Feedback Mechanism of Focal Vascular Lesion Formation in Transgenic Apolipoprotein(a) Mice

Abstract

Apolipoprotein(a) (apo(a)), the distinguishing protein of atherogenic lipoprotein(a), directs accumulation of the lipoprotein(a) particle to sites in the arterial wall where atherosclerotic lipid lesions develop in man and in transgenic mice expressing human apo(a). It has been proposed that focal apo(a) accumulation in the transgenic mouse vessel wall causes the observed severe local inhibition of transforming growth factor-␤ (TGF-␤) activity and the consequent activation of the smooth muscle cells, which subsequently accumulate lipid to form lesions if the mice are fed a high fat diet. We show that blocking formation of these vascular lesions by two independent mechanisms, tamoxifen treatment and increasing high density lipoprotein, also abolishes apo(a) accumulation, inhibition of TGF-␤ activity, and activation of smooth muscle cells. The data are consistent with a feedback mechanism in which an initial accumulation of apo(a) inhibits local TGF-␤ activity, leading to further accumulation of apo(a). Breaking the feedback loop prevents smooth muscle cell activation and therefore lipid lesion development.An elevated plasma concentration of the lipoprotein Lp(a) 1 causes focal deposition of Lp(a) in the vessel wall and represents a major independent risk factor for vascular diseases, including atherosclerosis, restenosis, and stroke (1-10). Lp(a) consists of a low density lipoprotein particle covalently linked to the additional protein, apolipoprotein(a) (apo(a)) (11). Plasma-derived Lp(a) accumulates in the vessel wall more readily than low density lipoprotein, reflecting the ability of its apo(a) component to bind to extracellular and cell surface targets (1, 2). The accumulation of Lp(a) occurs at focal sites in the vessel wall for reasons that are poorly understood, although several observations suggest that it occurs at sites of endothelial injury or dysfunction, where the "response to injury" hypothesis proposes that atherosclerotic lesions are initiated (12). For example, Lp(a) localizes in the vessel wall of rabbits where the endothelium has been physically injured by balloon catheter (13). In humans, Lp(a) is localized in atherosclerotic plaques and accumulates at sites of microvascular inflammation, where endothelial permeability is known to be increased (14). Once in the vessel wall, Lp(a) may further enhance initial endothelial dysfunction, as indicated by studies which show that high Lp(a) levels are associated with impaired endothelium-dependent vasodilation before atherosclerotic lesions are detectable by angiography (15,16).A potential mechanism by which apo(a) might promote endothelial dysfunction and atherogenesis is the inhibition of plasminogen activation, suggested by the sequence homology of apo(a) to plasminogen (17). Reduced plasmin activity would be expected to have two major atherogenic consequences, both of which have been confirmed in vivo. Reduced plasmin activity in the presence of apo(a) reduces clot lysis, which may stimulate lesion development by prolonging the lifetime of mural t...

Lipoprotein(a) vascular accumulation in mice. In vivo analysis of the role of lysine binding sites using recombinant adenovirus.

“…Potentially atherogenic consequences of reduced plasmin activity include a reduction in clot lysis and plasmin-dependent activation of TGF-b, a cytokine involved in the maintenance of normal phenotype and function of endothelial and smooth muscle cells in the vessel wall. Studies carried out using apo(a) transgenic mice have given support to these predictions, demonstrating increased formation of fatty streak lesions (15), reduced levels of plasmin and TGF-b (16,17), and diminished clot lysis (18).…”

Relationship between lipoprotein(a), fibrinogen, and fibronectin in non‐diabetic hemodialyzed uremic patients

“…8,23 -25 Further studies are needed to better understand the pathophysiological mechanisms responsible for elevated Lp(a) levels in HD patients, the pathways responsible for its atherothrombogenic actions, and its possible relationship or interaction with coagulation disorders and inflammatory markers such as cytokines and acutephase proteins. 17,[23][24][25][26] Two wellknown acute-phase proteins, Lp(a) and fibrinogen, were found to increase significantly during a single HD session compared with baseline (pre-HD) values. 17,23 The HD procedure itself has been suggested as a potential source of inflammation.…”

“…25 Local inhibition of TGF-b activity by Lp(a) seems to be an initial key, which may partly explain the atherothrombogenic action of Lp(a) and its relation with coagulation disorders that result from smooth muscle cell proliferation and the subsequent lipid accumulation and platelet adhesion to formed lesions, whereas fibrinogen and fibronectin could be the ligands supporting local platelet adhesion and aggregation. [25][26][27] Apo(a) binds in vitro to fibrinogen and fibronectin, and this complex might play a role in anchoring Lp(a) or free apo(a) to the subendothelial matrix. On the other hand, factors that influence fibronectin polymerization into the extracellular matrix may affect the composition of the extracellular matrix and the organization of cell-matrix adhesion sites.…”

Adenovirus-mediated apo(a)-antisense-RNA expression efficiently inhibits apo(a) synthesis in vitro and in vivo

“…These mice developed atherosclerosis due to focal apo(a) accumulation in the vessel wall leading to inhibition of transforming growth factor-␤ (TGF-␤) activity, activation of smooth muscle cells, and subsequent accumulation of lipids in the vessel wall. 11,13,14 Additionally, the atherogenic potential of Lp(a) was demonstrated in double transgenic mice expressing both human apo(a) and human apoB-100. 12 Due to its great atherogenicity, many attempts were made in the past to medicate individuals with increased Lp(a) levels with drugs or diets.…”