Aging is the major risk factor for the development of vascular proliferative diseases such as hypertension and atherosclerosis that lead to coronary vascular disease and stroke. Increased cytokine levels, due to increased inflammatory response of the vessel wall, have been implicated in the development of atherosclerosis in aged patients. The matrix metalloproteinase-9 (MMP-9) ,induced in response to cytokines plays an important role in VSM cell migration from media to intima. Our preliminary observations indicate that VSM cell proliferation is significantly increased in aged rats compared to the young rats. We have observed that IL-1beta-stimulated increase in MMP-9 secretion is mediated through activation of ERK +. We have also observed that nitric oxide (NO) inhibits ERIC activation that leads to the inhibition of MMP- 9 secretion. Despite the significant progress made in the understanding of the IL-1beta-mediated intracellular regulatory mechanisms that increase MMP-9 secretion, the mechanism of action of the inhibitory agents, namely NO, that decreases MMP-9 secretion remain obscure. An understanding of these inhibitory mechanisms can aid in the development of therapeutic strategies to inhibit vascular proliferative diseases associated with old age. The overall hypothesis of this proposal is that decrease in NO-mediated inhibition of MMP-9 secretion is a critical determinant of the increased VSM cell migration and proliferation observed in aged patients.
Two specific aims will be pursued. 1) To determine whether ERK/MMP-9 signaling in response to IL-1beta stimulation is increased in VSM cells of aged rats compared to the young rats. 2) To determine whether eNOS gene transfer in VSM cells isolated from aged rats will alleviate the differences between old and young animals for IL-1beta-stimulated ERK activation, MMP-9 secretion and VSM cell migration and proliferation. The investigation will provide new information concerning the mechanisms of NO regulation of MMP-9 secretion and is likely to explain how the endothelial dysfunction in old age can lead to vascular proliferative diseases.
