Effect on Metalloprotease Inhibition on Age-Associated Arterial Remodeling

National Institute On Aging

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Abstract

Aging reprograms the arterial wall via proinflammation signals partially mediated by matrix metalloproteinases (MMPs) activation;however, whether inactivation of MMPs could slow the arterial aging process remain undefined. This study shows that with aging, arterial proinflammatory molecules, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factorbeta 1 (TGF-beta1) and MMP-2/13 converging p-SMAD2/3 signaling and common transcription factor Ets-1increases in FXBN rats with aging. Interestingly, 16-month-old rats treated daily with the MMP inhibitor (MMPI), PD166793 (5mg/kg) for 8 mo substantially inhibited arterial MMP-2/13 activation in situ and attenuated an age-associated increase in systolic blood pressure(SBP), intima thickness (IT), media thickness (MT), MCP-1, TGF-beta1, p-SMAD2/3, and levels of ets-1 and collagen I . Further, in vitro studies show that exposure of young VSMC to MCP-1 via its receptor, CCR-2 signaling, increase TGF-beta1 and MMP-2 activity, and conversely, exposure of young VSMC to TGF-beta1 increases levels of MCP-1, and MMP-2 activation, both to levels of untreated old cells. Collagen deposition and VSMC invasion capacity resulting from this autocatalytic signaling triad are effectively reduced by a broad MMP inhibitor GM6001. Thus, inactivation of MMPs, a breaker of local proinflammation loop signaling, could be a novel approach to the prevention of arterial aging and age-related arterial disease. Interestingly, caloric restriction (CR) , mimicking MMP inhibition, significantly improves arterial health. Immunostaining showed that intimal VSMC number was increased in old compared to young AL rats , but was substantially reduced in the CR rat with aging. The intima-medial collagen deposition was increased , and the elastin fraction was decreased in the old AL rat. Impressively, aortic collagen and elastin fibers did not significantly change in the CR rat during aging. Notably, age enhanced in situ MMP2 and MCP-1 activation within the aortic wall in the AL rat, but these were blunted in the aorta of the old CR rats. Additionally, a potent pro-fibrogenic cytokine TGF-1, a product of MMP-2 cleavage, and its downstream signaling molecule p-SMAD-2 were enhanced in old compared to young AL rats, but CR reduced this effect. The intima-media gradient of a potent chemo-attractant, platelet derived growth factor (PDGF) was increased in old compared to young AL rats, but this was attenuated in CR rats. In addition, CR decreased early passage VSMC invasive capability in vitro in response to PDGF, both in young (26%) and old (15%). Interestingly, CR substantially decreased MCP-1 expression in early passage VSMC compared to cells from AL rats. In summary, CR, like MMP inhibitor, retards age-associated arterial restructuring in rats, at least in part, via reduction of MMP2, MCP-1, and TGF-1 activation, the intima-media PDGF gradient, and VSMC invasive capability.