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 in governing the age-associated proinflammatory status within the arterial wall are documented in this study. 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. 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. Furthermore, age-associated central arterial wall stiffness is linked to extracellular matrix (ECM) remodeling, including fibrosis and vascular calcification. Ang II induces both MMP2 and calpain-1 expression and activity in the arterial wall. But the role of calpain-1 in MMP2 activation and ECM remodeling remains unknown. Thus, we did further investigation. Dual histo-immunolabeling demonstrates co-localization of calpain-1 and MMP2 within old rat vascular smooth muscle cells. Over-expression of calpain-1 induces MMP2 transcripts, protein levels and activity, in part, by increasing the ratio of membrane-type 1 MMP (MT1MMP) to tissue inhibitor of metalloproteinases 2 (TIMP2). The effect of calpain-1 over-expression-induced MMP2 activation is linked to increased collagen I and III production and vascular calcification. In addition, over-expression of calpain-1 also induces transforming growth factor-beta1/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. These effects are partially abolished by TIMP2.Interestingly, both calpain-1 and collagen II increase with aging within human aortic intima. In the aged human aortic wall, both calpain-1 and collagen II are highly expressed in arteriosclerotic plaque areas compared to grossly normal areas. Cross-talk of two proteases, calpain-1 and MMP2, leads to secretion of active MMP2, which modulates ECM remodeling via enhancing collagen production and facilitating vascular calcification. Recent studies indicate that calpain-1 is markedly expressed in the shoulder, base, and cap of human atherosclerotic plaques. These results establish calpain-1 as a novel molecular candidate to facilitate age-associated ECM remodeling and its attendant risk for atherosclerosis. The detailed molecular and cellular mechanisms behind age-associated atherosclerosis and atherosclerotic plaque instability are under investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000236-08
Application #
9147246
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Pintus, Gianfranco; Giordo, Roberta; Wang, Yushi et al. (2018) Reduced vasorin enhances angiotensin II signaling within the aging arterial wall. Oncotarget 9:27117-27132
Wang, Mingyi; Monticone, Robert E; McGraw, Kimberly R (2018) Proinflammatory Arterial Stiffness Syndrome: A Signature of Large Arterial Aging. J Vasc Res 55:210-223
Zhu, Wanqu; Kim, Byoung Choul; Wang, Mingyi et al. (2018) TGF?1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness. Sci Rep 8:2668
AlGhatrif, Majd; Wang, Mingyi; Fedorova, Olga V et al. (2017) The Pressure of Aging. Med Clin North Am 101:81-101
Wang, Mingyi; Shah, Ajay M (2015) Age-associated pro-inflammatory remodeling and functional phenotype in the heart and large arteries. J Mol Cell Cardiol 83:101-11
Wang, Mingyi; Kim, Soo Hyuk; Monticone, Robert E et al. (2015) Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. Hypertension 65:698-703
Wang, Mingyi; Monticone, Robert E; Lakatta, Edward G (2014) Proinflammation of aging central arteries: a mini-review. Gerontology 60:519-29
Wang, Mingyi; Jiang, Liqun; Monticone, Robert E et al. (2014) Proinflammation: the key to arterial aging. Trends Endocrinol Metab 25:72-9
Jiang, Liqun; Zhang, Jing; Monticone, Robert E et al. (2012) Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis. Hypertension 60:1192-9
Krug, Alexander W; Allenhöfer, Lena; Monticone, Robert et al. (2010) Elevated mineralocorticoid receptor activity in aged rat vascular smooth muscle cells promotes a proinflammatory phenotype via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and epidermal growth factor receptor-dependent pathwa Hypertension 55:1476-83

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