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Unchecked thrombin is bad news for troubled arteries
Eric Camerer
Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
Address correspondence to: Eric Camerer, University of California, San Francisco, CVRI, 600 16th Street, MC 2240, San Francisco, CA 94158-2517, USA. Phone: (415) 476-6172; Fax: (415) 476-8173; E-mail: [email protected].
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Published June 1, 2007 - More info
J Clin Invest. 2007;117(6):1486–1489. https://doi.org/10.1172/JCI32473.
© 2007 The American Society for Clinical Investigation
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Abstract
Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCII deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII–/– mice were embryonically lethal. In HCII+/– mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor–1–positive (PAR-1–positive) cells was increased in the thickened vascular wall of HCII+/– mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII+/– mice. The intimal hyperplasia in HCII+/– mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.
Authors
Ken-ichi Aihara, Hiroyuki Azuma, Masashi Akaike, Yasumasa Ikeda, Masataka Sata, Nobuyuki Takamori, Shusuke Yagi, Takashi Iwase, Yuka Sumitomo, Hirotaka Kawano, Takashi Yamada, Toru Fukuda, Takahiro Matsumoto, Keisuke Sekine, Takashi Sato, Yuko Nakamichi, Yoko Yamamoto, Kimihiro Yoshimura, Tomoyuki Watanabe, Takashi Nakamura, Akimasa Oomizu, Minoru Tsukada, Hideki Hayashi, Toshiki Sudo, Shigeaki Kato, Toshio Matsumoto
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Thrombin generation
As the main effector protease of the coagulation cascade (Figure 1), thrombin is required for hemostasis in response to injury. Thrombin is generated when tissue factor (TF), a transmembrane protein, binds plasma coagulation factors (1). Normally, TF is found mainly on cells in the extravascular compartment, and disruption of vascular integrity upon injury allows plasma coagulation factors to interact with TF. Factor VIIa complexes with TF to activate factor X, either directly or via factor IX activation, and the protease Xa converts prothrombin to thrombin. Active thrombin then cleaves fibrinogen to fibrin and triggers platelet activation and a variety of other cellular responses via G protein–coupled protease-activated receptors (PARs). Four main inhibitors keep thrombin generation and activity in check: TF pathway inhibitor (TFPI), antithrombin (AT, also known as ATIII), heparin cofactor II (HCII), and thrombomodulin (TM) through activated protein C (APC). Imbalances in this system can have important consequences, as evidenced by the multiple human genetic diseases associated with loss of coagulation factor or inhibitor function.
Figure 1Perturbing the inhibitor balance has uncovered a possible role for thrombin signaling in vascular remodeling. Vascular injury may activate the coagulation cascade (only the extrinsic cascade is shown) by allowing plasma factor VII to interact with its extravascular cofactor TF. The TF:VIIa complex activates factor X, and Xa converts prothrombin to thrombin with the help of cofactor factor Va. Thrombin not only triggers thrombosis by cleaving fibrinogen and activating platelets through PARs (PAR4 in mice, PAR1 and PAR4 in humans), but also activates mural cells and leukocytes through PAR1. Partial loss (by haploinsufficiency of TFPI, or HCII in the current study by Aihara et al.; ref. 14) or interruption (by APC resistance induced by the presence of factor V Leiden) of natural inhibitor function is associated with enhanced pathologic remodeling in animal models; AT appears to be an exception. Conversely, recombinant anticoagulant therapy (e.g., use of VIIai, TFPI, TM, or hirudin) reduces remodeling, as does loss or inhibition of the thrombin receptor PAR1. This suggests that thrombin contributes to pathologic remodeling and may imply a direct pathway from TF exposure to vascular injury through PAR1 signaling (red) (14), although other effectors of thrombin or upstream coagulation factors may also contribute to this process. VIIai, active site-inhibited VIIa.
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Pathological thrombin generation may have both acute and cumulative effects on arterial patency
In atherosclerotic plaques and injured arteries, TF expression is induced in smooth muscle cells and macrophages and is thus enriched and more proximal to the vessel lumen than in normal arteries (2). Thus even superficial injury, whether spontaneous or induced by percutaneous coronary intervention (PCI), exposes TF, lipid surfaces, and matrix proteins to circulating coagulation zymogens and platelets, triggering thrombin generation and platelet activation (Figure 2). In the short term, this leads to formation of thrombi that may or may not grow to a size sufficient to cause symptoms. In the long term, repeated or continuous exposure of endothelial cells, smooth muscle cells, and macrophages to active coagulation factors, fibrin, and platelet-released products might contribute to expansion of arterial lesions. Similar mechanisms might promote restenosis and/or thrombosis after stent placement, where compromised reendothelialization may result in prolonged exposure of TF to plasma.
Figure 2How might HCII deficiency exacerbate responses to arterial injury? Arterial injury may trigger thrombin formation by exposing extravascular TF to circulating coagulation zymogens (see Figure 1). Thrombin activates platelets and converts fibrinogen to fibrin, thus triggering thrombosis and thus, potentially, acute vascular occlusion. Both thrombin and upstream proteases VIIa and Xa may also contribute long-term to arterial remodeling and narrowing (stenosis) by signaling to circulating and mural cells through PARs. At least in vitro, PAR activation triggers leukocyte chemotaxis, endothelial contraction/secretion/expression of adhesion molecules, and smooth muscle cell proliferation/migration. The thrombin inhibitor HCII may be uniquely suited to inhibiting thrombin in the vessel wall, since it is activated by DS, which is synthesized by smooth muscle cells and fibroblasts. AT, by contrast, is only activated by HS enriched in the subendothelial matrix. Tissue-specific thrombin inhibition may thus explain why even partial loss of HCII activity exacerbates arterial remodeling in response to injury or hyperlipidemia in mice, as shown by Aihara et al. in this issue of the JCI (14). m, mice; h, humans.
How might exposure of mural cells to coagulation proteases promote atherosclerosis and neointima formation after arterial injury? Coagulation is one of the first responses to tissue injury, and coagulation proteases can regulate cellular behaviors through PARs (3). Thrombin activates PAR1 and PAR4; upstream proteases (VIIa and Xa) can activate PAR1 and PAR2. Responses to PAR signaling in cell culture hint that coagulation proteases and PARs together may help orchestrate not only hemostasis but also inflammation and repair after injury (4). Analogous to TF, both PAR1 and PAR2 are highly expressed in human atheroma relative to normal arteries and are induced in the arterial wall in response to injury in animal models (5). It is thus conceivable that hyperactivation of and hyperresponsiveness to coagulation proteases in the setting of arterial injury leads to excessive and therefore pathogenic repair responses (Figure 2).
A growing body of evidence from animal models supports a causal role for coagulation proteases and PAR signaling in arterial disease (Figure 1). Recombinant inhibitors (6–8) or PAR1 antagonists (9) ameliorate whereas anticoagulant deficiencies exacerbate (10–12) pathologic remodeling. Lack of effects of the anticoagulant heparin (13) and variable responses to another anticoagulant — hirudin (6) — in these models may point to roles for upstream proteases (6) or subtleties in anticoagulant function (discussed below). The study by Aihara et al. (14) in this issue of the JCI adds another piece to this puzzle with possible promise for a novel treatment strategy.
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