Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells

Liqun Jiang, Mingyi Wang, Jing Zhang, Robert E. Monticone, Richard Telljohann, Gaia Spinetti, Gianfranco Pintus, Edward G. Lakatta

Research output: Contribution to journalArticle

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Abstract

Background: Angiotensin II (Ang II) signalling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMS) and to other proinflammatory features of arterial aging. Calpain-1 activation is required fo MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequencies of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown. Methodology/Principal Findings: 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 (39-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. Concluson/Significance: Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signalling cascade that is linked to cytoskeleton protein retructuring, 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.

Original languageEnglish
Article numbere2231
JournalPLoS One
Volume3
Issue number5
DOIs
Publication statusPublished - May 21 2008

Fingerprint

calpain
Calpain
angiotensin II
Vascular Smooth Muscle
blood vessels
Angiotensin II
smooth muscle
myocytes
Smooth Muscle Myocytes
Muscle
Cells
Rats
calpastatin
Chemical activation
rats
Matrix Metalloproteinase Inhibitors
Vimentin
Transcription
Fibroblasts
vimentin

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells. / Jiang, Liqun; Wang, Mingyi; Zhang, Jing; Monticone, Robert E.; Telljohann, Richard; Spinetti, Gaia; Pintus, Gianfranco; Lakatta, Edward G.

In: PLoS One, Vol. 3, No. 5, e2231, 21.05.2008.

Research output: Contribution to journalArticle

Jiang, Liqun ; Wang, Mingyi ; Zhang, Jing ; Monticone, Robert E. ; Telljohann, Richard ; Spinetti, Gaia ; Pintus, Gianfranco ; Lakatta, Edward G. / Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells. In: PLoS One. 2008 ; Vol. 3, No. 5.
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AU - Telljohann, Richard

AU - Spinetti, Gaia

AU - Pintus, Gianfranco

AU - Lakatta, Edward G.

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