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Central Arterial Aging: Humans to Molecules
Author(s) -
Wang Mingyi,
Lakatta Edward G
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.414.4
Subject(s) - angiotensin ii , endocrinology , medicine , angiotensin ii receptor type 1 , calpain , receptor , matrix metalloproteinase , vascular smooth muscle , chemistry , transforming growth factor , biology , biochemistry , smooth muscle , enzyme
Aging is a major risk factor for cardiovascular diseases, i.e., atherosclerosis and hypertension. The cellular and molecular mechanisms of age‐associated arterial restructuring, however, are not fully understood. Our series of studies have shown that levels of angiotensin II (Ang II) protein, its precursor, angiotensinogen and the receptor AT1, as well as its downstream signaling products monocyte chemoatractant protein‐1 (MCP‐1), matrix metalloproteinase type II (MMP‐2), calapain‐1, and transforming growth factor beta‐1 (TGF‐β1 are markedly increased in vivo within the aortic walls and in vitro in early passage primary vascular smooth muscle cells (VSMC) in rats, nonhuman primates, and humans. Exposure of Ang II to young rat VSMC (8 mo) increases levels of MCP‐1, MMP‐2, calpain‐1, and TGF‐β1 activation in a dose‐and time‐dependent manner, up to those of untreated old cells (30 mo). These effects are substantially reduced by a blockade of AT1 signaling. Furthermore, we also found that MMP‐2 activation is central to the Ang II/MCP‐1/TGF‐β1 signaling cascade during aging. Chronic administration of Ang II (50‐200 ng/kg/min) to young rats, via an osmotic minipump, converts the structural and molecular profile of MMP‐2, MCP‐1, calpain‐1, and TGF‐β1 activation, collagen deposition, and intimal medial thickening towards that of untreated old animals. Collectively, these findings indicate that increased Ang II signaling plays a causal role in arterial aging.