Heparin Cofactor II Modulates the Response to Vascular Injury

Abstract

Abstract-Heparin cofactor II (HCII) has several biochemical properties that distinguish it from other serpins: (1) it specifically inhibits thrombin; (2) the mechanism of inhibition involves binding of an acidic domain in HCII to thrombin exosite I; and (3) the rate of inhibition increases dramatically in the presence of dermatan sulfate molecules having specific structures. Human studies suggest that high plasma HCII levels are protective against in-stent restenosis and atherosclerosis. Studies with HCII knockout mice directly support the hypothesis that HCII interacts with dermatan sulfate in the arterial wall after endothelial injury and thereby exerts an antithrombotic effect. In addition, HCII deficiency appears to promote neointima formation and atherogenesis in mice. These results suggest that HCII plays a unique and important role in vascular homeostasis. Key Words: heparin cofactor II Ⅲ thrombin Ⅲ thrombosis Ⅲ atherogenesis Ⅲ restenosis T hirty years have elapsed since Briginshaw and Shanberge demonstrated that human plasma contains 2 heparindependent inhibitors of thrombin. 1,2 They reported that the 2 inhibitors could be separated by gel filtration and ionexchange chromatography. One of the inhibitors resembled the known protein antithrombin (formerly called antithrombin III) because it inactivated both thrombin and factor Xa and had easily detectable progressive (ie, heparinindependent) antithrombin activity. The second inhibitor did not react with factor Xa and had comparatively weak progressive antithrombin activity, yet it appeared to comprise a significant fraction of the total heparin cofactor activity in plasma. A few years later, Tollefsen and Blank demonstrated that 125 I-thrombin forms 2 SDS-stable complexes in plasma containing heparin, 3 and other investigators noted that the heparin cofactor activity of plasma exceeds the amount predicted from the antithrombin antigen concentration. 4,5 The existence of a second heparin cofactor (now called heparin cofactor II or HCII) was firmly established when the inhibitor was purified to homogeneity from human plasma and was shown to be distinct from antithrombin. 6 Although much has been learned about the structure, mechanism of action, and genetics of HCII, relatively little is known about its physiological function. This review summarizes our current knowledge of the biochemistry of HCII and then focus on recent insights gained from clinical studies and experiments with knockout mice. Biochemistry of HCIIThe HCII gene (designated SERPIND1 in humans) has been identified in a variety of vertebrate species, including humans, chimpanzee, rhesus monkey, house mouse, Norway rat, rabbit, cow, chicken, African clawed frog, European flounder, and zebrafish (http://www.ncbi.nlm.nih.gov/ entrez/). HCII mRNA is highly expressed in the liver, which appears to be the major source of plasma HCII. 7 Low levels of HCII mRNA are also detectable in other tissues, but the significance of extrahepatic expression of HCII is unclear. 8 HCII circulates in human plasma at...

Molecular and expression analysis of a family of the Amblyomma americanum tick Lospins

“…For instance, antithrombin, heparin cofactor II, chemokines and selectin, whose functions are regulated by GAG binding, are involved in mediation of essential biological processes such as blood coagulation, inflammatory response, immune cell migration, tumor cell metastasis and smooth muscle cell proliferation (Munoz and Linhardt, 2004). Similarly in invertebrates, GAG binding proteins were associated with immunity (Kamimura et al, 2006;Robertson et al, 2006) and development (Tollefsen, 2007) in Drosophila. Microbodies also known as peroxisomes in vertebrates, glyoxysomes, glycosomes and hydrogenosomes, depending on their chemical composition, are small electrondense membrane-bound organelles that perform a variety of metabolic functions, including the ␤-oxidation of fatty acids and the biosynthesis of cholesterol and bile acids in eukaryotes (Gould et al, 1990;Gatto et al, 2000).…”

Beta2‐glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti–β2‐glycoprotein I autoantibodies

“…Mice with low levels of HCII exhibit a number of abnormalities, including increased susceptibility to atheroma formation (33), evidence of an enhanced prothrombotic tendency upon vessel wall injury (28), elevated levels of inflammation markers, and signs of oxidative stress in the arterial vessel walls (33). Activators of HCII are dermatan sulfate, heparan sulfate, and heparin (45). In the presence of atheroma, dermatan sulfate structure is altered, making it less efficient in activating HCII (46).…”

Unchecked thrombin is bad news for troubled arteries

“…Like AT, HCII is a serpin whose activity increases several orders of magnitude in the presence of heparin or heparan sulfate (HS) glycosaminoglycans (GAGs) (15). Yet HCII is limited to thrombin in specificity and is not only less abundant than AT but also both inferior in basal antithrombin activity and a secondary player in heparinmediated anticoagulation.…”

“…Photochemically-induced arterial injury did uncover a hyperthrombotic phenotype in HCII-knockout mice (17), so HCII function does complement that of other anticoagulants. The key appears to be location; notable recent advances in HCII biology have come from studies of its tissue-specific activation (15). A unique feature of HCII is that, unlike AT, it can be activated by dermatan sulfate (DS) as well as HS GAGs.…”