Biomarkers of drug-induced vascular injury.
In pre-clinical safety studies, drug-induced vascular injury is an issue of concern because there are no obvious diagnostic markers for pre-clinical or clinical monitoring and there is an intellectual gap in our understanding of the pathogenesis of this lesion. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary targets, smooth muscle and endothelial cells are unknown. However, evaluation of novel markers for potential clinical monitoring with a mechanistic underpinning would add value in risk assessment and management. This mini review focuses on the progress to identify diagnostic markers of drug-induced vascular injury. Von Willebrand factor (vWF), released upon perturbation of endothelial cells, is transiently increased in plasma prior to morphological evidence of damage in dogs or rats treated with vascular toxicants. Therefore, vWF might be a predictive biomarker of vascular injury. However, vWF is not an appropriate biomarker of lesion progression or severity since levels return to baseline values when there is morphological evidence of injury. A potential mechanistically linked biomarker of vascular injury is caveolin-1. Expression of this protein, localized primarily to smooth muscle and endothelial cells, decreases with the onset of vascular damage. Since vascular injury involves multiple mediators and cell types, evaluation of a panel rather than a single biomarker may be more useful in monitoring early and severe progressive vascular injury.
Brott
D
D
Safety Assessment, AstraZeneca Pharmaceuticals, CRDL-138, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.
Gould
S
S
Jones
H
H
Schofield
J
J
Prior
H
H
Valentin
J P
JP
Bjurstrom
S
S
Kenne
K
K
Schuppe-Koistinen
I
I
Katein
A
A
Foster-Brown
L
L
Betton
G
G
Richardson
R
R
Evans
G
G
Louden
C
C
D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D001808:Blood Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006439:Hemodynamics; D006801:Humans; D014841:von Willebrand Factor / Q000032:analysis*
D015415:Biomarkers; D014841:von Willebrand Factor