Transforming Growth Factor-β Mediates Balance Between Inflammation and Fibrosis During Plaque Progression

Abstract

Abstract-The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-␤, and a pivotal role for TGF-␤ in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-␤ inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-␤ receptor II (TGF␤RII:Fc), which inhibits TGF-␤ signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 g, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-␤ signaling treatment resulted in a prominent increase in CD3-and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGF␤RII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGF␤RII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-␤ in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.

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

“…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.…”

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

“…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.…”

Distinctive Expression of Chemokines and Transforming Growth Factor-β Signaling in Human Arterial Endothelium during Atherosclerosis

“…In mouse models of accelerated atherosclerosis, there is evidence for an antiatherogenic role for TGF-␤, for its partial disruption has been shown to induce expression levels of the proatherogenic leukocyte adhesive molecules ICAM-1 and VCAM-1 48 and to result in a more inflammatory and less fibrotic lesion type. 49 Recent evidence from in vitro studies indicates that TGF-␤ activation leads to the induction of proatherogenic responses in the human endothelium by aggravated endothelial permeability through SMAD2-dependent p38 activation 50,51 and by induction of proatherogenic genes such as lectin-like oxidized LDL receptor-1, 52 the atherothrombotic factor PAI-1, 53 and the leukocyte adhesive proteins ICAM-1 54,55 and MCP-1.…”