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

Jiang, Liqun and Wang, Mingyi and Zhang, Jing and Monticone, Robert E. and Telljohann, Richard and Spinetti, Gaia and Pintus, Gianfranco and Lakatta, Edward G. (2008) Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells. PLoS One, Vol. 3 (5), e2231. ISSN 1932-6203. Article.

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DOI: 10.1371/journal.pone.0002231


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. 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 (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/Significance: 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.

Item Type:Article
ID Code:810
Uncontrolled Keywords:Angiotensin II (Ang II), matrix metalloproteinase type II (MMP2), Calpain-1, vascular smooth muscle cells (VSMC)
Subjects:Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Public Library of Science
Deposited On:18 Aug 2009 10:03

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