Objective-Impairment of transforming growth factor (TGF)-1 signaling accelerates atherosclerosis in experimental mice. However, it is uncertain whether increased TGF-1 expression would retard atherosclerosis. The role of TGF-1 in aneurysm formation is also controversial. We tested whether overexpression of active TGF-1 in hyperlipidemic mice affects atherogenesis and aortic dilation. Methods and Results-We generated apolipoprotein E-null mice with transgenes that allow regulated overexpression of active TGF-1 in their hearts. Compared to littermate controls, these mice had elevated cardiac and plasma TGF-1, less aortic root atherosclerosis (PՅ0.002), fewer lesions in the thoracic and abdominal aortae (PՅ0.01), less aortic root dilation (PϽ0.001), and fewer pseudoaneurysms (Pϭ0.02). Mechanistic studies revealed no effect of TGF-1 overexpression on plasma lipids or cytokines, or on peripheral lymphoid organ cells. However, aortae of TGF-1-overexpressing mice had fewer T-lymphocytes, more collagen, less lipid, lower expression of inflammatory cytokines and matrix metalloproteinase-13, and higher expression of tissue inhibitor of metalloproteinase-2. Conclusions-When overexpressed in the heart and plasma, TGF-1 is an antiatherogenic, vasculoprotective cytokine that limits atherosclerosis and prevents aortic dilation. These actions are associated with significant changes in cellularity, collagen and lipid accumulation, and gene expression in the artery wall. Key Words: aneurysm Ⅲ atherosclerosis Ⅲ growth substances Ⅲ inflammation Ⅲ plaque T GF-1 is a pleiotropic cytokine that circulates in plasma and is produced by several cardiovascular cell types including smooth muscle and endothelial cells, monocytes, macrophages, and T cells. 1,2 Several studies associate variations in TGF-1 expression or signaling with atherosclerosis and aneurysm formation; however, the precise relationships between TGF-1, atherosclerosis, and aneurysm formation are incompletely understood.Human studies largely support an antiatherogenic role for TGF-1, with most studies revealing a negative correlation between plasma TGF-1 concentration and the presence or extent of atherosclerosis. [3][4][5][6] Although some animal studies suggest that TGF-1 could accelerate atherosclerosis by increasing vascular extracellular matrix accumulation and lipid retention, 7-10 several studies in hyperlipidemic mice instead portray TGF-1 as an antiatherogenic cytokine that limits atherosclerosis largely through immunosuppressive effects. Almost all of these murine studies involve systemic suppression of TGF- activity, for example by injection of antibodies to TGF-, infusion of a soluble TGF- receptor, or transgene-mediated abrogation of TGF- signaling in T cells. [11][12][13][14] These studies show that less systemic TGF- activity accelerates atherosclerosis, but they do not address whether enhancement of TGF-1 signaling would be antiatherogenic. A recent gene-transfer study suggests that elevated systemic expression of TGF-1 might suppress ...
