Review
Biomarkers of drug-induced vascular injury

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Abstract

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.

Introduction

Drug-induced vascular injury is an issue of concern because there are no obvious diagnostic markers for either pre-clinical or clinical monitoring and there is an intellectual gap in our understanding of the pathogenesis of this lesion. Vascular injury can occur in dogs following administration of various xenobiotics (Dogterom et al., 1992), including vasodilators (minoxidil, theobromine, hydralazine and type III phosphodiesterase inhibitors), adrenergic inotropic amines (isoproterenol, dopamine and dobutamine) and endothelin receptor antagonists. The pathogenesis, mechanism of injury and development of this lesion are unclear. In addition, drug-induced vascular lesions observed in animals are considered species specific and are not known to occur in humans (Sobota, 1989, Sobota et al., 1980); however, this could be related to our lack of knowledge and methods for monitoring these potential adverse effects in humans. Until these methods become available, it will be difficult to make claims of species specificity. Additionally, lack of consistency in characterizing the key components of vascular damage and histopathologic terminology has resulted in communication gaps between scientists who share responsibility for ultimately making a judgment on human risk.

Poor understanding of the pathogenesis, limitations of animal models and lack of valid diagnostic markers for non-clinical and clinical monitoring have elevated this issue to a shared level of concern between regulatory authorities, the pharmaceutical industry and clinicians engaged in developing novel therapies. This has led to considerable emphasis on identifying potential areas of non-clinical research aimed at discovering novel diagnostic biomarkers with pre-clinical and clinical application.

Section snippets

Hemodynamic parameters

Historically, the regulatory authorities and pharmaceutical companies have been able to manage the potential risk of drug-induced vascular toxicity as the occurrence correlated with decreases in blood pressure, concomitant reflex tachycardia and increases in coronary blood-flow (Mesfin et al., 1987, Mesfin et al., 1995). Therefore, based on these data, it was generally accepted that as long as therapeutic doses of candidate drugs in humans did not induce profound hypotension and prominent

Markers of endothelial cell injury

Perturbation of endothelial cells stimulates the release of several proteins including von Willebrand Factor (vWF), vWF propeptide (vWFpp), endothelin and nitric oxide (NO). Of these proteins, vWF is of most interest since it has been a clinical marker for years and it can also be evaluated in various pre-clinical species.

Dogs treated with a potassium channel opener caused plasma vWF to increase 3 h post-dosing and this increase returned to baseline 24 h post-dosing (Fig. 2A). In the dog,

Markers of smooth muscle cell injury

Caveolin-1 (cav-1) and smooth muscle alpha actin (SMA) are two proteins that can be released from smooth muscle cells upon injury. Evaluation of cav-1 as a mechanistically linked biomarker of drug-induced vascular injury is based on previous reports describing a relationship between drug-induced vascular injury, vasodilatation and increases in intracellular cyclic adenosine monophosphate (cAMP) levels in endothelial and smooth muscle cells.

Caveolae, (“pit-like” structures) located on the

Conclusions

The unreliability of heart rate and mean arterial blood pressure as definitive pre-clinical surrogates for predicting drug-induced vascular injury has stimulated research activities aimed at discovering novel biomarkers of this process. It is clear that a single biomarker will not predict lesion formation, progression, severity and resolution since vascular injury involves multiple mediators and cell types. Therefore, evaluation of a panel rather than a single biomarker may be more useful for

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