distinct propensity of humans to develop vascular proliferative complic ations of diabetes.