Vascular hemostasis – a biochemist's perspective

2001

YEAR BOOK

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University College Dublin

Therese Kinsella

Vascular hemostasis – a biochemist's perspective

Figure 1. Biosynthesis of Prostanoids.
Click here to view enlarged diagram

Dr Therese Kinsella was the recipient of the Royal Irish Academy Medal for Biochemistry in 2000. This is a summary of her Medal lecture.

Humans have evolved an intricate system designed to maintain blood in the fluid state, but it must be primed to react in an explosive manner to stem blood loss in response to blood vessel injury through the formation of a thrombus or blood clot. This system of vascular homeostasis, or hemostasis, involves the complex interplay of various cellular and molecular components within the vasculature.

The prostanoids, which include the prostaglandins (PGs) and thromboxane (TXA), are small hormone-like lipid mediators that regulate diverse processes within the human body (Figure 1) . In keeping with their unstable natures, prostanoids have short half-lives and act locally to mediate their specific cellular effects. The prostanoids thromboxane and prostacyclin (PGI ₂ ) play key, yet opposing, roles in the maintenance of vascular hemostasis: thromboxane promotes blood clot formation by stimulating the aggregation of platelets, the cellular like bodies in the blood which form an essential component of the clot, and causes a narrowing or constriction of the blood vessel wall, reducing blood flow to the site of vessel injury. Prostacyclin, on the other hand, inhibits these processes by blocking platelet aggregation and by causing relaxation of the blood vessel. These opposing actions of thromboxane and prostacyclin play a central role in the maintenance of circulatory hemostasis and, accordingly, imbalances in their levels have been implicated in a number of cardiovascular disorders.

Both thromboxane and prostacyclin act or signal by binding to specific proteins, termed receptors, located on the surface of their target cell (Figure 2) . In humans, thromboxane signals through two distinct but closely related thromboxane receptors, referred to as the thromboxane receptor alpha and thromboxane receptor beta. The physiologic significance of the existence of two receptors for thromboxane in humans, but not in other species, is currently unknown but is an area of intensive research within my laboratory. Thus, the main focus of this RIA lecture was to summarise some of our key findings relating to prostanoid regulation of vascular hemostasis with particular emphasis on the role of thromboxane and prostacyclin in this central physiologic process.

Figure 2. Expression of thromboxane receptor alpha on the cell surface.

Specifically, our studies have established that, whereas both the thromboxane receptors alpha and beta are widely expressed in cells and tissues associated with the vasculature, they are expressed at different levels. Secondly, our studies have also established that the thromboxane receptors alpha and beta respond similarly following their activation by thromboxane.

The isoprostanes represent a novel group of hormone like lipid mediators whose levels are dramatically raised when the body's oxygen levels are limiting, resulting in damage, or free radical injury, to cells or tissues within the body. Raised levels of the isoprostanes are associated with a number of disease states, including heart disease, lung disease and Alzheimer's disease, to name but a few.

In our studies we have discovered that one of the isoprostanes signals by activating the human thromboxane receptors. Taken together, these data provide convincing evidence that the thromboxane receptors alpha and beta, in addition to their activation by thromboxane, can also mediate the adverse actions of oxidative injury, which occurs during or following the onset of a number of human diseases.

Alpha Signalling

Beta Signalling

Figure 3. Signalling by thromboxane receptor alpha, but not beta, is regulated by prostacyclin.
Click here to view enlarged diagram

Finally, as previously indicated, the prostanoids thromboxane and prostacyclin play opposing roles in vascular hemostasis. A key finding from our studies established that signalling by the thromboxane receptor alpha, but not the beta receptor, is inhibited by the counter-balancing prostacyclin (Figure 3). The implication from these studies is that the alpha receptor may be the thromboxane receptor involved in regulated vascular hemostasis. On the other hand, these studies also reveal that signalling by the thromboxane receptor beta remains active or unchecked, even in the presence of inhibitory prostanoids, such as prostacyclin. These findings have profound implications with respect to our understanding of vascular hemostasis and may lead to new and novel therapeutic approaches to the treatment of heart disease.

Contact: Dr B. Therese Kinsella,
Department of Biochemistry
& Conway Institute of Biomolecular and Biomedical Research,
UCD, Dublin 4;
E-mail: Therese.Kinsella@ucd.ie