No abstract

One of the major conceptual advances in our understanding of the pathogenesis of age-associated cardiovascular diseases has been the insight that age-related oxidative stress may promote vascular inflammation even in the absence of traditional risk factors associated with atherogenesis (e.g., hypertension or metabolic diseases). In the present review we summarize recent experimental data suggesting that mitochondrial production of reactive oxygen species, innate immunity, the local TNF-alpha-converting enzyme (TACE)-TNF-alpha, and the renin-angiotensin system may underlie NF-kappaB induction and endothelial activation in aged arteries. The theme that emerges from this review is that multiple proinflammatory pathways converge on NF-kappaB in the aged arterial wall, and that the transcriptional activity of NF-kappaB is regulated by multiple nuclear factors during aging, including nuclear enzymes poly(ADP-ribose) polymerase (PARP-1) and SIRT-1. We also discuss the possibility that nucleophosmin (NPM or nuclear phosphoprotein B23), a known modulator of the cellular oxidative stress response, may also regulate NF-kappaB activity in endothelial cells.

Objective-To study matrix metalloproteinase 2 (MMP-2) effects on transforming growth factor-␤1 (TGF-␤1) activation status and downstream signaling during arterial aging. Methods and Results-Western blotting and immunostaining showed that latent and activated TGF-␤1 are markedly increased within the aorta of aged Fisher 344 cross-bred Brown Norway (30 months of age) rats compared with adult (8 months of age) rats. Aortic TGF-␤1-type II receptor (T␤RII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age. Moreover, TGF-␤1 staining is colocalized with that of activated MMP-2 within the aged arterial wall and vascular smooth muscle cell (VSMC) in vitro, and this physical association was confirmed by coimmunoprecipitation. Incubation of young aortic rings ex vivo or VSMCs in vitro with activated MMP-2 enhanced active TGF-␤1, collagen, and fibronectin expression to the level of untreated old counterparts, and this effect was abolished via inhibitors of MMP-2. Interestingly, in old untreated rings or VSMCs, the increased TGF-␤1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2. Conclusions-Active TGF-␤1, its receptor, and receptor-mediated signaling increase within the aortic wall with aging.TGF-␤1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity. Thus, MMP-2-activated TGF-␤1, and subsequently T␤RII signaling, is a novel molecular mechanism for arterial aging.

Increased angiotensin II (Ang II), matrix metalloproteinase type II (MMP2), and sympathetic activity accompany age-associated arterial remodeling. To analyze this relationship, we infused a low subpressor dose of Ang II into young (8 months old) rats. This increased carotid arterial MMP2 transcription, translation, and activation, as well as transforming growth factor-␤1 activity and collagen deposition. A higher Ang II concentration, which increased arterial pressure to that of old (30 months old) untreated rats, produced carotid media thickening and intima infiltration by vascular smooth muscle cells (VSMCs). Ex vivo, Ang II increased MMP2 activity in carotid rings from young rats to that of untreated old rats. Ang II also increased the ability of early passage VSMCs from young rats to invade a synthetic basement membrane, similar to that of untreated VSMCs from old rats. The MMP inhibitor GM6001 and the AT 1 receptor antagonist Losartan inhibited these effects. The ␣-adrenoreceptor agonist phenylephrine increased arterial Ang II protein, causing MMP2 activation and intima and media thickening. Exposure of young VSMCs to phenylephrine in vitro increased Ang II protein and MMP2 activity to the levels of old VSMCs; Losartan abolished these effects. Thus, Ang II-induced effects on MMP2, transforming growth factor-␤1, collagen, and VSMCs are central to the arterial remodeling that accompanies advancing age. (Am J Pathol 2005,

Abstract-Studies in animal models demonstrate that angiotensin II and its downstream signaling molecules, that is, matrix metalloproteinases and monocyte chemoattractant protein-1, increase within the diffusely thickened intima of central arteries with aging. Whether such age-related changes occur within the human arterial wall is unknown. We harvested "grossly normal thoracic aortas" from 5 young (20Ϯ3 years) and 5 old white males (65Ϯ6 years) at necropsy, after death from traumatic causes. The intimae of older samples were markedly and diffusely thickened compared with younger intimae and contained increased levels of angiotensin-converting enzyme, angiotensin II, angiotensin II receptor type 1, matrix metalloproteinases 2/9, monocyte chemoattractant protein-1, and collagen I and III proteins. In situ activities of metalloproteinases 2/9 were also significantly enhanced within old, normal aortas. The thickened intima of older aortas also contained a 5-fold increase in the embryonic form of smooth muscle myosin heavy chain-labeled cells than that of younger aortas, and these fetal-type cells were colocalized with angiotensin II protein staining. The ability of isolated smooth muscle cells to invade an artificial basement membrane in response to a monocyte chemoattractant protein-1 gradient increased with age. Furthermore, angiotensin II increased the invasive capacity of young smooth muscle cells, and this effect was reduced by a metalloproteinase inhibitor or an angiotensin II receptor blocker. Thus, in the absence of lipid infiltration, the aged human aortic wall exhibits a proinflammatory profile that renders it a fertile substrate for the development of arterial disease, for example, atherosclerosis and hypertension. (Hypertension. 2007;50:219-227.)