FEEDBACK MECHANISM OF FOCAL VASCULAR LESION FORMATION IN TRANSGENIC APOLIPOPROTEIN(A) MICE

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 develo p in man and in transgenic mice expressing human apo(a). It has been p roposed that focal apo(a) accumulation in the transgenic mouse vessel wall causes the observed severe local inhibition of transforming growt h factor-beta (TGF-beta) activity and the consequent activation of the smooth muscle cells, which subsequently accumulate lipid to form lesi ons if the mice are fed a high fat diet, We show that blocking formati on of these vascular lesions by two independent mechanisms, tamoxifen treatment and increasing high density lipoprotein, also abolishes apo( a) accumulation, inhibition of TGF-beta activity, and activation of sm ooth muscle cells. The data are consistent with a feedback mechanism i n which an initial accumulation of apo(a) inhibits local TGF-beta acti vity, leading to further accumulation of apo(a). Breaking the feedback loop prevents smooth muscle cell activation and therefore lipid lesio n development.