Inhibition of Transforming Growth Factor-β Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice

Mallat, Ziad; Gojová, Andrea; Marchiol, Carmen; Esposito, Bruno; Kamaté, Caroline; Merval, Régine; Fradelizi, D; Tedgui, Alain

doi:10.1161/hh2201.099415

Cited by 437 publications

(341 citation statements)

References 43 publications

(37 reference statements)

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“…ApoE:cathepsin K double knockout mice had reduced atherosclerotic lesions together with increased collagen component of ECM, whereas apoE-and LDL receptor-deficient mice that were given TGF-␤ inhibitors had decreased vascular ECM and more plaque hemorrhages. [31][32][33] In our study, losartan nearly doubled the relative collagen portion of the lesions. Although these results seem to be at odds with effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to limit ECM deposition in nonatherogenic disorders, they echo observations made in other models of atherosclerosis, including the Watanabe heritable hyperlipidemic rabbits and atherosclerotic mini-pigs, in which angiotensin-converting enzyme inhibitors/angiotensin receptor blockers increased ECM, including collagen, in the aortas.…”

Section: Discussionsupporting

confidence: 58%

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Suganuma¹,

Babaev²,

Motojima³

et al. 2007

Journal of the American Society of Nephrology

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Although increased extracellular matrix (ECM) is pathogenic in a variety of chronic tissue injuries, reduced and/or disrupted ECM may be detrimental in atherosclerosis and rather destabilize existing atherosclerotic lesions. This study therefore assessed the effects of angiotensin II (AngII) antagonism on ECM components of advanced atherosclerosis. Twenty-four-week-old apolipoprotein E-deficient mice were treated with the AngII antagonist losartan for 12 wk. Controls received water or hydralazine. AngII antagonism significantly reduced progression of established atherosclerosis, whereas hydralazine showed no benefit despite similar decrease in BP. Although there was no difference in the macrophage component, AngII antagonism increased the relative collagen portion of the lesions; lessened elastin fragmentation, increased the total elastin content of the aorta; and reduced the mRNA and activity/ protein of the elastolytic proteases, cathepsin S, and metalloproteinase-9. Extracellular elastin degradation by cultured smooth muscle cells (SMC) was reduced by losartan, as was SMC invasion through an elastin gel barrier. Thus, AngII antagonism lessens progression of atherosclerosis, increases collagen, and preserves elastin components of ECM within the vascular lesions, which, at least in part, is modulated by effects on SMC. These effects not only decrease further expansion of advanced lesions but also stabilize the established atherosclerotic plaques and may underlie the decreased incidence of acute cardiovascular events that are observed in patients in whom AngII antagonism is begun after atherosclerosis is already established.

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Section: Discussionsupporting

confidence: 58%

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Suganuma¹,

Babaev²,

Motojima³

et al. 2007

Journal of the American Society of Nephrology

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“…The role of TGF-␤ in atherosclerosis development is complex with decreased atherosclerotic fibrosis but increased inflammation observed with the inhibition of TGF-␤ signaling. 57,58 However, both SAA and TGF-␤ may play a proatherogenic role in the development of atherosclerosis because of their induction of vascular biglycan content and increase in proteoglycan-LDL binding affinity.…”

Section: Discussionmentioning

confidence: 99%

Serum Amyloid A, but Not C-Reactive Protein, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner

Wilson

Thompson

Webb

et al. 2008

The American Journal of Pathology

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Inflammatory markers serum amyloid A (SAA) and C-reactive protein (CRP) are predictive of cardiac disease and are proposed to play causal roles in the development of atherosclerosis, in which the retention of lipoproteins by vascular wall proteoglycans is critical. The purpose of this study was to determine whether SAA and/or CRP alters vascular proteoglycan synthesis and lipoprotein retention in a pro-atherogenic manner. Vascular smooth muscle cells were stimulated with either SAA or CRP (1 to 100 mg/L) and proteoglycans were then isolated and characterized. SAA, but not CRP, increased proteoglycan sulfate incorporation by 50 to 100% in a dose-dependent manner (P < 0.0001), increased glycosaminoglycan chain length, and increased low-density lipoprotein (LDL) binding affinity (K d , 29 g/ml LDL versus 90 g/ml LDL for SAA versus control proteoglycans; P < 0.005). Furthermore, SAA up-regulated biglycan via the induction of endogenous transforming growth factor (TGF)-␤. To determine whether SAA stimulated proteoglycan synthesis in vivo, ApoE ؊/؊ mice were injected with an adenovirus expressing human SAA-1, a null virus, or saline. Mice that received adenovirus expressing SAA had increased TGF-␤ concentrations in plasma and increased aortic biglycan content compared with mice that received either null virus or saline. Thus, SAA alters vascular proteoglycans in a pro-atherogenic manner via the stimulation of TGF-␤ and may play a causal role in the development of atherosclerosis.

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“…TGF-␤1/Smad Signaling in Vascular Inflammation-The composite anti-proliferative and anti-inflammatory effects of TGF-␤1 on both the immune and nonimmune cellular constituents of the atherosclerotic lesion suggest an inhibitory role in atherogenesis. For example, blockade of the TGF-␤1 ligand or TGF-␤ type II receptor accelerates the development of atherosclerotic lesion formation in ApoE Ϫ/Ϫ atherosclerotic prone mice (23,58,59). In patients, serum concentration of active TGF-␤1 inversely correlates with the severity of atherosclerotic disease (60).…”

Section: Cd25mentioning

confidence: 99%

Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25− T Cells and T Regulatory Cells

Cao

Wara

Icli

et al. 2009

Journal of Biological Chemistry

119

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Inhibition of Transforming Growth Factor-β Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice

Cited by 437 publications

References 43 publications

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Serum Amyloid A, but Not C-Reactive Protein, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner

Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25− T Cells and T Regulatory Cells

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