Wang, Mingyi and Zhang, Jing and Cabo, Rafael de and Jiang, Li-Qun and Spinetti, Gaia and Pintus, Gianfranco and Monticone, Robert E. and Ingram, Donald K. and Lakatta, Edward G. (2006) Calorie restriction reduces MMP-2 activity and retards age-associated aortic restructuring in rats. Circulation, Vol. 114 (18), p. 335. eISSN 1524-4539. Article.
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Calorie restriction (CR) is a reproducible approach to extend longevity in rodents. Arterial intimal thickening, with increased matrix-metalloproteinase-type-II (MMP2) activation and changes in other variables in table, that accompany aging, are risk factors for atherosclerotic events, which negatively impact lifespan. However, the effects of CR on arterial restructuring and MMP2 activation with aging remain elusive. To address this question we used the aorta and early passage vascular smooth muscle cells (VSMC) isolated from ad libitum (AL)-fed young (6 mo) and old (24 mo) and age-matched, 40% restricted CR F344 rats. Immunostaining showed that intimal VSMC number was increased by 4.4 fold in old compared to young AL rats (table), but was substantially reduced in the CR rat with aging. The intima-medial collagen deposition was increased by 1.5 fold, and the elastin fraction was decreased by 1.8 fold 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 activity within the aortic wall in the AL rat by 6.0 fold, but this was blunted in the aorta of the old CR rats. Additionally, a potent pro-fibrogenic cytokine TGF-ß1, a product of MMP-2 cleavage, and its downstream signaling molecule p-SMAD-2 were enhanced by 5.0 fold, and by 3.3 fold respectively, in old compared to young AL rats, but CR reduced this effect. The intima-media gradient of a potent chemoattractant, platelet derived growth factor (PDGF) was increased 2.2 fold 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%). In summary CR retards age-associated arterial restructuring in rats, at least in part, via reduction of MMP2 and TGF-ß1 activation, the intima-media PDGF gradient, and VSMC invasive capability.
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