COLLAGEN CROSSLINKS IN HYPERTENSION OF AGING

We propose to investigate the role of glucose-derived arterial wall
collagen crosslinking in the pathogenesis of age-related changes in blood
pressure. The specific aims are to: I) Characterize the relationship between accumulated glucose-derived
collagen crosslinks and arterial hypertension in normal, spontaneously
hypertensive, alloxan-diabetic, and alloxan-diabetic spontaneously
hypertensive rats as a function of increasing age; II) Evaluate the effect of aminoguanidine, an inhibitor of glucose-derived
collagen crosslinking, on both quantity of accumulated advanced
glycosylation products and development of hypertension in these four
experimental groups of animals; III) Quantitate both advanced glycosylation product accumulation and
collagen crosslinking in human arteries obtained at autopsy from
normotensive and hypertensive subjects; IV) Quantitate both advanced glycosylation product accumulation and
collagen crosslinking in skin punch biopsy specimens from defined groups of
normotensive and hypertensive clinic patients. These studies will involve newly developed spectrofluorometric and
radioimmunoassay techniques for measuring specific advanced glycosylation
product crosslinks, and three newly adapted methods from collagen
structural studies for determining the extent of collagen crosslinking.
The availability of aminoguanidine, a recently described inhibitor of
glucose-derived collagen crosslink formation, will make it possible to
determine for the first time in these studies, the extent to which observed
correlations between age-related glucose-derived collagen crosslink
accumulation and the development of age-related hypertension are causally
related.