title: Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells.
abstract: BACKGROUND
  Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown.
  
  
  RESULTS
  The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001.
  
  
  CONCLUSIONS
  Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis.
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Liqun
authors.initials: L
authors.lastname: Jiang
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wang
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: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pintus
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000375:Aging / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000201:enzymology*; D002154:Calpain / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D000804:Angiotensin II; D002154:Calpain; D020778:Matrix Metalloproteinase 2