Effect on Metalloprotease Inhibition on Age-Associated Arterial Remodeling

National Institute On Aging

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Abstract

Age-associated arterial remodeling involves arterial wall collagen deposition and elastin fragmentation, as well as an increase in arterial pressure. This arterial remodeling is linked to proinflammatory signaling, including transforming growth factor-beta1, monocyte chemoattractant protein 1, and proendothelin 1, activated by extracellular matrix metalloproteinases (MMPs) and orchestrated, in part, by the transcriptional factor ets-1. We tested the hypothesis that inhibition of MMP activation can decelerate the age-associated arterial proinflammation and its attendant increase in arterial pressure. Indeed, chronic administration of a broad-spectrum MMP inhibitor, PD166739, via a daily gavage, to 16-month-old rats for 8 months markedly blunted the expected age-associated increases in arterial pressure. This was accompanied by the following: (1) inhibition of the age-associated increases in aortic gelatinase and interstitial collagenase activity in situ; (2) preservation of the elastic fiber network integrity; (3) a reduction of collagen deposition; (4) a reduction of monocyte chemoattractant protein 1 and transforming growth factor-beta1 activation; (5) a diminution in the activity of the profibrogenic signaling molecule SMAD-2/3 phosphorylation; (6) inhibition of proendothelin 1 activation; and (7) downregulation of expression of ets-1. Acute exposure of cultured vascular smooth muscle cells in vitro to proendothelin 1 increased both the transcription and translation of ets-1, and these effects were markedly reduced by MMP inhibition. Furthermore, infection of vascular smooth muscle cells with an adenovirus harboring a full-length ets-1 cDNA increased activities of both transforming growth factor-beta1 and monocyte chemoattractant protein 1. Collectively, our results indicate that MMP inhibition retards age-associated arterial proinflammatory signaling, and this is accompanied by preservation of intact elastin fibers, a reduction in collagen, and blunting of an age-associated increase in blood pressure. Importantly, 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-beta1, 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-beta1 activation, the intima-media PDGF gradient, and VSMC invasive capability.