PubMed · 5365693
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C Raby, H Bertrand. 1969-11-22. [Dextran and dynamic coagulation].. https://pubmed.ncbi.nlm.nih.gov/5365693/
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Endothelial production of nitric oxide (nitrogen monoxide, NO) has become a major research area in vascular biology. Some of the most important effects that NO exerts in the vascular wall are potentially vasoprotective, because these effects maintain important physiological functions such as vasodilation, anticoagulation, leucocyte adhesion, smooth muscle proliferation, and the antioxidative capacity. During the last 2 decades it has become apparent that a variety of diseases are associated with an impairment of endothelium-dependent NO activity. One of the major causes is believed to be an increased production of reactive oxygen species, in particular superoxide, which have been shown to interfere with many steps of the NO--cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has been found in diverse conditions such as atherosclerosis, hypertension, diabetes, hypercholesterolemia, heart failure, and cigarette smoking. The aim of this review is to examine the cellular and molecular mechanisms whereby NO exerts potentially vasoprotective effects and to discuss pharmacologic approaches targeting the NO pathway in view of their potential to improve endothelial function and to reduce the progression of atherosclerotic vascular disease. We conclude that there is compelling evidence for vasoprotective actions of NO which are mediated by cGMP-dependent and cGMP-independent mechanisms. These effects may contribute to the beneficial effects of established drugs such as ACE inhibitors or statins. Unfortunately, clinical data on the effect of long-term treatment with nitrates on the progression of coronary artery disease are lacking. Finally, L-arginine or new activators of the NO pathway may become therapeutic options in the future.
Factor XIII and fibrinogen are unusual among clotting factors in that neither is a serine protease. Fibrin is the main protein constituent of the blood clot, which is stabilized by factor XIIIa through an amide or isopeptide bond that ligates adjacent fibrin monomers. Many of the structural and functional features of factor XIII and fibrin(ogen) have been elucidated by protein and gene analysis, site-directed mutagenesis, and x-ray crystallography. However, some of the molecular aspects involved in the complex processes of insoluble fibrin formation in vivo and in vitro remain unresolved. The findings of a relationship between fibrinogen, factor XIII, and cardiovascular or other thrombotic disorders have focused much attention on these 2 proteins. Of particular interest are associations between common variations in the genes of factor XIII and altered risk profiles for thrombosis. Although there is much debate regarding these observations, the implications for our understanding of clot formation and therapeutic intervention may be of major importance. In this review, we have summarized recent findings on the structure and function of factor XIII. This is followed by a review of the effects of genetic polymorphisms on protein structure/function and their relationship to disease.
The protein C/protein S system is known to regulate thrombin generation in vivo by cleaving factors Va and VIIIa. We have examined the activity of activated protein C in several tissue factor-initiated models of coagulation. We used 4 models: monocytes as the tissue factor source with platelets as the thrombin-generating surface; endothelial cells as the tissue factor source with platelets as the thrombin-generating surface; endothelial cells as both the tissue factor source and the thrombin-generating surface; and relipidated tissue factor with lipid vesicles providing the surface for thrombin generation. With the lipid surface, activated protein C dose-dependently reduced thrombin generation. Similarly, when endothelial cells provided the only surface for thrombin generation, activated protein C dose-dependently decreased thrombin generation significantly. By contrast, whenever platelets were present, activated protein C only minimally affected the amount of thrombin generated. When endothelial cells were the tissue factor source with platelets providing the surface for thrombin generation, activated protein C did increase the time until the burst of thrombin generation but had minimal effects on the total amount of thrombin generated. Activated protein C had essentially no effect on thrombin generation when monocytes were the tissue factor source with platelets providing the surface for thrombin generation. From the studies reported here, we conclude that in vivo, despite the important role of the protein C system in regulating thrombosis, activated protein C does not serve as a primary regulator of platelet-dependent thrombin generation.