Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin

Abstract

Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.

From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

“…Activation of the coagulation cascade is tightly linked to the development of NAFLD-associated pathologies, particularly steatohepatitis and fibrosis Owens et al, 2012). Here, we found that subchronic TCDD exposure is also coupled to increased intrahepatic coagulation, marked by increased thrombin generation and hepatic fibrin(ogen) deposition.…”

“…Coagulation-driven steatohepatitis is mediated in part through activation of PAR-1 Owens et al, 2012). We have previously observed that PAR-1 expression is induced in livers of mice exposed repeatedly to TCDD (Nault et al, 2015b).…”

“…Activation of the coagulation cascade is coupled to the development and progression of NAFLD pathologies Owens et al, 2012). Notably, repeated exposure to TCDD in wildtype mice significantly increased plasma thrombin-antithrombin (TAT) levels, a stable biomarker of coagulation cascade activation (Fig.…”

“…Development of liver diseases such as the NAFLD has been associated with tissue factor (TF)-dependent activation of the blood coagulation cascade Owens et al, 2012). Coagulation cascade activation results in generation of the serine protease thrombin, which cleaves soluble fibrinogen leading to deposition of insoluble fibrin polymers in the liver .…”

Comparison of natural and recombinant tissue factor proteins: new insights

“…A variety of agonists and interactions can upregulate the expression of TF (Carlsen and Prydz , 1988 ;Cermak et al , 1993 ;Celi et al , 1994 ). More recently, it has been suggested that the toll-like receptors TLR4 and TLR6 contribute to the expression of TF on monocytes and monocytic cells Zhou et al , 2011 ;Owens et al , 2012 ) induced by oxidized low-density lipoproteins and anti-β 2 -glycoprotein I/ β 2 -glycoprotein I. It has been also shown that plateletderived growth factor CC (Gebhard et al , 2010 ) and the platelet factor 4/heparin-antibody complex (Kasthuri et al , 2012 ) can induce monocyte TF expression.…”