A growing body of evidence that increased large artery thickening and stiffness and endothelial dysfunction in apparently otherwise healthy older persons, along with the ensuing increase in systolic and pulse pressure that was formerly thought to be part of normal aging, precede clinical disease and predict a higher risk for developing clinical atherosclerosis, hypertension, and stroke. Some of these vascular changes that occur with aging in normotensive humans, including endothelial dysfunction, have been observed in hypertensive patients at an earlier age and are more marked than in normotensive subjects. Such otherwise asymptomatic individuals might be considered to manifest unsuccessful vascular aging. When stated in this context, unsuccessful vascular aging becomes the risk factor for eventual clinical disease manifestations. Thus, what clinical medicine and epidemiology now refer to as vascular disease should be regarded as the vascular agingvascular disease interaction. ? ? It follows that therapies to prevent or delay cardiovascular changes that accompany aging may reduce the risk for age-associated cardiovascular diseases. An understanding of the nature and effectiveness of such therapies, however, requires an understanding of heart and arterial aging at the cellular and molecular levels. Fortunately, many of the age-associated changes in cardiac and arterial structure or function that have been observed in humans also occur across a wide range of other species. Insights gained from cellular and molecular studies in these animal models provide clues that will assist in directing future efforts toward developing novel therapies for age-associated arterial and cardiac structural and functional remodeling in humans.? ? Studies of this unit have demonstrated that the grossly normal older human aortic wall, particularly the intima, in the absence of lipid infiltration, is diffusely thickened and manifests numerous SMCs, an increase in sporadic clusters of macrophages, an occasional mast cell, and a large amount of collagen types III and I. ? Angiotensinogen expression significantly increases in aortic SMCs from older compared with younger rats. The transcription, protein level, and activity of ACE also increase within the aortic wall from older rats and nonhuman primates. Thus, the increased production of local Ang II within the aged arterial wall in humans is facilitated by an enhancement of both ACE- and chymase-dependent pathways. AT1 transcription, protein abundance, and biological effects are increased in older versus younger rats. Ang II signaling cascade molecules, including MCP-1, and MMPs, increase within the arterial wall from older human donors as in animal models. A chronic infusion of Ang II to young rats increases carotid medial thickening and intimal infiltration by SMCs, collagen deposition, and increased arterial MMP2 transcription, translation, and activation, as well as increased TGF-B1 activity. ? ? These structural and molecular changes mimic those that occur in old, untreated rats. Increases in Ang II and age-associated arterial remodeling in humans are accompanied by increased MMP2 activity, as in rats and nonhuman primates. Aortic MMP9 is also increased in specimens from older human donors. Interestingly, an exposure of Ang II and its age-associated downstream molecules MCP-1, calpain, TGF-B1, tumor necrosis factor-?, and interleukin-1 to young SMCs increases MMP2 up to the level of old untreated SMCs. Our preliminary data support that early passage untreated SMCs from older human donors secreted more MMPs than younger SMCs, as has been observed previously in rats. SMC infiltration of the intima in humans is consistent with previous studies in rats and nonhuman primates. Surprisingly, most of the intimal SMCs within the human aortic wall of old donors are fetal-like cells. A chronic infusion of Ang II into rats increases renal SMemb, which is also substantially inhibited by an AT1 blocker. Exposure of SMCs from older donors to Ang II increases SMemb expression, which is abolished by the AT1 antagonist. Thus, Ang II treatment of SMCs in vitro reprograms those cells to express fetal myosin. The invasive capability of older human SMCs is enhanced, as observed previously in aortic SMCs from older rats. Furthermore, exposure of Ang II to human, young SMCs in the present study increases their invasive capacity. MMP activity is required for invasion of cultured SMCs through a synthetic basement membrane barrier. The increase in Ang II-induced MMP activation in younger aortas of animal models is accompanied by MCP-1 expression in the aortic SMCs. Ang II promotes SMC invasion in response to an MCP-1 chemoattractant gradient in human SMCs, and this effect is substantially reduced by GM6001, an MMP inhibitor or by Sar1Gly8-Ang II acetate hydrate, an AT1 antagonist. Thus, these findings suggest that increased Ang II signaling via increased MMP activity and upregulated MCP-1 may play a pivotal role in the increased invasive capacity of SMCs within an older aortic wall. ? ? TGF-B1 is a powerful profibrotic cytokine during arterial aging; increased Ang II signaling and MMP2 activity are accompanied by elevated TGF-B1 and TGF-B receptor type-II. Collagen deposition is increased diffusely within the aortic wall of older human donors, predominantly in the intima, as in animal models. The activation of latent TGF-B1 leading to enhanced aortic SMAD (similar to mother against decapentaplegic) signaling and subsequently to an increase in fibronectin and collagen expression in the aged aortic wall depends on the concomitant age-associated increase in MMP-2 activity. Interestingly, chronic Ang II infusion increases MMP2, TGF-B1 expression, and collagen production within the aortic wall in young rats to the level that occurs in old, untreated rats. Thus, the Ang IIinduced activation of TGF-B1 via MMP activation is a potential molecular mechanism for increased arterial fibrosis in older persons.
| Wang, Mingyi; Zhang, Jing; Jiang, Li-Qun et al. (2007) Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 50:219-27 |
| Baur, Joseph A; Pearson, Kevin J; Price, Nathan L et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-42 |
| Wang, Mingyi; Zhang, Jing; Spinetti, Gaia et al. (2005) Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats. Am J Pathol 167:1429-42 |
