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 metalloproteinase (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 factorVbeta 1 (TGFbeta-1), MMP-2/13, nconverging p-SMAD2/3 signaling and common transcription factor Ets-1n 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, increases 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. The collagen deposition and VSMC invasion capacity resulting from this autocatalytic, proinflammatory signaling 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.