Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging.
To elucidate potential mechanisms of enhanced type 2 matrix metalloprotease levels and activity within the thickened aged rat aorta, the present study measured its mRNA and protein levels and those of its membrane bound activator, MT1-MMP, its endogenous tissue inhibitor, TIMP-2, tissue type, and urokinase plasminogen activators and their receptors, and an inhibitor of plasminogen activation in aortae from Fisher 344X Brown Norway rats, 2 to 30 months of age. Semiquantitative immunohistochemistry, in situ hybridization, and in situ zymography of aortae detected a marked age-associated increase in gelatinolytic activity of type 2 metalloprotease within the thickened intima, internal elastic lamina, and elastic fibers in the inner part of the thickened tunica media, whereas the intimal tissue inhibitor of metalloprotease-2 mRNA and protein levels were not age related. Both activators of plasminogen and their receptors increased approximately 2-fold within the intima between 2 to 30 months. Similar, but not identical, age-associated changes in factors that regulate protease activity within the aortic media were also observed. We conclude that discordant regulation of factors that determine the activation status of type 2 matrix metalloprotease, coupled with an increase in the expression of its zymogen, occur with aging, which lead to an increase in the amount of activated protease. These factors are candidate mechanisms for age-associated vascular remodeling, a potent risk factor for vascular diseases with advancing age.
Wang
Mingyi
M
Laboratory of Cardiovascular Sciences, Gerontology Research Center, National Institute on Aging/National Institutes of Health, Baltimore, Md 21224-6825, USA.
Lakatta
Edward G
EG
D000375:Aging; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology*; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000235:genetics; D018093:Gelatinases / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007700:Kinetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000276:immunology / Q000378:metabolism; D010960:Plasminogen Activators / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic
D004792:Enzyme Precursors; D017395:Plasminogen Activator Inhibitor 1; C524900:Plaur protein, rat; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019716:Tissue Inhibitor of Metalloproteinase-2; D010960:Plasminogen Activators; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2