Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats

-To characterize remodeling of elastic arteries with aging and to investigate its potential mechanisms, matrix metalloproteinase-2 (MMP-2), intracellular adhesive molecule-1 (ICAM-1), transforming growth factor-beta (TGF-beta), and fibronectin protein levels were measured in the aortas of young adult (6 months) and aged (30 months) Fischer 344XBN rats. At 30 versus 6 months, the thickness of the intima was 5-fold greater and contained marked increases in TGF-beta and ICAM-1, and fibronectin expression was enhanced throughout the aortic wall. Total MMP-2 protein (Western blot) of 30-month-old rats was increased 8-fold over that of 6-month-old rats (0.166+/-0.032 versus 0.020+/-0.006; P<0.01), and staining and activity were regionally localized to the intima, often near breaks in the internal elastic membrane and lamellae. Early passage, explanted smooth muscle cells (SMC) from aged aorta secreted more MMP-2 than those from young aorta; while basal MMP-2 production did not differ with age, after stimulation with cytokines (interleukin-1, tumor necrosis factor-alpha, or TGF-beta, 10 ng/mL each for 24 hours), MMP-2 production in SMC from 30-month-old rats increased to levels greater than those in 6-month-old rats. Thus, enhanced expression of TGF-beta, MMP-2, and ICAM-1 in the thickened vascular intima of aged rats may in part be produced by exaggerated SMC responses to cytokines and may have potential roles in intimal remodeling with aging.