Tissue Factor Overexpression in Rat Arterial Neointima Models Thrombosis and Progression of Advanced Atherosclerosis

Hasenstab, David; Lea, Holly; Hart, Charles E.; Lok, Si; Clowes, Alexander W.

doi:10.1161/01.cir.101.22.2651

Cited by 69 publications

(41 citation statements)

References 21 publications

(15 reference statements)

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“…Neointima formation and vascular remodeling are characteristics of early atherosclerotic lesions, and these pathological processes may involve EC dysfunction, VSMC proliferation and migration, and ECM deposition (20,21). Therefore, modulation of EC function and VSMC growth is of critical importance in the prevention and treatment of early atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Zhang

Zhao

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

109

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Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERKp38, JAK-STAT, and AngII-ROS-NF-κB signaling pathways and upregulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.atherosclerosis | endothelial cell | gene therapy | smooth muscle cell | signaling pathway A ccumulating evidence indicates that endothelial cell (EC) dysfunction and the proliferation and migration of vascular smooth muscle cells (VSMCs) are salient features of early atherosclerotic lesions, and that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis (1, 2). Angiotensin II (AngII) promotes EC dysfunction and VSMC proliferation and migration by increasing the expression of monocyte chemoattractant protein 1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), leading to aggravation of atherosclerotic lesions (3-5). Delivery of ACE inhibitors or AngII type 1 receptor (AT 1 R) blockers to limit AngII bioactivity is an effective approach against atherosclerosis.Recent studies show that endogenous levels of AngII are regulated by the opposing action of two carboxypeptidases, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). The latter is thought to counterbalance ACE by cleaving AngI into the inactive angiotensin 1-9 and cleaving AngII into the vasodilating and antiproliferative angiotensin 1-7 [Ang(1-7)]. ACE2 is thus considered a potential therapeutic target of RAS for the treatment of cardiovascular diseases by virtue of its key role in the formation of vasoprotective peptides from AngII (6-8). Our recent study using a rabbit atherosclerosis model showed that ACE2 overexpression stabilized aortic plaques at a late stage and attenuated the progression of early atherosclerotic lesions. These ther...

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Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Zhang

Zhao

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

109

View full text Add to dashboard Cite

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“…17,18 TF binds factor VIIa, resulting in activation of factors IX and X, ultimately leading to fibrin formation. TF overexpression in a rat model accelerated neointimal development and thrombus formation, 19 indicating that TF plays a significant role in the pathogenesis of thrombosis and in the development of atherosclerosis.…”

Section: Mets and Hypercoagulabilitymentioning

confidence: 99%

Upregulation of Monocyte Tissue Factor Activity Is Significantly Associated With Low-Grade Chronic Inflammation and Insulin Resistance in Patients With Metabolic Syndrome

Nakagomi

Sasaki

Ishikawa

et al. 2010

Circ J

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“…Tissue factor [85] is a potent pro-coagulant and matrix degrading proteinase that is involved in the rupture of the fibrous cap and promotes thrombosis. Macrophages are major source within the atherosclerotic plaque of tissue factor, a membrane bound glycoprotein receptor that triggers the thrombotic cascade.…”

Section: Thrombus Formationmentioning

confidence: 99%

LDL as a Cause of Atherosclerosis

Tomkin

Owens²

2012

TOATHERTJ

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The low density lipoprotein particle is the major transporter of cholesterol around the body and has been shown to be a strong independent risk factor for atherosclerotic events. This review discusses the normal and abnormal metabolism of low density lipoprotein (LDL). Mechanisms by which LDL causes atherosclerosis are discussed with particular reference to the importance of alteration in LDL composition including attachment of other proteins to the circulating LDL particle.

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Tissue Factor Overexpression in Rat Arterial Neointima Models Thrombosis and Progression of Advanced Atherosclerosis

Abstract: These results suggest that tissue factor plays a direct role in neointimal development by coagulation-dependent and -independent pathways.

Cited by 69 publications

References 21 publications

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Upregulation of Monocyte Tissue Factor Activity Is Significantly Associated With Low-Grade Chronic Inflammation and Insulin Resistance in Patients With Metabolic Syndrome

LDL as a Cause of Atherosclerosis

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