title: Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis.
abstract: Age-associated central arterial wall stiffness is linked to extracellular matrix remodeling, including fibrosis and vascular calcification. Angiotensin II induces both matrix metalloproteinase 2 (MMP2) and calpain-1 expression and activity in the arterial wall. However, the role of calpain-1 in MMP2 activation and extracellular matrix remodeling remains unknown. Dual histo-immunolabeling demonstrates colocalization of calpain-1 and MMP2 within old rat vascular smooth muscle cells. Overexpression of calpain-1 induces MMP2 transcripts, protein levels, and activity, in part, by increasing the ratio of membrane type 1 MMPs to tissue inhibitor of metalloproteinases 2. These effects of calpain-1 overexpression-induced MMP2 activation are linked to increased collagen I and III production and vascular calcification. In addition, overexpression of calpain-1 also induces transforming growth factor-β1/Smad signaling, elastin degradation, alkaline phosphatase activation, and total calcium content but reduces the expression of calcification inhibitors, osteopontin, and osteonectin, in cultured vascular smooth muscle cells in vitro and in carotid artery rings ex vivo. Furthermore, both calpain-1 and collagen II increase with aging within human aortic intima. Interestingly, in aged human aortic wall, both calpain-1 and collagen II are highly expressed in artherosclerotic plaque areas compared with grossly normal areas. Cross-talk of 2 proteases, calpain-1 and MMP2, leads to secretion of active MMP2, which modulates extracellular matrix remodeling via enhancing collagen production and facilitating vascular calcification. These results establish calpain-1 as a novel molecular candidate to retard age-associated extracellular matrix remodeling and its attendant risk for hypertension and atherosclerosis.
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. jiangli@mail.nih.gov
authors.forename: Liqun
authors.initials: L
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Monticone
authors.forename: Richard
authors.initials: R
authors.lastname: Telljohann
authors.forename: James
authors.initials: J
authors.lastname: Wu
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wang
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000293:Adolescent; D000368:Aged; D000375:Aging; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005355:Fibrosis; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D004549:Elastin; D002154:Calpain; C484806:CAPN1 protein, human; D020778:Matrix Metalloproteinase 2